%0 Journal Article %J Front Genet %D 2023 %T Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. %A de Las Fuentes, Lisa %A Schwander, Karen L %A Brown, Michael R %A Bentley, Amy R %A Winkler, Thomas W %A Sung, Yun Ju %A Munroe, Patricia B %A Miller, Clint L %A Aschard, Hugo %A Aslibekyan, Stella %A Bartz, Traci M %A Bielak, Lawrence F %A Chai, Jin Fang %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Feitosa, Mary F %A Guo, Xiuqing %A Hartwig, Fernando P %A Horimoto, Andrea %A Kolcic, Ivana %A Lim, Elise %A Liu, Yongmei %A Manning, Alisa K %A Marten, Jonathan %A Musani, Solomon K %A Noordam, Raymond %A Padmanabhan, Sandosh %A Rankinen, Tuomo %A Richard, Melissa A %A Ridker, Paul M %A Smith, Albert V %A Vojinovic, Dina %A Zonderman, Alan B %A Alver, Maris %A Boissel, Mathilde %A Christensen, Kaare %A Freedman, Barry I %A Gao, Chuan %A Giulianini, Franco %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Kühnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Sofer, Tamar %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Verweij, Niek %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhan, Yiqiang %A Amin, Najaf %A Arking, Dan E %A Ballantyne, Christie %A Eric Boerwinkle %A Brody, Jennifer A %A Broeckel, Ulrich %A Campbell, Archie %A Canouil, Mickaël %A Chai, Xiaoran %A Chen, Yii-Der Ida %A Chen, Xu %A Chitrala, Kumaraswamy Naidu %A Concas, Maria Pina %A de Faire, Ulf %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Do, Ahn %A Faul, Jessica D %A Fisher, Virginia %A Floyd, James S %A Forrester, Terrence %A Friedlander, Yechiel %A Girotto, Giorgia %A Gu, C Charles %A Hallmans, Goran %A Heikkinen, Sami %A Heng, Chew-Kiat %A Homuth, Georg %A Hunt, Steven %A Ikram, M Arfan %A Jacobs, David R %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Langefeld, Carl D %A Liang, Jingjing %A Liu, Kiang %A Liu, Jianjun %A Lohman, Kurt %A Mägi, Reedik %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Milaneschi, Yuri %A Nauck, Matthias %A Nelson, Christopher P %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pereira, Alexandre C %A Perls, Thomas %A Peters, Annette %A Polasek, Ozren %A Raitakari, Olli T %A Rice, Kenneth %A Rice, Treva K %A Rich, Stephen S %A Sabanayagam, Charumathi %A Schreiner, Pamela J %A Shu, Xiao-Ou %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Starr, John M %A Strauch, Konstantin %A Tai, E Shyong %A Taylor, Kent D %A Tsai, Michael Y %A Uitterlinden, André G %A van Heemst, Diana %A Waldenberger, Melanie %A Wang, Ya-Xing %A Wei, Wen-Bin %A Wilson, Gregory %A Xuan, Deng %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Becker, Diane M %A Bonnefond, Amélie %A Bowden, Donald W %A Cooper, Richard S %A Deary, Ian J %A Divers, Jasmin %A Esko, Tõnu %A Franks, Paul W %A Froguel, Philippe %A Gieger, Christian %A Jonas, Jost B %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A North, Kari E %A Ntalla, Ioanna %A Penninx, Brenda %A Samani, Nilesh J %A Snieder, Harold %A Spedicati, Beatrice %A van der Harst, Pim %A Völzke, Henry %A Wagenknecht, Lynne E %A Weir, David R %A Wojczynski, Mary K %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Chasman, Daniel I %A Evans, Michele K %A Fox, Ervin R %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kardia, Sharon L R %A Krieger, Jose Eduardo %A Mook-Kanamori, Dennis O %A Peyser, Patricia A %A Province, Michael M %A Psaty, Bruce M %A Rudan, Igor %A Sim, Xueling %A Smith, Blair H %A van Dam, Rob M %A van Duijn, Cornelia M %A Wong, Tien Yin %A Arnett, Donna K %A Rao, Dabeeru C %A Gauderman, James %A Liu, Ching-Ti %A Morrison, Alanna C %A Rotter, Jerome I %A Fornage, Myriam %X

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

%B Front Genet %V 14 %P 1235337 %8 2023 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/38028628?dopt=Abstract %R 10.3389/fgene.2023.1235337 %0 Journal Article %J Nat Commun %D 2022 %T DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases. %A Wielscher, Matthias %A Mandaviya, Pooja R %A Kuehnel, Brigitte %A Joehanes, Roby %A Mustafa, Rima %A Robinson, Oliver %A Zhang, Yan %A Bodinier, Barbara %A Walton, Esther %A Mishra, Pashupati P %A Schlosser, Pascal %A Wilson, Rory %A Tsai, Pei-Chien %A Palaniswamy, Saranya %A Marioni, Riccardo E %A Fiorito, Giovanni %A Cugliari, Giovanni %A Karhunen, Ville %A Ghanbari, Mohsen %A Psaty, Bruce M %A Loh, Marie %A Bis, Joshua C %A Lehne, Benjamin %A Sotoodehnia, Nona %A Deary, Ian J %A Chadeau-Hyam, Marc %A Brody, Jennifer A %A Cardona, Alexia %A Selvin, Elizabeth %A Smith, Alicia K %A Miller, Andrew H %A Torres, Mylin A %A Marouli, Eirini %A Gào, Xin %A van Meurs, Joyce B J %A Graf-Schindler, Johanna %A Rathmann, Wolfgang %A Koenig, Wolfgang %A Peters, Annette %A Weninger, Wolfgang %A Farlik, Matthias %A Zhang, Tao %A Chen, Wei %A Xia, Yujing %A Teumer, Alexander %A Nauck, Matthias %A Grabe, Hans J %A Doerr, Macus %A Lehtimäki, Terho %A Guan, Weihua %A Milani, Lili %A Tanaka, Toshiko %A Fisher, Krista %A Waite, Lindsay L %A Kasela, Silva %A Vineis, Paolo %A Verweij, Niek %A van der Harst, Pim %A Iacoviello, Licia %A Sacerdote, Carlotta %A Panico, Salvatore %A Krogh, Vittorio %A Tumino, Rosario %A Tzala, Evangelia %A Matullo, Giuseppe %A Hurme, Mikko A %A Raitakari, Olli T %A Colicino, Elena %A Baccarelli, Andrea A %A Kähönen, Mika %A Herzig, Karl-Heinz %A Li, Shengxu %A Conneely, Karen N %A Kooner, Jaspal S %A Köttgen, Anna %A Heijmans, Bastiaan T %A Deloukas, Panos %A Relton, Caroline %A Ong, Ken K %A Bell, Jordana T %A Eric Boerwinkle %A Elliott, Paul %A Brenner, Hermann %A Beekman, Marian %A Levy, Daniel %A Waldenberger, Melanie %A Chambers, John C %A Dehghan, Abbas %A Jarvelin, Marjo-Riitta %K C-Reactive Protein %K CpG Islands %K DNA Methylation %K Humans %K Inflammation %K Nucleotide Motifs %X

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

%B Nat Commun %V 13 %P 2408 %8 2022 May 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35504910?dopt=Abstract %R 10.1038/s41467-022-29792-6 %0 Journal Article %J Nat Commun %D 2022 %T Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways. %A Young, William J %A Lahrouchi, Najim %A Isaacs, Aaron %A Duong, ThuyVy %A Foco, Luisa %A Ahmed, Farah %A Brody, Jennifer A %A Salman, Reem %A Noordam, Raymond %A Benjamins, Jan-Walter %A Haessler, Jeffrey %A Lyytikäinen, Leo-Pekka %A Repetto, Linda %A Concas, Maria Pina %A van den Berg, Marten E %A Weiss, Stefan %A Baldassari, Antoine R %A Bartz, Traci M %A Cook, James P %A Evans, Daniel S %A Freudling, Rebecca %A Hines, Oliver %A Isaksen, Jonas L %A Lin, Honghuang %A Mei, Hao %A Moscati, Arden %A Müller-Nurasyid, Martina %A Nursyifa, Casia %A Qian, Yong %A Richmond, Anne %A Roselli, Carolina %A Ryan, Kathleen A %A Tarazona-Santos, Eduardo %A Thériault, Sébastien %A van Duijvenboden, Stefan %A Warren, Helen R %A Yao, Jie %A Raza, Dania %A Aeschbacher, Stefanie %A Ahlberg, Gustav %A Alonso, Alvaro %A Andreasen, Laura %A Bis, Joshua C %A Eric Boerwinkle %A Campbell, Archie %A Catamo, Eulalia %A Cocca, Massimiliano %A Cutler, Michael J %A Darbar, Dawood %A De Grandi, Alessandro %A De Luca, Antonio %A Ding, Jun %A Ellervik, Christina %A Ellinor, Patrick T %A Felix, Stephan B %A Froguel, Philippe %A Fuchsberger, Christian %A Gögele, Martin %A Graff, Claus %A Graff, Mariaelisa %A Guo, Xiuqing %A Hansen, Torben %A Heckbert, Susan R %A Huang, Paul L %A Huikuri, Heikki V %A Hutri-Kähönen, Nina %A Ikram, M Arfan %A Jackson, Rebecca D %A Junttila, Juhani %A Kavousi, Maryam %A Kors, Jan A %A Leal, Thiago P %A Lemaitre, Rozenn N %A Lin, Henry J %A Lind, Lars %A Linneberg, Allan %A Liu, Simin %A Macfarlane, Peter W %A Mangino, Massimo %A Meitinger, Thomas %A Mezzavilla, Massimo %A Mishra, Pashupati P %A Mitchell, Rebecca N %A Mononen, Nina %A Montasser, May E %A Morrison, Alanna C %A Nauck, Matthias %A Nauffal, Victor %A Navarro, Pau %A Nikus, Kjell %A Paré, Guillaume %A Patton, Kristen K %A Pelliccione, Giulia %A Pittman, Alan %A Porteous, David J %A Pramstaller, Peter P %A Preuss, Michael H %A Raitakari, Olli T %A Reiner, Alexander P %A Ribeiro, Antonio Luiz P %A Rice, Kenneth M %A Risch, Lorenz %A Schlessinger, David %A Schotten, Ulrich %A Schurmann, Claudia %A Shen, Xia %A Shoemaker, M Benjamin %A Sinagra, Gianfranco %A Sinner, Moritz F %A Soliman, Elsayed Z %A Stoll, Monika %A Strauch, Konstantin %A Tarasov, Kirill %A Taylor, Kent D %A Tinker, Andrew %A Trompet, Stella %A Uitterlinden, Andre %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Weng, Lu-Chen %A Whitsel, Eric A %A Wilson, James G %A Avery, Christy L %A Conen, David %A Correa, Adolfo %A Cucca, Francesco %A Dörr, Marcus %A Gharib, Sina A %A Girotto, Giorgia %A Grarup, Niels %A Hayward, Caroline %A Jamshidi, Yalda %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kääb, Stefan %A Kähönen, Mika %A Kanters, Jørgen K %A Kooperberg, Charles %A Lehtimäki, Terho %A Lima-Costa, Maria Fernanda %A Liu, Yongmei %A Loos, Ruth J F %A Lubitz, Steven A %A Mook-Kanamori, Dennis O %A Morris, Andrew P %A O'Connell, Jeffrey R %A Olesen, Morten Salling %A Orini, Michele %A Padmanabhan, Sandosh %A Pattaro, Cristian %A Peters, Annette %A Psaty, Bruce M %A Rotter, Jerome I %A Stricker, Bruno %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Wilson, James F %A Arking, Dan E %A Ramirez, Julia %A Lambiase, Pier D %A Sotoodehnia, Nona %A Mifsud, Borbala %A Newton-Cheh, Christopher %A Munroe, Patricia B %K Arrhythmias, Cardiac %K Death, Sudden, Cardiac %K Electrocardiography %K Genetic Testing %K Humans %K Male %X

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

%B Nat Commun %V 13 %P 5144 %8 2022 Sep 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/36050321?dopt=Abstract %R 10.1038/s41467-022-32821-z %0 Journal Article %J JCI Insight %D 2022 %T Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases. %A Li, Yong %A Cheng, Yurong %A Consolato, Francesco %A Schiano, Guglielmo %A Chong, Michael R %A Pietzner, Maik %A Nguyen, Ngoc Quynh H %A Scherer, Nora %A Biggs, Mary L %A Kleber, Marcus E %A Haug, Stefan %A Göçmen, Burulça %A Pigeyre, Marie %A Sekula, Peggy %A Steinbrenner, Inga %A Schlosser, Pascal %A Joseph, Christina B %A Brody, Jennifer A %A Grams, Morgan E %A Hayward, Caroline %A Schultheiss, Ulla T %A Krämer, Bernhard K %A Kronenberg, Florian %A Peters, Annette %A Seissler, Jochen %A Steubl, Dominik %A Then, Cornelia %A Wuttke, Matthias %A Marz, Winfried %A Eckardt, Kai-Uwe %A Gieger, Christian %A Eric Boerwinkle %A Psaty, Bruce M %A Coresh, Josef %A Oefner, Peter J %A Paré, Guillaume %A Langenberg, Claudia %A Scherberich, Jürgen E %A Yu, Bing %A Akilesh, Shreeram %A Devuyst, Olivier %A Rampoldi, Luca %A Köttgen, Anna %K Blood Pressure %K Genome-Wide Association Study %K Humans %K Hypertension %K Renal Insufficiency, Chronic %K Uromodulin %X

Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.

%B JCI Insight %V 7 %8 2022 May 23 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/35446786?dopt=Abstract %R 10.1172/jci.insight.157035 %0 Journal Article %J Mol Psychiatry %D 2021 %T Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. %A de Las Fuentes, Lisa %A Sung, Yun Ju %A Noordam, Raymond %A Winkler, Thomas %A Feitosa, Mary F %A Schwander, Karen %A Bentley, Amy R %A Brown, Michael R %A Guo, Xiuqing %A Manning, Alisa %A Chasman, Daniel I %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Campbell, Archie %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Hartwig, Fernando P %A Horimoto, A R V R %A Li, Changwei %A Li-Gao, Ruifang %A Liu, Yongmei %A Marten, Jonathan %A Musani, Solomon K %A Ntalla, Ioanna %A Rankinen, Tuomo %A Richard, Melissa %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Tayo, Bamidele O %A Vojinovic, Dina %A Warren, Helen R %A Xuan, Deng %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin-Fang %A Chen, Xu %A Christensen, Kaare %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Girotto, Giorgia %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Kühnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Rueedi, Rico %A Shu, Xiao-Ou %A Snieder, Harold %A Sofer, Tamar %A Takeuchi, Fumihiko %A Verweij, Niek %A Ware, Erin B %A Weiss, Stefan %A Yanek, Lisa R %A Amin, Najaf %A Arking, Dan E %A Arnett, Donna K %A Bergmann, Sven %A Eric Boerwinkle %A Brody, Jennifer A %A Broeckel, Ulrich %A Brumat, Marco %A Burke, Gregory %A Cabrera, Claudia P %A Canouil, Mickaël %A Chee, Miao Li %A Chen, Yii-Der Ida %A Cocca, Massimiliano %A Connell, John %A de Silva, H Janaka %A de Vries, Paul S %A Eiriksdottir, Gudny %A Faul, Jessica D %A Fisher, Virginia %A Forrester, Terrence %A Fox, Ervin F %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven %A Ikram, M Arfan %A Irvin, Marguerite R %A Kähönen, Mika %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Kraja, Aldi T %A Krieger, J E %A Langefeld, Carl D %A Li, Yize %A Liang, Jingjing %A Liewald, David C M %A Liu, Ching-Ti %A Liu, Jianjun %A Lohman, Kurt K %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mook-Kanamori, Dennis O %A Nalls, Mike A %A Nelson, Christopher P %A Norris, Jill M %A O'Connell, Jeff %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Pedersen, Nancy L %A Perls, Thomas %A Peters, Annette %A Petersmann, Astrid %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David J %A Raffel, Leslie J %A Rice, Treva K %A Rotter, Jerome I %A Rudan, Igor %A Rueda-Ochoa, Oscar-Leonel %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Schreiner, Pamela J %A Shikany, James M %A Sidney, Stephen S %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Starr, John M %A Strauch, Konstantin %A Swertz, Morris A %A Teumer, Alexander %A Tham, Yih Chung %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Ende, M Yldau %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya-Xing %A Wei, Wen-Bin %A Weir, David R %A Wen, Wanqing %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Bowden, Donald W %A Deary, Ian J %A Dörr, Marcus %A Esko, Tõnu %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kammerer, Candace M %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Marques-Vidal, Pedro %A Penninx, Brenda W J H %A Samani, Nilesh J %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Cooper, Richard S %A Correa, Adolfo %A Evans, Michele K %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kelly, Tanika N %A Kritchevsky, Stephen B %A Levy, Daniel %A Palmas, Walter R %A Pereira, A C %A Province, Michael M %A Psaty, Bruce M %A Ridker, Paul M %A Rotimi, Charles N %A Tai, E Shyong %A van Dam, Rob M %A van Duijn, Cornelia M %A Wong, Tien Yin %A Rice, Kenneth %A Gauderman, W James %A Morrison, Alanna C %A North, Kari E %A Kardia, Sharon L R %A Caulfield, Mark J %A Elliott, Paul %A Munroe, Patricia B %A Franks, Paul W %A Rao, Dabeeru C %A Fornage, Myriam %K Blood Pressure %K Epistasis, Genetic %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Polymorphism, Single Nucleotide %X

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

%B Mol Psychiatry %V 26 %P 2111-2125 %8 2021 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/32372009?dopt=Abstract %R 10.1038/s41380-020-0719-3 %0 Journal Article %J HGG Adv %D 2021 %T Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. %A Sun, Daokun %A Richard, Melissa %A Musani, Solomon K %A Sung, Yun Ju %A Winkler, Thomas W %A Schwander, Karen %A Chai, Jin Fang %A Guo, Xiuqing %A Kilpeläinen, Tuomas O %A Vojinovic, Dina %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Brown, Michael R %A Chitrala, Kumaraswamy %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Liu, Yongmei %A Manning, Alisa K %A Noordam, Raymond %A Smith, Albert V %A Harris, Sarah E %A Kühnel, Brigitte %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Rauramaa, Rainer %A van der Most, Peter J %A Wang, Rujia %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Arking, Dan E %A Arnett, Donna K %A Barac, Ana %A Eric Boerwinkle %A Broeckel, Ulrich %A Chakravarti, Aravinda %A Chen, Yii-Der Ida %A Cupples, L Adrienne %A Davigulus, Martha L %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Vries, Paul S %A Delaney, Joseph A C %A Roux, Ana V Diez %A Dörr, Marcus %A Faul, Jessica D %A Fretts, Amanda M %A Gallo, Linda C %A Grabe, Hans Jörgen %A Gu, C Charles %A Harris, Tamara B %A Hartman, Catharina C A %A Heikkinen, Sami %A Ikram, M Arfan %A Isasi, Carmen %A Johnson, W Craig %A Jonas, Jost Bruno %A Kaplan, Robert C %A Komulainen, Pirjo %A Krieger, Jose E %A Levy, Daniel %A Liu, Jianjun %A Lohman, Kurt %A Luik, Annemarie I %A Martin, Lisa W %A Meitinger, Thomas %A Milaneschi, Yuri %A O'Connell, Jeff R %A Palmas, Walter R %A Peters, Annette %A Peyser, Patricia A %A Pulkki-Råback, Laura %A Raffel, Leslie J %A Reiner, Alex P %A Rice, Kenneth %A Robinson, Jennifer G %A Rosendaal, Frits R %A Schmidt, Carsten Oliver %A Schreiner, Pamela J %A Schwettmann, Lars %A Shikany, James M %A Shu, Xiao-Ou %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Sotoodehnia, Nona %A Strauch, Konstantin %A Tai, E Shyong %A Taylor, Kent %A Uitterlinden, André G %A van Duijn, Cornelia M %A Waldenberger, Melanie %A Wee, Hwee-Lin %A Wei, Wen-Bin %A Wilson, Gregory %A Xuan, Deng %A Yao, Jie %A Zeng, Donglin %A Zhao, Wei %A Zhu, Xiaofeng %A Zonderman, Alan B %A Becker, Diane M %A Deary, Ian J %A Gieger, Christian %A Lakka, Timo A %A Lehtimäki, Terho %A North, Kari E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Snieder, Harold %A Wang, Ya-Xing %A Weir, David R %A Zheng, Wei %A Evans, Michele K %A Gauderman, W James %A Gudnason, Vilmundur %A Horta, Bernardo L %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Morrison, Alanna C %A Pereira, Alexandre C %A Psaty, Bruce M %A Amin, Najaf %A Fox, Ervin R %A Kooperberg, Charles %A Sim, Xueling %A Bierut, Laura %A Rotter, Jerome I %A Kardia, Sharon L R %A Franceschini, Nora %A Rao, Dabeeru C %A Fornage, Myriam %X

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

%B HGG Adv %V 2 %8 2021 Jan 14 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34734193?dopt=Abstract %R 10.1016/j.xhgg.2020.100013 %0 Journal Article %J Mol Psychiatry %D 2021 %T Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. %A Wang, Heming %A Noordam, Raymond %A Cade, Brian E %A Schwander, Karen %A Winkler, Thomas W %A Lee, Jiwon %A Sung, Yun Ju %A Bentley, Amy R %A Manning, Alisa K %A Aschard, Hugues %A Kilpeläinen, Tuomas O %A Ilkov, Marjan %A Brown, Michael R %A Horimoto, Andrea R %A Richard, Melissa %A Bartz, Traci M %A Vojinovic, Dina %A Lim, Elise %A Nierenberg, Jovia L %A Liu, Yongmei %A Chitrala, Kumaraswamynaidu %A Rankinen, Tuomo %A Musani, Solomon K %A Franceschini, Nora %A Rauramaa, Rainer %A Alver, Maris %A Zee, Phyllis C %A Harris, Sarah E %A van der Most, Peter J %A Nolte, Ilja M %A Munroe, Patricia B %A Palmer, Nicholette D %A Kühnel, Brigitte %A Weiss, Stefan %A Wen, Wanqing %A Hall, Kelly A %A Lyytikäinen, Leo-Pekka %A O'Connell, Jeff %A Eiriksdottir, Gudny %A Launer, Lenore J %A de Vries, Paul S %A Arking, Dan E %A Chen, Han %A Eric Boerwinkle %A Krieger, Jose E %A Schreiner, Pamela J %A Sidney, Stephen %A Shikany, James M %A Rice, Kenneth %A Chen, Yii-Der Ida %A Gharib, Sina A %A Bis, Joshua C %A Luik, Annemarie I %A Ikram, M Arfan %A Uitterlinden, André G %A Amin, Najaf %A Xu, Hanfei %A Levy, Daniel %A He, Jiang %A Lohman, Kurt K %A Zonderman, Alan B %A Rice, Treva K %A Sims, Mario %A Wilson, Gregory %A Sofer, Tamar %A Rich, Stephen S %A Palmas, Walter %A Yao, Jie %A Guo, Xiuqing %A Rotter, Jerome I %A Biermasz, Nienke R %A Mook-Kanamori, Dennis O %A Martin, Lisa W %A Barac, Ana %A Wallace, Robert B %A Gottlieb, Daniel J %A Komulainen, Pirjo %A Heikkinen, Sami %A Mägi, Reedik %A Milani, Lili %A Metspalu, Andres %A Starr, John M %A Milaneschi, Yuri %A Waken, R J %A Gao, Chuan %A Waldenberger, Melanie %A Peters, Annette %A Strauch, Konstantin %A Meitinger, Thomas %A Roenneberg, Till %A Völker, Uwe %A Dörr, Marcus %A Shu, Xiao-Ou %A Mukherjee, Sutapa %A Hillman, David R %A Kähönen, Mika %A Wagenknecht, Lynne E %A Gieger, Christian %A Grabe, Hans J %A Zheng, Wei %A Palmer, Lyle J %A Lehtimäki, Terho %A Gudnason, Vilmundur %A Morrison, Alanna C %A Pereira, Alexandre C %A Fornage, Myriam %A Psaty, Bruce M %A van Duijn, Cornelia M %A Liu, Ching-Ti %A Kelly, Tanika N %A Evans, Michele K %A Bouchard, Claude %A Fox, Ervin R %A Kooperberg, Charles %A Zhu, Xiaofeng %A Lakka, Timo A %A Esko, Tõnu %A North, Kari E %A Deary, Ian J %A Snieder, Harold %A Penninx, Brenda W J H %A Gauderman, W James %A Rao, Dabeeru C %A Redline, Susan %A van Heemst, Diana %K Blood Pressure %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Polymorphism, Single Nucleotide %K Sleep %X

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

%B Mol Psychiatry %V 26 %P 6293-6304 %8 2021 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/33859359?dopt=Abstract %R 10.1038/s41380-021-01087-0 %0 Journal Article %J Nat Genet %D 2021 %T The trans-ancestral genomic architecture of glycemic traits. %A Chen, Ji %A Spracklen, Cassandra N %A Marenne, Gaëlle %A Varshney, Arushi %A Corbin, Laura J %A Luan, Jian'an %A Willems, Sara M %A Wu, Ying %A Zhang, Xiaoshuai %A Horikoshi, Momoko %A Boutin, Thibaud S %A Mägi, Reedik %A Waage, Johannes %A Li-Gao, Ruifang %A Chan, Kei Hang Katie %A Yao, Jie %A Anasanti, Mila D %A Chu, Audrey Y %A Claringbould, Annique %A Heikkinen, Jani %A Hong, Jaeyoung %A Hottenga, Jouke-Jan %A Huo, Shaofeng %A Kaakinen, Marika A %A Louie, Tin %A Marz, Winfried %A Moreno-Macias, Hortensia %A Ndungu, Anne %A Nelson, Sarah C %A Nolte, Ilja M %A North, Kari E %A Raulerson, Chelsea K %A Ray, Debashree %A Rohde, Rebecca %A Rybin, Denis %A Schurmann, Claudia %A Sim, Xueling %A Southam, Lorraine %A Stewart, Isobel D %A Wang, Carol A %A Wang, Yujie %A Wu, Peitao %A Zhang, Weihua %A Ahluwalia, Tarunveer S %A Appel, Emil V R %A Bielak, Lawrence F %A Brody, Jennifer A %A Burtt, Noël P %A Cabrera, Claudia P %A Cade, Brian E %A Chai, Jin Fang %A Chai, Xiaoran %A Chang, Li-Ching %A Chen, Chien-Hsiun %A Chen, Brian H %A Chitrala, Kumaraswamy Naidu %A Chiu, Yen-Feng %A de Haan, Hugoline G %A Delgado, Graciela E %A Demirkan, Ayse %A Duan, Qing %A Engmann, Jorgen %A Fatumo, Segun A %A Gayán, Javier %A Giulianini, Franco %A Gong, Jung Ho %A Gustafsson, Stefan %A Hai, Yang %A Hartwig, Fernando P %A He, Jing %A Heianza, Yoriko %A Huang, Tao %A Huerta-Chagoya, Alicia %A Hwang, Mi Yeong %A Jensen, Richard A %A Kawaguchi, Takahisa %A Kentistou, Katherine A %A Kim, Young Jin %A Kleber, Marcus E %A Kooner, Ishminder K %A Lai, Shuiqing %A Lange, Leslie A %A Langefeld, Carl D %A Lauzon, Marie %A Li, Man %A Ligthart, Symen %A Liu, Jun %A Loh, Marie %A Long, Jirong %A Lyssenko, Valeriya %A Mangino, Massimo %A Marzi, Carola %A Montasser, May E %A Nag, Abhishek %A Nakatochi, Masahiro %A Noce, Damia %A Noordam, Raymond %A Pistis, Giorgio %A Preuss, Michael %A Raffield, Laura %A Rasmussen-Torvik, Laura J %A Rich, Stephen S %A Robertson, Neil R %A Rueedi, Rico %A Ryan, Kathleen %A Sanna, Serena %A Saxena, Richa %A Schraut, Katharina E %A Sennblad, Bengt %A Setoh, Kazuya %A Smith, Albert V %A Sparsø, Thomas %A Strawbridge, Rona J %A Takeuchi, Fumihiko %A Tan, Jingyi %A Trompet, Stella %A van den Akker, Erik %A van der Most, Peter J %A Verweij, Niek %A Vogel, Mandy %A Wang, Heming %A Wang, Chaolong %A Wang, Nan %A Warren, Helen R %A Wen, Wanqing %A Wilsgaard, Tom %A Wong, Andrew %A Wood, Andrew R %A Xie, Tian %A Zafarmand, Mohammad Hadi %A Zhao, Jing-Hua %A Zhao, Wei %A Amin, Najaf %A Arzumanyan, Zorayr %A Astrup, Arne %A Bakker, Stephan J L %A Baldassarre, Damiano %A Beekman, Marian %A Bergman, Richard N %A Bertoni, Alain %A Blüher, Matthias %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Bowden, Donald W %A Cai, Qiuyin %A Campbell, Archie %A Campbell, Harry %A Chang, Yi Cheng %A de Geus, Eco J C %A Dehghan, Abbas %A Du, Shufa %A Eiriksdottir, Gudny %A Farmaki, Aliki Eleni %A Frånberg, Mattias %A Fuchsberger, Christian %A Gao, Yutang %A Gjesing, Anette P %A Goel, Anuj %A Han, Sohee %A Hartman, Catharina A %A Herder, Christian %A Hicks, Andrew A %A Hsieh, Chang-Hsun %A Hsueh, Willa A %A Ichihara, Sahoko %A Igase, Michiya %A Ikram, M Arfan %A Johnson, W Craig %A Jørgensen, Marit E %A Joshi, Peter K %A Kalyani, Rita R %A Kandeel, Fouad R %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kiess, Wieland %A Kolcic, Ivana %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Läll, Kristi %A Lam, Kelvin %A Lawlor, Deborah A %A Lee, Nanette R %A Lemaitre, Rozenn N %A Li, Honglan %A Lin, Shih-Yi %A Lindström, Jaana %A Linneberg, Allan %A Liu, Jianjun %A Lorenzo, Carlos %A Matsubara, Tatsuaki %A Matsuda, Fumihiko %A Mingrone, Geltrude %A Mooijaart, Simon %A Moon, Sanghoon %A Nabika, Toru %A Nadkarni, Girish N %A Nadler, Jerry L %A Nelis, Mari %A Neville, Matt J %A Norris, Jill M %A Ohyagi, Yasumasa %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Qi, Qibin %A Raven, Dennis %A Reilly, Dermot F %A Reiner, Alex %A Rivideneira, Fernando %A Roll, Kathryn %A Rudan, Igor %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sattar, Naveed %A Schürmann, Annette %A Shi, Jinxiu %A Stringham, Heather M %A Taylor, Kent D %A Teslovich, Tanya M %A Thuesen, Betina %A Timmers, Paul R H J %A Tremoli, Elena %A Tsai, Michael Y %A Uitterlinden, Andre %A van Dam, Rob M %A van Heemst, Diana %A van Hylckama Vlieg, Astrid %A Van Vliet-Ostaptchouk, Jana V %A Vangipurapu, Jagadish %A Vestergaard, Henrik %A Wang, Tao %A Willems van Dijk, Ko %A Zemunik, Tatijana %A Abecasis, Gonçalo R %A Adair, Linda S %A Aguilar-Salinas, Carlos Alberto %A Alarcón-Riquelme, Marta E %A An, Ping %A Aviles-Santa, Larissa %A Becker, Diane M %A Beilin, Lawrence J %A Bergmann, Sven %A Bisgaard, Hans %A Black, Corri %A Boehnke, Michael %A Eric Boerwinkle %A Böhm, Bernhard O %A Bønnelykke, Klaus %A Boomsma, D I %A Bottinger, Erwin P %A Buchanan, Thomas A %A Canouil, Mickaël %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Cheng, Ching-Yu %A Collins, Francis S %A Correa, Adolfo %A Cucca, Francesco %A de Silva, H Janaka %A Dedoussis, George %A Elmståhl, Sölve %A Evans, Michele K %A Ferrannini, Ele %A Ferrucci, Luigi %A Florez, Jose C %A Franks, Paul W %A Frayling, Timothy M %A Froguel, Philippe %A Gigante, Bruna %A Goodarzi, Mark O %A Gordon-Larsen, Penny %A Grallert, Harald %A Grarup, Niels %A Grimsgaard, Sameline %A Groop, Leif %A Gudnason, Vilmundur %A Guo, Xiuqing %A Hamsten, Anders %A Hansen, Torben %A Hayward, Caroline %A Heckbert, Susan R %A Horta, Bernardo L %A Huang, Wei %A Ingelsson, Erik %A James, Pankow S %A Jarvelin, Marjo-Ritta %A Jonas, Jost B %A Jukema, J Wouter %A Kaleebu, Pontiano %A Kaplan, Robert %A Kardia, Sharon L R %A Kato, Norihiro %A Keinanen-Kiukaanniemi, Sirkka M %A Kim, Bong-Jo %A Kivimaki, Mika %A Koistinen, Heikki A %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Kuh, Diana %A Kumari, Meena %A Kutalik, Zoltán %A Laakso, Markku %A Lakka, Timo A %A Launer, Lenore J %A Leander, Karin %A Li, Huaixing %A Lin, Xu %A Lind, Lars %A Lindgren, Cecilia %A Liu, Simin %A Loos, Ruth J F %A Magnusson, Patrik K E %A Mahajan, Anubha %A Metspalu, Andres %A Mook-Kanamori, Dennis O %A Mori, Trevor A %A Munroe, Patricia B %A Njølstad, Inger %A O'Connell, Jeffrey R %A Oldehinkel, Albertine J %A Ong, Ken K %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pedersen, Oluf %A Pennell, Craig E %A Porteous, David J %A Pramstaller, Peter P %A Province, Michael A %A Psaty, Bruce M %A Qi, Lu %A Raffel, Leslie J %A Rauramaa, Rainer %A Redline, Susan %A Ridker, Paul M %A Rosendaal, Frits R %A Saaristo, Timo E %A Sandhu, Manjinder %A Saramies, Jouko %A Schneiderman, Neil %A Schwarz, Peter %A Scott, Laura J %A Selvin, Elizabeth %A Sever, Peter %A Shu, Xiao-Ou %A Slagboom, P Eline %A Small, Kerrin S %A Smith, Blair H %A Snieder, Harold %A Sofer, Tamar %A Sørensen, Thorkild I A %A Spector, Tim D %A Stanton, Alice %A Steves, Claire J %A Stumvoll, Michael %A Sun, Liang %A Tabara, Yasuharu %A Tai, E Shyong %A Timpson, Nicholas J %A Tonjes, Anke %A Tuomilehto, Jaakko %A Tusie, Teresa %A Uusitupa, Matti %A van der Harst, Pim %A van Duijn, Cornelia %A Vitart, Veronique %A Vollenweider, Peter %A Vrijkotte, Tanja G M %A Wagenknecht, Lynne E %A Walker, Mark %A Wang, Ya X %A Wareham, Nick J %A Watanabe, Richard M %A Watkins, Hugh %A Wei, Wen B %A Wickremasinghe, Ananda R %A Willemsen, Gonneke %A Wilson, James F %A Wong, Tien-Yin %A Wu, Jer-Yuarn %A Xiang, Anny H %A Yanek, Lisa R %A Yengo, Loic %A Yokota, Mitsuhiro %A Zeggini, Eleftheria %A Zheng, Wei %A Zonderman, Alan B %A Rotter, Jerome I %A Gloyn, Anna L %A McCarthy, Mark I %A Dupuis, Josée %A Meigs, James B %A Scott, Robert A %A Prokopenko, Inga %A Leong, Aaron %A Liu, Ching-Ti %A Parker, Stephen C J %A Mohlke, Karen L %A Langenberg, Claudia %A Wheeler, Eleanor %A Morris, Andrew P %A Barroso, Inês %K Alleles %K Blood Glucose %K Epigenesis, Genetic %K Gene Expression Profiling %K Genome, Human %K Genome-Wide Association Study %K Glycated Hemoglobin %K Humans %K Multifactorial Inheritance %K Physical Chromosome Mapping %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K White People %X

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

%B Nat Genet %V 53 %P 840-860 %8 2021 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/34059833?dopt=Abstract %R 10.1038/s41588-021-00852-9 %0 Journal Article %J Circulation %D 2019 %T Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. %A Agha, Golareh %A Mendelson, Michael M %A Ward-Caviness, Cavin K %A Joehanes, Roby %A Huan, Tianxiao %A Gondalia, Rahul %A Salfati, Elias %A Brody, Jennifer A %A Fiorito, Giovanni %A Bressler, Jan %A Chen, Brian H %A Ligthart, Symen %A Guarrera, Simonetta %A Colicino, Elena %A Just, Allan C %A Wahl, Simone %A Gieger, Christian %A Vandiver, Amy R %A Tanaka, Toshiko %A Hernandez, Dena G %A Pilling, Luke C %A Singleton, Andrew B %A Sacerdote, Carlotta %A Krogh, Vittorio %A Panico, Salvatore %A Tumino, Rosario %A Li, Yun %A Zhang, Guosheng %A Stewart, James D %A Floyd, James S %A Wiggins, Kerri L %A Rotter, Jerome I %A Multhaup, Michael %A Bakulski, Kelly %A Horvath, Steven %A Tsao, Philip S %A Absher, Devin M %A Vokonas, Pantel %A Hirschhorn, Joel %A Fallin, M Daniele %A Liu, Chunyu %A Bandinelli, Stefania %A Eric Boerwinkle %A Dehghan, Abbas %A Schwartz, Joel D %A Psaty, Bruce M %A Feinberg, Andrew P %A Hou, Lifang %A Ferrucci, Luigi %A Sotoodehnia, Nona %A Matullo, Giuseppe %A Peters, Annette %A Fornage, Myriam %A Assimes, Themistocles L %A Whitsel, Eric A %A Levy, Daniel %A Baccarelli, Andrea A %K Adult %K Aged %K Cohort Studies %K Coronary Disease %K CpG Islands %K DNA Methylation %K Europe %K Female %K Genome-Wide Association Study %K Humans %K Incidence %K Leukocytes %K Male %K Middle Aged %K Myocardial Infarction %K Population Groups %K Prognosis %K Prospective Studies %K Risk %K United States %X

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

%B Circulation %V 140 %P 645-657 %8 2019 Aug 20 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/31424985?dopt=Abstract %R 10.1161/CIRCULATIONAHA.118.039357 %0 Journal Article %J PLoS One %D 2019 %T Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. %A Ward-Caviness, Cavin K %A de Vries, Paul S %A Wiggins, Kerri L %A Huffman, Jennifer E %A Yanek, Lisa R %A Bielak, Lawrence F %A Giulianini, Franco %A Guo, Xiuqing %A Kleber, Marcus E %A Kacprowski, Tim %A Groß, Stefan %A Petersman, Astrid %A Davey Smith, George %A Hartwig, Fernando P %A Bowden, Jack %A Hemani, Gibran %A Müller-Nuraysid, Martina %A Strauch, Konstantin %A Koenig, Wolfgang %A Waldenberger, Melanie %A Meitinger, Thomas %A Pankratz, Nathan %A Eric Boerwinkle %A Tang, Weihong %A Fu, Yi-Ping %A Johnson, Andrew D %A Song, Ci %A de Maat, Moniek P M %A Uitterlinden, André G %A Franco, Oscar H %A Brody, Jennifer A %A McKnight, Barbara %A Chen, Yii-Der Ida %A Psaty, Bruce M %A Mathias, Rasika A %A Becker, Diane M %A Peyser, Patricia A %A Smith, Jennifer A %A Bielinski, Suzette J %A Ridker, Paul M %A Taylor, Kent D %A Yao, Jie %A Tracy, Russell %A Delgado, Graciela %A Trompet, Stella %A Sattar, Naveed %A Jukema, J Wouter %A Becker, Lewis C %A Kardia, Sharon L R %A Rotter, Jerome I %A Marz, Winfried %A Dörr, Marcus %A Chasman, Daniel I %A Dehghan, Abbas %A O'Donnell, Christopher J %A Smith, Nicholas L %A Peters, Annette %A Morrison, Alanna C %K Alleles %K Coronary Disease %K Fibrinogen %K Genetic Pleiotropy %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Incidence %K Mendelian Randomization Analysis %K Models, Genetic %K Multivariate Analysis %K Myocardial Infarction %K Odds Ratio %X

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

%B PLoS One %V 14 %P e0216222 %8 2019 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/31075152?dopt=Abstract %R 10.1371/journal.pone.0216222 %0 Journal Article %J Metabolites %D 2019 %T Metabolomics Identifies Novel Blood Biomarkers of Pulmonary Function and COPD in the General Population. %A Yu, Bing %A Flexeder, Claudia %A McGarrah, Robert W %A Wyss, Annah %A Morrison, Alanna C %A North, Kari E %A Eric Boerwinkle %A Kastenmüller, Gabi %A Gieger, Christian %A Suhre, Karsten %A Karrasch, Stefan %A Peters, Annette %A Wagner, Gregory R %A Michelotti, Gregory A %A Mohney, Robert P %A Schulz, Holger %A London, Stephanie J %X

Determination of metabolomic signatures of pulmonary function and chronic obstructive pulmonary disease (COPD) in the general population could aid in identification and understanding of early disease processes. Metabolome measurements were performed on serum from 4742 individuals (2354 African-Americans and 1529 European-Americans from the Atherosclerosis Risk in Communities study and 859 Europeans from the Cooperative Health Research in the Region of Augsburg study). We examined 368 metabolites in relation to cross-sectional measures of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), their ratio (FEV1/FVC) and COPD using multivariable regression followed by meta-analysis. At a false discovery rate of 0.05, 95 metabolites were associated with FEV1 and 100 with FVC (73 overlapping), including inverse associations with branched-chain amino acids and positive associations with glutamine. Ten metabolites were associated with FEV1/FVC and seventeen with COPD (393 cases). Enriched pathways of amino acid metabolism were identified. Associations with FEV1 and FVC were not driven by individuals with COPD. We identified novel metabolic signatures of pulmonary function and COPD in African and European ancestry populations. These may allow development of biomarkers in the general population of early disease pathogenesis, before pulmonary function has decreased to levels diagnostic for COPD.

%B Metabolites %V 9 %8 2019 Apr 01 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/30939782?dopt=Abstract %R 10.3390/metabo9040061 %0 Journal Article %J Am J Epidemiol %D 2019 %T Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. %A de Vries, Paul S %A Brown, Michael R %A Bentley, Amy R %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Schwander, Karen %A Kraja, Aldi T %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Huffman, Jennifer E %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Deng, Xuan %A Dorajoo, Rajkumar %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Evangelou, Evangelos %A Graff, Mariaelisa %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kühnel, Brigitte %A Laguzzi, Federica %A Lee, Joseph H %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Matoba, Nana %A Nolte, Ilja M %A Pietzner, Maik %A Riaz, Muhammad %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Wang, Yajuan %A Ware, Erin B %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Ballantyne, Christie %A Eric Boerwinkle %A Broeckel, Ulrich %A Campbell, Archie %A Canouil, Mickaël %A Charumathi, Sabanayagam %A Chen, Yii-Der Ida %A Connell, John M %A de Faire, Ulf %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Ding, Jingzhong %A Dominiczak, Anna F %A Duan, Qing %A Eaton, Charles B %A Eppinga, Ruben N %A Faul, Jessica D %A Fisher, Virginia %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Ghanbari, Mohsen %A Giulianini, Franco %A Grabe, Hans J %A Grove, Megan L %A Gu, C Charles %A Harris, Tamara B %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hixson, James E %A Howard, Barbara V %A Ikram, M Arfan %A Jacobs, David R %A Johnson, Craig %A Jonas, Jost Bruno %A Kammerer, Candace M %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooperberg, Charles %A Krieger, Jose E %A Kritchevsky, Steve B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lemaitre, Rozenn N %A Li, Yize %A Liang, Jingjing %A Liu, Jianjun %A Liu, Kiang %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Mosley, Thomas H %A Mukamal, Kenneth J %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A Sotoodehnia, Nona %A O'Connell, Jeff R %A Palmer, Nicholette D %A Pazoki, Raha %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Reiner, Alex P %A Rice, Treva K %A Rich, Stephen S %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Smith, Blair H %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tan, Nicholas %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A van Heemst, Diana %A Vuckovic, Dragana %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Yujie %A Wang, Zhe %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo L %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Penninx, Brenda %A Pereira, Alexandre C %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wang, Ya Xing %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Zheng, Wei %A Elliott, Paul %A North, Kari E %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Liu, Ching-Ti %A Liu, Yongmei %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Kardia, Sharon L R %A Zhu, Xiaofeng %A Rotimi, Charles N %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Liu, Jingmin %A Rotter, Jerome I %A Gauderman, W James %A Province, Michael A %A Munroe, Patricia B %A Rice, Kenneth %A Chasman, Daniel I %A Cupples, L Adrienne %A Rao, Dabeeru C %A Morrison, Alanna C %K Adolescent %K Adult %K Aged %K Alcohol Drinking %K Cholesterol, HDL %K Cholesterol, LDL %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Life Style %K Lipids %K Male %K Middle Aged %K Phenotype %K Racial Groups %K Triglycerides %K Vascular Endothelial Growth Factor B %K Young Adult %X

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

%B Am J Epidemiol %V 188 %P 1033-1054 %8 2019 Jun 01 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/30698716?dopt=Abstract %R 10.1093/aje/kwz005 %0 Journal Article %J Nat Genet %D 2019 %T Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. %A Bentley, Amy R %A Sung, Yun J %A Brown, Michael R %A Winkler, Thomas W %A Kraja, Aldi T %A Ntalla, Ioanna %A Schwander, Karen %A Chasman, Daniel I %A Lim, Elise %A Deng, Xuan %A Guo, Xiuqing %A Liu, Jingmin %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Huffman, Jennifer E %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Richard, Melissa A %A Noordam, Raymond %A Baker, Jenna %A Chen, Guanjie %A Aschard, Hugues %A Bartz, Traci M %A Ding, Jingzhong %A Dorajoo, Rajkumar %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Zhao, Wei %A Graff, Mariaelisa %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Hung, Yi-Jen %A Jackson, Anne U %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kühnel, Brigitte %A Leander, Karin %A Lin, Keng-Hung %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Matoba, Nana %A Nolte, Ilja M %A Pietzner, Maik %A Prins, Bram %A Riaz, Muhammad %A Robino, Antonietta %A Said, M Abdullah %A Schupf, Nicole %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Wang, Tzung-Dau %A Wang, Yajuan %A Ware, Erin B %A Wen, Wanqing %A Xiang, Yong-Bing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Adeyemo, Adebowale %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Arzumanyan, Zorayr %A Aung, Tin %A Ballantyne, Christie %A Barr, R Graham %A Bielak, Lawrence F %A Eric Boerwinkle %A Bottinger, Erwin P %A Broeckel, Ulrich %A Brown, Morris %A Cade, Brian E %A Campbell, Archie %A Canouil, Mickaël %A Charumathi, Sabanayagam %A Chen, Yii-Der Ida %A Christensen, Kaare %A Concas, Maria Pina %A Connell, John M %A de Las Fuentes, Lisa %A de Silva, H Janaka %A de Vries, Paul S %A Doumatey, Ayo %A Duan, Qing %A Eaton, Charles B %A Eppinga, Ruben N %A Faul, Jessica D %A Floyd, James S %A Forouhi, Nita G %A Forrester, Terrence %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gharib, Sina A %A Gigante, Bruna %A Giulianini, Franco %A Grabe, Hans J %A Gu, C Charles %A Harris, Tamara B %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hixson, James E %A Ikram, M Arfan %A Jia, Yucheng %A Joehanes, Roby %A Johnson, Craig %A Jonas, Jost Bruno %A Justice, Anne E %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Kolcic, Ivana %A Kooperberg, Charles %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Liang, Jingjing %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Kiang %A Loh, Marie %A Lohman, Kurt K %A Louie, Tin %A Luzzi, Anna %A Mägi, Reedik %A Mahajan, Anubha %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Morris, Andrew P %A Murray, Alison D %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Papanicolau, George J %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Poulter, Neil %A Raitakari, Olli T %A Reiner, Alex P %A Renstrom, Frida %A Rice, Treva K %A Rich, Stephen S %A Robinson, Jennifer G %A Rose, Lynda M %A Rosendaal, Frits R %A Rudan, Igor %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Tiemeier, Henning %A Turner, Stephen T %A Uitterlinden, André G %A van Heemst, Diana %A Waldenberger, Melanie %A Wang, Heming %A Wang, Lan %A Wang, Lihua %A Wei, Wen Bin %A Williams, Christine A %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Young, Kristin %A Yu, Caizheng %A Yuan, Jian-Min %A Zhou, Jie %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Cooper, Richard S %A de Faire, Ulf %A Deary, Ian J %A Elliott, Paul %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo L %A Juang, Jyh-Ming Jimmy %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Laurie, Cathy C %A Lee, I-Te %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Pereira, Alexandre C %A Rauramaa, Rainer %A Redline, Susan %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wang, Jun-Sing %A Wang, Ya Xing %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zeggini, Eleftheria %A Zheng, Wei %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Liu, Yongmei %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Province, Michael A %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Franceschini, Nora %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Rao, Dabeeru C %A Rotimi, Charles N %A Cupples, L Adrienne %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Life Style %K Linkage Disequilibrium %K Lipids %K Male %K Middle Aged %K Smoking %K Young Adult %X

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

%B Nat Genet %V 51 %P 636-648 %8 2019 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/30926973?dopt=Abstract %R 10.1038/s41588-019-0378-y %0 Journal Article %J Hum Mol Genet %D 2019 %T A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure. %A Sung, Yun Ju %A de Las Fuentes, Lisa %A Winkler, Thomas W %A Chasman, Daniel I %A Bentley, Amy R %A Kraja, Aldi T %A Ntalla, Ioanna %A Warren, Helen R %A Guo, Xiuqing %A Schwander, Karen %A Manning, Alisa K %A Brown, Michael R %A Aschard, Hugues %A Feitosa, Mary F %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Aslibekyan, Stella %A Bartz, Traci M %A Dorajoo, Rajkumar %A Li, Changwei %A Liu, Yongmei %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kammerer, Candace M %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kühnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A McKenzie, Colin A %A Nelson, Christopher P %A Noordam, Raymond %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Waken, Robert J %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan E %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Eric Boerwinkle %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cade, Brian %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Gu, C Charles %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven C %A Irvin, Marguerite R %A Jia, Yucheng %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Kooperberg, Charles B %A Krieger, Jose E %A Kubo, Michiaki %A Kutalik, Zoltán %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Joseph H %A Lehne, Benjamin %A Levy, Daniel %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Louie, Tin %A Mägi, Reedik %A Matsuda, Koichi %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Mosley, Thomas H %A Nalls, Mike A %A Nasri, Ubaydah %A O'Connell, Jeff R %A Ogunniyi, Adesola %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Sims, Mario %A Sitlani, Colleen M %A Smith, Blair H %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Wilson, Gregory %A Wojczynski, Mary K %A Xiang, Yong-Bing %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A Weir, David R %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost Bruno %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Perls, Thomas %A Rauramaa, Rainer %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Hixson, James %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Psaty, Bruce M %A van Dam, Rob M %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotimi, Charles N %A Bierut, Laura J %A Zhu, Xiaofeng %A Cupples, L Adrienne %A Province, Michael A %A Rotter, Jerome I %A Franks, Paul W %A Rice, Kenneth %A Elliott, Paul %A Caulfield, Mark J %A Gauderman, W James %A Munroe, Patricia B %A Rao, Dabeeru C %A Morrison, Alanna C %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Antiporters %K Arterial Pressure %K Blood Pressure %K Caspase 9 %K Ethnicity %K Female %K Gene-Environment Interaction %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Membrane Proteins %K Middle Aged %K Polymorphism, Genetic %K Racial Groups %K Receptors, Vasopressin %K Smoking %K Sulfate Transporters %K Tumor Suppressor Proteins %K Young Adult %X

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

%B Hum Mol Genet %V 28 %P 2615-2633 %8 2019 Aug 01 %G eng %N 15 %1 https://www.ncbi.nlm.nih.gov/pubmed/31127295?dopt=Abstract %R 10.1093/hmg/ddz070 %0 Journal Article %J Nat Commun %D 2019 %T Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. %A Noordam, Raymond %A Bos, Maxime M %A Wang, Heming %A Winkler, Thomas W %A Bentley, Amy R %A Kilpeläinen, Tuomas O %A de Vries, Paul S %A Sung, Yun Ju %A Schwander, Karen %A Cade, Brian E %A Manning, Alisa %A Aschard, Hugues %A Brown, Michael R %A Chen, Han %A Franceschini, Nora %A Musani, Solomon K %A Richard, Melissa %A Vojinovic, Dina %A Aslibekyan, Stella %A Bartz, Traci M %A de Las Fuentes, Lisa %A Feitosa, Mary %A Horimoto, Andrea R %A Ilkov, Marjan %A Kho, Minjung %A Kraja, Aldi %A Li, Changwei %A Lim, Elise %A Liu, Yongmei %A Mook-Kanamori, Dennis O %A Rankinen, Tuomo %A Tajuddin, Salman M %A van der Spek, Ashley %A Wang, Zhe %A Marten, Jonathan %A Laville, Vincent %A Alver, Maris %A Evangelou, Evangelos %A Graff, Maria E %A He, Meian %A Kühnel, Brigitte %A Lyytikäinen, Leo-Pekka %A Marques-Vidal, Pedro %A Nolte, Ilja M %A Palmer, Nicholette D %A Rauramaa, Rainer %A Shu, Xiao-Ou %A Snieder, Harold %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Adolfo, Correa %A Ballantyne, Christie %A Bielak, Larry %A Biermasz, Nienke R %A Eric Boerwinkle %A Dimou, Niki %A Eiriksdottir, Gudny %A Gao, Chuan %A Gharib, Sina A %A Gottlieb, Daniel J %A Haba-Rubio, José %A Harris, Tamara B %A Heikkinen, Sami %A Heinzer, Raphaël %A Hixson, James E %A Homuth, Georg %A Ikram, M Arfan %A Komulainen, Pirjo %A Krieger, Jose E %A Lee, Jiwon %A Liu, Jingmin %A Lohman, Kurt K %A Luik, Annemarie I %A Mägi, Reedik %A Martin, Lisa W %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Nalls, Mike A %A O'Connell, Jeff %A Peters, Annette %A Peyser, Patricia %A Raitakari, Olli T %A Reiner, Alex P %A Rensen, Patrick C N %A Rice, Treva K %A Rich, Stephen S %A Roenneberg, Till %A Rotter, Jerome I %A Schreiner, Pamela J %A Shikany, James %A Sidney, Stephen S %A Sims, Mario %A Sitlani, Colleen M %A Sofer, Tamar %A Strauch, Konstantin %A Swertz, Morris A %A Taylor, Kent D %A Uitterlinden, André G %A van Duijn, Cornelia M %A Völzke, Henry %A Waldenberger, Melanie %A Wallance, Robert B %A van Dijk, Ko Willems %A Yu, Caizheng %A Zonderman, Alan B %A Becker, Diane M %A Elliott, Paul %A Esko, Tõnu %A Gieger, Christian %A Grabe, Hans J %A Lakka, Timo A %A Lehtimäki, Terho %A North, Kari E %A Penninx, Brenda W J H %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wu, Tangchun %A Xiang, Yong-Bing %A Zheng, Wei %A Arnett, Donna K %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon %A Kelly, Tanika N %A Kritchevsky, Stephen B %A Loos, Ruth J F %A Pereira, Alexandre C %A Province, Mike %A Psaty, Bruce M %A Rotimi, Charles %A Zhu, Xiaofeng %A Amin, Najaf %A Cupples, L Adrienne %A Fornage, Myriam %A Fox, Ervin F %A Guo, Xiuqing %A Gauderman, W James %A Rice, Kenneth %A Kooperberg, Charles %A Munroe, Patricia B %A Liu, Ching-Ti %A Morrison, Alanna C %A Rao, Dabeeru C %A van Heemst, Diana %A Redline, Susan %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Chromosome Mapping %K Female %K Genetic Loci %K Humans %K Lipids %K Male %K Middle Aged %K Phylogeny %K Polymorphism, Single Nucleotide %K Sleep %K Young Adult %X

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

%B Nat Commun %V 10 %P 5121 %8 2019 Nov 12 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31719535?dopt=Abstract %R 10.1038/s41467-019-12958-0 %0 Journal Article %J Nat Commun %D 2019 %T Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. %A Kilpeläinen, Tuomas O %A Bentley, Amy R %A Noordam, Raymond %A Sung, Yun Ju %A Schwander, Karen %A Winkler, Thomas W %A Jakupović, Hermina %A Chasman, Daniel I %A Manning, Alisa %A Ntalla, Ioanna %A Aschard, Hugues %A Brown, Michael R %A de Las Fuentes, Lisa %A Franceschini, Nora %A Guo, Xiuqing %A Vojinovic, Dina %A Aslibekyan, Stella %A Feitosa, Mary F %A Kho, Minjung %A Musani, Solomon K %A Richard, Melissa %A Wang, Heming %A Wang, Zhe %A Bartz, Traci M %A Bielak, Lawrence F %A Campbell, Archie %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Li, Changwei %A Lohman, Kurt K %A Marten, Jonathan %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Graff, Mariaelisa %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Zhao, Jing Hua %A Kraja, Aldi T %A Kühnel, Brigitte %A Laguzzi, Federica %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Rueedi, Rico %A Stringham, Heather M %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Verweij, Niek %A Ware, Erin B %A Wen, Wanqing %A Li, Xiaoyin %A Yanek, Lisa R %A Amin, Najaf %A Arnett, Donna K %A Eric Boerwinkle %A Brumat, Marco %A Cade, Brian %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Concas, Maria Pina %A Connell, John %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Demirkan, Ayse %A Ding, Jingzhong %A Eaton, Charles B %A Faul, Jessica D %A Friedlander, Yechiel %A Gabriel, Kelley P %A Ghanbari, Mohsen %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven C %A Ikram, M Arfan %A Jonas, Jost B %A Koh, Woon-Puay %A Komulainen, Pirjo %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Leander, Karin %A Lemaitre, Rozenn N %A Lewis, Cora E %A Liang, Jingjing %A Liu, Jianjun %A Mägi, Reedik %A Manichaikul, Ani %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Mohlke, Karen L %A Mosley, Thomas H %A Murray, Alison D %A Nalls, Mike A %A Nang, Ei-Ei Khaing %A Nelson, Christopher P %A Nona, Sotoodehnia %A Norris, Jill M %A Nwuba, Chiamaka Vivian %A O'Connell, Jeff %A Palmer, Nicholette D %A Papanicolau, George J %A Pazoki, Raha %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David J %A Poveda, Alaitz %A Raitakari, Olli T %A Rich, Stephen S %A Risch, Neil %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schreiner, Pamela J %A Scott, Robert A %A Sidney, Stephen S %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Sofer, Tamar %A Starr, John M %A Sternfeld, Barbara %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Tsai, Michael Y %A Tuomilehto, Jaakko %A Uitterlinden, André G %A van der Ende, M Yldau %A van Heemst, Diana %A Voortman, Trudy %A Waldenberger, Melanie %A Wennberg, Patrik %A Wilson, Gregory %A Xiang, Yong-Bing %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A de Faire, Ulf %A Deary, Ian J %A Elliott, Paul %A Esko, Tõnu %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Kato, Norihiro %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Samani, Nilesh J %A Shu, Xiao-Ou %A van der Harst, Pim %A Van Vliet-Ostaptchouk, Jana V %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wang, Ya X %A Wareham, Nicholas J %A Weir, David R %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Evans, Michele K %A Franks, Paul W %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kelly, Tanika N %A Liu, Yongmei %A North, Kari E %A Pereira, Alexandre C %A Ridker, Paul M %A Tai, E Shyong %A van Dam, Rob M %A Fox, Ervin R %A Kardia, Sharon L R %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Province, Michael A %A Redline, Susan %A van Duijn, Cornelia M %A Rotter, Jerome I %A Kooperberg, Charles B %A Gauderman, W James %A Psaty, Bruce M %A Rice, Kenneth %A Munroe, Patricia B %A Fornage, Myriam %A Cupples, L Adrienne %A Rotimi, Charles N %A Morrison, Alanna C %A Rao, Dabeeru C %A Loos, Ruth J F %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Asian People %K Black People %K Brazil %K Calcium-Binding Proteins %K Cholesterol %K Cholesterol, HDL %K Cholesterol, LDL %K Exercise %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Hispanic or Latino %K Humans %K LIM-Homeodomain Proteins %K Lipid Metabolism %K Lipids %K Male %K Membrane Proteins %K Microtubule-Associated Proteins %K Middle Aged %K Muscle Proteins %K Nerve Tissue Proteins %K Transcription Factors %K Triglycerides %K White People %K Young Adult %X

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

%B Nat Commun %V 10 %P 376 %8 2019 Jan 22 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30670697?dopt=Abstract %R 10.1038/s41467-018-08008-w %0 Journal Article %J Nat Genet %D 2019 %T Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Esko, Tõnu %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Manning, Alisa K %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Winkler, Thomas W %A Abecasis, Goncalo %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Allison, Matthew %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Butterworth, Adam S %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der I %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Galbany, Jordi Corominas %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Davies, Gail %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A Heijer, Martin %A Hollander, Anneke I %A Ruijter, Hester M %A Dennis, Joe G %A Denny, Josh C %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dube, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Faul, Jessica D %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrieres, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grabe, Hans-Jörgen %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeff %A Hakonarson, Hakon %A Hammerschlag, Anke R %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Have, Christian T %A Hayward, Caroline %A He, Liang %A Heard-Costa, Nancy L %A Heath, Andrew C %A Heid, Iris M %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Kiemeney, Lambertus A %A Kim, Eric %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Kooperberg, Charles %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Lange, Leslie A %A Langenberg, Claudia %A Larson, Eric B %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Liu, Yongmei %A Lo, Ken S %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Medland, Sarah E %A Meidtner, Karina %A Milani, Lili %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Nyholt, Dale R %A O'Connel, Jeffrey R %A O'Donoghue, Michelle L %A Loohuis, Loes M Olde %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Polderman, Tinca J %A Puolijoki, Hannu %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Robertson, Neil R %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati H %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Smith, Albert V %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen E %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Edwards, Digna R Velez %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Ware, Erin B %A Wareham, Nicholas J %A Warren, Helen R %A Waterworth, Dawn M %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Witte, Daniel R %A Wood, Andrew R %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhao, Wei %A Zhou, Wei %A Zondervan, Krina T %A Rotter, Jerome I %A Pospisilik, John A %A Rivadeneira, Fernando %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Lettre, Guillaume %A North, Kari E %A Lindgren, Cecilia M %A Hirschhorn, Joel N %A Loos, Ruth J F %X

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

%B Nat Genet %V 51 %P 1191-1192 %8 2019 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/31160809?dopt=Abstract %R 10.1038/s41588-019-0447-2 %0 Journal Article %J Blood %D 2018 %T DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. %A Ward-Caviness, Cavin K %A Huffman, Jennifer E %A Everett, Karl %A Germain, Marine %A van Dongen, Jenny %A Hill, W David %A Jhun, Min A %A Brody, Jennifer A %A Ghanbari, Mohsen %A Du, Lei %A Roetker, Nicholas S %A de Vries, Paul S %A Waldenberger, Melanie %A Gieger, Christian %A Wolf, Petra %A Prokisch, Holger %A Koenig, Wolfgang %A O'Donnell, Christopher J %A Levy, Daniel %A Liu, Chunyu %A Truong, Vinh %A Wells, Philip S %A Trégouët, David-Alexandre %A Tang, Weihong %A Morrison, Alanna C %A Eric Boerwinkle %A Wiggins, Kerri L %A McKnight, Barbara %A Guo, Xiuqing %A Psaty, Bruce M %A Sotoodenia, Nona %A Boomsma, Dorret I %A Willemsen, Gonneke %A Ligthart, Lannie %A Deary, Ian J %A Zhao, Wei %A Ware, Erin B %A Kardia, Sharon L R %A van Meurs, Joyce B J %A Uitterlinden, André G %A Franco, Oscar H %A Eriksson, Per %A Franco-Cereceda, Anders %A Pankow, James S %A Johnson, Andrew D %A Gagnon, France %A Morange, Pierre-Emmanuel %A de Geus, Eco J C %A Starr, John M %A Smith, Jennifer A %A Dehghan, Abbas %A Björck, Hanna M %A Smith, Nicholas L %A Peters, Annette %K Aging %K DNA Methylation %K Epigenesis, Genetic %K Hemostasis %K Humans %X

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; = 6.6 10) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene () and the 3 fibrinogen subunit-encoding genes (, , and ) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

%B Blood %V 132 %P 1842-1850 %8 2018 Oct 25 %G eng %N 17 %1 https://www.ncbi.nlm.nih.gov/pubmed/30042098?dopt=Abstract %R 10.1182/blood-2018-02-831347 %0 Journal Article %J Nat Genet %D 2018 %T Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stephanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Eric Boerwinkle %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A de Borst, Martin H %A de Geus, Eco J %A Deary, Ian J %A Deelen, Joris %A Del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Jarvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Åsa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %K Adult %K Aged %K Aged, 80 and over %K Blood Pressure %K Cardiovascular Diseases %K Cells, Cultured %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Testing %K Genetics, Population %K Genome-Wide Association Study %K Human Umbilical Vein Endothelial Cells %K Humans %K Hypertension %K Life Style %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %X

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/30224653?dopt=Abstract %R 10.1038/s41588-018-0205-x %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, René %A Zhu, Gu %A Macé, Aurélien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A Del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michele M %A Chen, Yii-Der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A Marz, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Eric Boerwinkle %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Biomarkers %K Bipolar Disorder %K Body Mass Index %K C-Reactive Protein %K Child %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Inflammation %K Liver %K Male %K Mendelian Randomization Analysis %K Metabolic Networks and Pathways %K Middle Aged %K Schizophrenia %K Young Adult %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/30388399?dopt=Abstract %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J PLoS One %D 2018 %T Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. %A Feitosa, Mary F %A Kraja, Aldi T %A Chasman, Daniel I %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Bentley, Amy R %A Brown, Michael R %A Schwander, Karen %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Wojczynski, Mary K %A Alver, Maris %A Boissel, Mathilde %A Cai, Qiuyin %A Campbell, Archie %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kühnel, Brigitte %A Laguzzi, Federica %A Luan, Jian'an %A Matoba, Nana %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Riaz, Muhammad %A Rueedi, Rico %A Robino, Antonietta %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Vitart, Veronique %A Wang, Yajuan %A Ware, Erin B %A Warren, Helen R %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Eric Boerwinkle %A Borecki, Ingrid %A Broeckel, Ulrich %A Brown, Morris %A Brumat, Marco %A Burke, Gregory L %A Canouil, Mickaël %A Chakravarti, Aravinda %A Charumathi, Sabanayagam %A Ida Chen, Yii-Der %A Connell, John M %A Correa, Adolfo %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Deng, Xuan %A Ding, Jingzhong %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Eppinga, Ruben N %A Evangelou, Evangelos %A Faul, Jessica D %A Felix, Stephan B %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gigante, Bruna %A Gu, C Charles %A Gu, Dongfeng %A Hagenaars, Saskia P %A Hallmans, Goran %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Howard, Barbara V %A Ikram, M Arfan %A John, Ulrich %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lin, Shiow %A Liu, Jianjun %A Liu, Jingmin %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Nalls, Mike A %A Nelson, Christopher P %A Sotoodehnia, Nona %A Norris, Jill M %A O'Connell, Jeff R %A Palmer, Nicholette D %A Perls, Thomas %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Roll, Kathryn %A Rose, Lynda M %A Rosendaal, Frits R %A Rotter, Jerome I %A Schmidt, Carsten O %A Schreiner, Pamela J %A Schupf, Nicole %A Scott, William R %A Sever, Peter S %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Turner, Stephen T %A Uitterlinden, André G %A Vollenweider, Peter %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Williams, Christine %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Kutalik, Zoltán %A Laakso, Markku %A Laurie, Cathy C %A Leander, Karin %A Lehtimäki, Terho %A Study, Lifelines Cohort %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Polasek, Ozren %A Porteous, David J %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Bouchard, Claude %A Christensen, Kaare %A Evans, Michele K %A Gudnason, Vilmundur %A Horta, Bernardo L %A Kardia, Sharon L R %A Liu, Yongmei %A Pereira, Alexandre C %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Gauderman, W James %A Zhu, Xiaofeng %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Rotimi, Charles N %A Cupples, L Adrienne %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Kooperberg, Charles %A Palmas, Walter %A Rice, Kenneth %A Morrison, Alanna C %A Elliott, Paul %A Caulfield, Mark J %A Munroe, Patricia B %A Rao, Dabeeru C %A Province, Michael A %A Levy, Daniel %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Alcohol Drinking %K Blood Pressure %K Cohort Studies %K Female %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Pedigree %K Polymorphism, Single Nucleotide %K Racial Groups %K Young Adult %X

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

%B PLoS One %V 13 %P e0198166 %8 2018 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/29912962?dopt=Abstract %R 10.1371/journal.pone.0198166 %0 Journal Article %J Nat Genet %D 2018 %T Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Esko, Tõnu %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Manning, Alisa K %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Winkler, Thomas W %A Abecasis, Goncalo %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Allison, Matthew %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Butterworth, Adam S %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der I %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Corominas Galbany, Jordi %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Davies, Gail %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A Heijer, Martin %A Hollander, Anneke I %A Ruijter, Hester M %A Dennis, Joe G %A Denny, Josh C %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dube, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Faul, Jessica D %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrieres, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grabe, Hans-Jörgen %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeff %A Hakonarson, Hakon %A Hammerschlag, Anke R %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Have, Christian T %A Hayward, Caroline %A He, Liang %A Heard-Costa, Nancy L %A Heath, Andrew C %A Heid, Iris M %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Kiemeney, Lambertus A %A Kim, Eric %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Kooperberg, Charles %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Lange, Leslie A %A Langenberg, Claudia %A Larson, Eric B %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Liu, Yongmei %A Lo, Ken S %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Medland, Sarah E %A Meidtner, Karina %A Milani, Lili %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Nyholt, Dale R %A O'Connel, Jeffrey R %A O'Donoghue, Michelle L %A Olde Loohuis, Loes M %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Polderman, Tinca J %A Puolijoki, Hannu %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Robertson, Neil R %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati H %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Smith, Albert V %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen E %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Velez Edwards, Digna R %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Ware, Erin B %A Wareham, Nicholas J %A Warren, Helen R %A Waterworth, Dawn M %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Witte, Daniel R %A Wood, Andrew R %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhao, Wei %A Zhou, Wei %A Zondervan, Krina T %A Rotter, Jerome I %A Pospisilik, John A %A Rivadeneira, Fernando %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Lettre, Guillaume %A North, Kari E %A Lindgren, Cecilia M %A Hirschhorn, Joel N %A Loos, Ruth J F %K Adult %K Animals %K Body Mass Index %K Drosophila %K Energy Intake %K Energy Metabolism %K Female %K Gene Frequency %K Genetic Variation %K Humans %K Male %K Obesity %K Proteins %K Syndrome %X

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

%B Nat Genet %V 50 %P 26-41 %8 2018 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29273807?dopt=Abstract %R 10.1038/s41588-017-0011-x %0 Journal Article %J Nat Genet %D 2018 %T Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stephanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Eric Boerwinkle %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A de Borst, Martin H %A de Geus, Eco J %A Deary, Ian J %A Deelen, Joris %A Del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Jarvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Åsa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %X

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

%B Nat Genet %V 50 %P 1755 %8 2018 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/30429575?dopt=Abstract %R 10.1038/s41588-018-0297-3 %0 Journal Article %J Nat Genet %D 2018 %T Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Esko, Tõnu %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Manning, Alisa K %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Winkler, Thomas W %A Abecasis, Goncalo %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Allison, Matthew %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Butterworth, Adam S %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der I %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Corominas Galbany, Jordi %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Davies, Gail %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A Heijer, Martin %A Hollander, Anneke I %A Ruijter, Hester M %A Dennis, Joe G %A Denny, Josh C %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dube, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Faul, Jessica D %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrieres, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grabe, Hans-Jörgen %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeff %A Hakonarson, Hakon %A Hammerschlag, Anke R %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Have, Christian T %A Hayward, Caroline %A He, Liang %A Heard-Costa, Nancy L %A Heath, Andrew C %A Heid, Iris M %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Kiemeney, Lambertus A %A Kim, Eric %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Kooperberg, Charles %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Lange, Leslie A %A Langenberg, Claudia %A Larson, Eric B %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Liu, Yongmei %A Lo, Ken S %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Medland, Sarah E %A Meidtner, Karina %A Milani, Lili %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Nyholt, Dale R %A O'Connel, Jeffrey R %A O'Donoghue, Michelle L %A Olde Loohuis, Loes M %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Polderman, Tinca J %A Puolijoki, Hannu %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Robertson, Neil R %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati H %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Smith, Albert V %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen E %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Velez Edwards, Digna R %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Ware, Erin B %A Wareham, Nicholas J %A Warren, Helen R %A Waterworth, Dawn M %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Witte, Daniel R %A Wood, Andrew R %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhao, Wei %A Zhou, Wei %A Zondervan, Krina T %A Rotter, Jerome I %A Pospisilik, John A %A Rivadeneira, Fernando %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Lettre, Guillaume %A North, Kari E %A Lindgren, Cecilia M %A Hirschhorn, Joel N %A Loos, Ruth J F %X

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

%B Nat Genet %V 50 %P 766-767 %8 2018 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29549330?dopt=Abstract %R 10.1038/s41588-018-0082-3 %0 Journal Article %J Nat Genet %D 2018 %T Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Esko, Tõnu %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Manning, Alisa K %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Winkler, Thomas W %A Abecasis, Goncalo %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Allison, Matthew %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Butterworth, Adam S %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der I %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Corominas Galbany, Jordi %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Davies, Gail %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A Heijer, Martin %A Hollander, Anneke I %A Ruijter, Hester M %A Dennis, Joe G %A Denny, Josh C %A Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dube, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Faul, Jessica D %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrieres, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grabe, Hans-Jörgen %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeff %A Hakonarson, Hakon %A Hammerschlag, Anke R %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Have, Christian T %A Hayward, Caroline %A He, Liang %A Heard-Costa, Nancy L %A Heath, Andrew C %A Heid, Iris M %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Kiemeney, Lambertus A %A Kim, Eric %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Kooperberg, Charles %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Lange, Leslie A %A Langenberg, Claudia %A Larson, Eric B %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Liu, Yongmei %A Lo, Ken S %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Medland, Sarah E %A Meidtner, Karina %A Milani, Lili %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Nyholt, Dale R %A O'Connel, Jeffrey R %A O'Donoghue, Michelle L %A Olde Loohuis, Loes M %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Polderman, Tinca J %A Puolijoki, Hannu %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Robertson, Neil R %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati H %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Smith, Albert V %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen E %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Velez Edwards, Digna R %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Ware, Erin B %A Wareham, Nicholas J %A Warren, Helen R %A Waterworth, Dawn M %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Witte, Daniel R %A Wood, Andrew R %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhou, Wei %A Zondervan, Krina T %A Rotter, Jerome I %A Pospisilik, John A %A Rivadeneira, Fernando %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Lettre, Guillaume %A North, Kari E %A Lindgren, Cecilia M %A Hirschhorn, Joel N %A Loos, Ruth J F %X

In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article.

%B Nat Genet %V 50 %P 765-766 %8 2018 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29549329?dopt=Abstract %R 10.1038/s41588-018-0050-y %0 Journal Article %J Nat Genet %D 2018 %T Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. %A Mahajan, Anubha %A Wessel, Jennifer %A Willems, Sara M %A Zhao, Wei %A Robertson, Neil R %A Chu, Audrey Y %A Gan, Wei %A Kitajima, Hidetoshi %A Taliun, Daniel %A Rayner, N William %A Guo, Xiuqing %A Lu, Yingchang %A Li, Man %A Jensen, Richard A %A Hu, Yao %A Huo, Shaofeng %A Lohman, Kurt K %A Zhang, Weihua %A Cook, James P %A Prins, Bram Peter %A Flannick, Jason %A Grarup, Niels %A Trubetskoy, Vassily Vladimirovich %A Kravic, Jasmina %A Kim, Young Jin %A Rybin, Denis V %A Yaghootkar, Hanieh %A Müller-Nurasyid, Martina %A Meidtner, Karina %A Li-Gao, Ruifang %A Varga, Tibor V %A Marten, Jonathan %A Li, Jin %A Smith, Albert Vernon %A An, Ping %A Ligthart, Symen %A Gustafsson, Stefan %A Malerba, Giovanni %A Demirkan, Ayse %A Tajes, Juan Fernandez %A Steinthorsdottir, Valgerdur %A Wuttke, Matthias %A Lecoeur, Cécile %A Preuss, Michael %A Bielak, Lawrence F %A Graff, Marielisa %A Highland, Heather M %A Justice, Anne E %A Liu, Dajiang J %A Marouli, Eirini %A Peloso, Gina Marie %A Warren, Helen R %A Afaq, Saima %A Afzal, Shoaib %A Ahlqvist, Emma %A Almgren, Peter %A Amin, Najaf %A Bang, Lia B %A Bertoni, Alain G %A Bombieri, Cristina %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Burtt, Noël P %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Cho, Yoon Shin %A Christensen, Cramer %A Eastwood, Sophie V %A Eckardt, Kai-Uwe %A Fischer, Krista %A Gambaro, Giovanni %A Giedraitis, Vilmantas %A Grove, Megan L %A de Haan, Hugoline G %A Hackinger, Sophie %A Hai, Yang %A Han, Sohee %A Tybjærg-Hansen, Anne %A Hivert, Marie-France %A Isomaa, Bo %A Jäger, Susanne %A Jørgensen, Marit E %A Jørgensen, Torben %A Käräjämäki, Annemari %A Kim, Bong-Jo %A Kim, Sung Soo %A Koistinen, Heikki A %A Kovacs, Peter %A Kriebel, Jennifer %A Kronenberg, Florian %A Läll, Kristi %A Lange, Leslie A %A Lee, Jung-Jin %A Lehne, Benjamin %A Li, Huaixing %A Lin, Keng-Hung %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jun %A Loh, Marie %A Mägi, Reedik %A Mamakou, Vasiliki %A McKean-Cowdin, Roberta %A Nadkarni, Girish %A Neville, Matt %A Nielsen, Sune F %A Ntalla, Ioanna %A Peyser, Patricia A %A Rathmann, Wolfgang %A Rice, Kenneth %A Rich, Stephen S %A Rode, Line %A Rolandsson, Olov %A Schönherr, Sebastian %A Selvin, Elizabeth %A Small, Kerrin S %A Stančáková, Alena %A Surendran, Praveen %A Taylor, Kent D %A Teslovich, Tanya M %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tin, Adrienne %A Tonjes, Anke %A Varbo, Anette %A Witte, Daniel R %A Wood, Andrew R %A Yajnik, Pranav %A Yao, Jie %A Yengo, Loic %A Young, Robin %A Amouyel, Philippe %A Boeing, Heiner %A Eric Boerwinkle %A Bottinger, Erwin P %A Chowdhury, Rajiv %A Collins, Francis S %A Dedoussis, George %A Dehghan, Abbas %A Deloukas, Panos %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Frossard, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Heckbert, Susan R %A Howson, Joanna M M %A Ingelsson, Martin %A Kathiresan, Sekar %A Kee, Frank %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lindgren, Cecilia M %A Männistö, Satu %A Meitinger, Thomas %A Melander, Olle %A Mohlke, Karen L %A Moitry, Marie %A Morris, Andrew D %A Murray, Alison D %A de Mutsert, Renée %A Orho-Melander, Marju %A Owen, Katharine R %A Perola, Markus %A Peters, Annette %A Province, Michael A %A Rasheed, Asif %A Ridker, Paul M %A Rivadineira, Fernando %A Rosendaal, Frits R %A Rosengren, Anders H %A Salomaa, Veikko %A Sheu, Wayne H-H %A Sladek, Rob %A Smith, Blair H %A Strauch, Konstantin %A Uitterlinden, André G %A Varma, Rohit %A Willer, Cristen J %A Blüher, Matthias %A Butterworth, Adam S %A Chambers, John Campbell %A Chasman, Daniel I %A Danesh, John %A van Duijn, Cornelia %A Dupuis, Josée %A Franco, Oscar H %A Franks, Paul W %A Froguel, Philippe %A Grallert, Harald %A Groop, Leif %A Han, Bok-Ghee %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Ingelsson, Erik %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal Singh %A Köttgen, Anna %A Kuulasmaa, Kari %A Laakso, Markku %A Lin, Xu %A Lind, Lars %A Liu, Yongmei %A Loos, Ruth J F %A Marchini, Jonathan %A Metspalu, Andres %A Mook-Kanamori, Dennis %A Nordestgaard, Børge G %A Palmer, Colin N A %A Pankow, James S %A Pedersen, Oluf %A Psaty, Bruce M %A Rauramaa, Rainer %A Sattar, Naveed %A Schulze, Matthias B %A Soranzo, Nicole %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Thorsteinsdottir, Unnur %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wareham, Nicholas J %A Wilson, James G %A Zeggini, Eleftheria %A Scott, Robert A %A Barroso, Inês %A Frayling, Timothy M %A Goodarzi, Mark O %A Meigs, James B %A Boehnke, Michael %A Saleheen, Danish %A Morris, Andrew P %A Rotter, Jerome I %A McCarthy, Mark I %K Alleles %K Chromosome Mapping %K Diabetes Mellitus, Type 2 %K Exome Sequencing %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K White People %X

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

%B Nat Genet %V 50 %P 559-571 %8 2018 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/29632382?dopt=Abstract %R 10.1038/s41588-018-0084-1 %0 Journal Article %J Nat Genet %D 2017 %T Exome-wide association study of plasma lipids in >300,000 individuals. %A Liu, Dajiang J %A Peloso, Gina M %A Yu, Haojie %A Butterworth, Adam S %A Wang, Xiao %A Mahajan, Anubha %A Saleheen, Danish %A Emdin, Connor %A Alam, Dewan %A Alves, Alexessander Couto %A Amouyel, Philippe %A Di Angelantonio, Emanuele %A Arveiler, Dominique %A Assimes, Themistocles L %A Auer, Paul L %A Baber, Usman %A Ballantyne, Christie M %A Bang, Lia E %A Benn, Marianne %A Bis, Joshua C %A Boehnke, Michael %A Eric Boerwinkle %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Brandslund, Ivan %A Brown, Morris %A Busonero, Fabio %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Y Eugene %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Connell, John M %A Cucca, Francesco %A Cupples, L Adrienne %A Damrauer, Scott M %A Davies, Gail %A Deary, Ian J %A Dedoussis, George %A Denny, Joshua C %A Dominiczak, Anna %A Dube, Marie-Pierre %A Ebeling, Tapani %A Eiriksdottir, Gudny %A Esko, Tõnu %A Farmaki, Aliki-Eleni %A Feitosa, Mary F %A Ferrario, Marco %A Ferrieres, Jean %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Frayling, Timothy M %A Frikke-Schmidt, Ruth %A Fritsche, Lars G %A Frossard, Philippe %A Fuster, Valentin %A Ganesh, Santhi K %A Gao, Wei %A Garcia, Melissa E %A Gieger, Christian %A Giulianini, Franco %A Goodarzi, Mark O %A Grallert, Harald %A Grarup, Niels %A Groop, Leif %A Grove, Megan L %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hirschhorn, Joel N %A Holmen, Oddgeir L %A Huffman, Jennifer %A Huo, Yong %A Hveem, Kristian %A Jabeen, Sehrish %A Jackson, Anne U %A Jakobsdottir, Johanna %A Jarvelin, Marjo-Riitta %A Jensen, Gorm B %A Jørgensen, Marit E %A Jukema, J Wouter %A Justesen, Johanne M %A Kamstrup, Pia R %A Kanoni, Stavroula %A Karpe, Fredrik %A Kee, Frank %A Khera, Amit V %A Klarin, Derek %A Koistinen, Heikki A %A Kooner, Jaspal S %A Kooperberg, Charles %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo %A Langenberg, Claudia %A Langsted, Anne %A Launer, Lenore J %A Lauritzen, Torsten %A Liewald, David C M %A Lin, Li An %A Linneberg, Allan %A Loos, Ruth J F %A Lu, Yingchang %A Lu, Xiangfeng %A Mägi, Reedik %A Mälarstig, Anders %A Manichaikul, Ani %A Manning, Alisa K %A Mäntyselkä, Pekka %A Marouli, Eirini %A Masca, Nicholas G D %A Maschio, Andrea %A Meigs, James B %A Melander, Olle %A Metspalu, Andres %A Morris, Andrew P %A Morrison, Alanna C %A Mulas, Antonella %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Neville, Matt J %A Nielsen, Jonas B %A Nielsen, Sune F %A Nordestgaard, Børge G %A Ordovas, Jose M %A Mehran, Roxana %A O'Donnell, Christoper J %A Orho-Melander, Marju %A Molony, Cliona M %A Muntendam, Pieter %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasko, Dorota %A Patel, Aniruddh P %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Pisinger, Charlotta %A Pistis, Giorgio %A Polasek, Ozren %A Poulter, Neil %A Psaty, Bruce M %A Rader, Daniel J %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Rich, Stephen S %A Ridker, Paul M %A Rioux, John D %A Robertson, Neil R %A Roden, Dan M %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sanna, Serena %A Sattar, Naveed %A Schmidt, Ellen M %A Scott, Robert A %A Sever, Peter %A Sevilla, Raquel S %A Shaffer, Christian M %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Smith, Albert V %A Smith, Blair H %A Somayajula, Sangeetha %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stirrups, Kathleen E %A Stitziel, Nathan %A Strauch, Konstantin %A Stringham, Heather M %A Surendran, Praveen %A Tada, Hayato %A Tall, Alan R %A Tang, Hua %A Tardif, Jean-Claude %A Taylor, Kent D %A Trompet, Stella %A Tsao, Philip S %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Van Zuydam, Natalie R %A Varbo, Anette %A Varga, Tibor V %A Virtamo, Jarmo %A Waldenberger, Melanie %A Wang, Nan %A Wareham, Nick J %A Warren, Helen R %A Weeke, Peter E %A Weinstock, Joshua %A Wessel, Jennifer %A Wilson, James G %A Wilson, Peter W F %A Xu, Ming %A Yaghootkar, Hanieh %A Young, Robin %A Zeggini, Eleftheria %A Zhang, He %A Zheng, Neil S %A Zhang, Weihua %A Zhang, Yan %A Zhou, Wei %A Zhou, Yanhua %A Zoledziewska, Magdalena %A Howson, Joanna M M %A Danesh, John %A McCarthy, Mark I %A Cowan, Chad A %A Abecasis, Goncalo %A Deloukas, Panos %A Musunuru, Kiran %A Willer, Cristen J %A Kathiresan, Sekar %K Coronary Artery Disease %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genetic Variation %K Genotype %K Humans %K Lipids %K Macular Degeneration %K Phenotype %K Risk Factors %X

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

%B Nat Genet %V 49 %P 1758-1766 %8 2017 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/29083408?dopt=Abstract %R 10.1038/ng.3977 %0 Journal Article %J Nat Genet %D 2017 %T Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. %A Christophersen, Ingrid E %A Rienstra, Michiel %A Roselli, Carolina %A Yin, Xiaoyan %A Geelhoed, Bastiaan %A Barnard, John %A Lin, Honghuang %A Arking, Dan E %A Smith, Albert V %A Albert, Christine M %A Chaffin, Mark %A Tucker, Nathan R %A Li, Molong %A Klarin, Derek %A Bihlmeyer, Nathan A %A Low, Siew-Kee %A Weeke, Peter E %A Müller-Nurasyid, Martina %A Smith, J Gustav %A Brody, Jennifer A %A Niemeijer, Maartje N %A Dörr, Marcus %A Trompet, Stella %A Huffman, Jennifer %A Gustafsson, Stefan %A Schurmann, Claudia %A Kleber, Marcus E %A Lyytikäinen, Leo-Pekka %A Seppälä, Ilkka %A Malik, Rainer %A Horimoto, Andrea R V R %A Perez, Marco %A Sinisalo, Juha %A Aeschbacher, Stefanie %A Thériault, Sébastien %A Yao, Jie %A Radmanesh, Farid %A Weiss, Stefan %A Teumer, Alexander %A Choi, Seung Hoan %A Weng, Lu-Chen %A Clauss, Sebastian %A Deo, Rajat %A Rader, Daniel J %A Shah, Svati H %A Sun, Albert %A Hopewell, Jemma C %A Debette, Stephanie %A Chauhan, Ganesh %A Yang, Qiong %A Worrall, Bradford B %A Paré, Guillaume %A Kamatani, Yoichiro %A Hagemeijer, Yanick P %A Verweij, Niek %A Siland, Joylene E %A Kubo, Michiaki %A Smith, Jonathan D %A Van Wagoner, David R %A Bis, Joshua C %A Perz, Siegfried %A Psaty, Bruce M %A Ridker, Paul M %A Magnani, Jared W %A Harris, Tamara B %A Launer, Lenore J %A Shoemaker, M Benjamin %A Padmanabhan, Sandosh %A Haessler, Jeffrey %A Bartz, Traci M %A Waldenberger, Melanie %A Lichtner, Peter %A Arendt, Marina %A Krieger, Jose E %A Kähönen, Mika %A Risch, Lorenz %A Mansur, Alfredo J %A Peters, Annette %A Smith, Blair H %A Lind, Lars %A Scott, Stuart A %A Lu, Yingchang %A Bottinger, Erwin B %A Hernesniemi, Jussi %A Lindgren, Cecilia M %A Wong, Jorge A %A Huang, Jie %A Eskola, Markku %A Morris, Andrew P %A Ford, Ian %A Reiner, Alex P %A Delgado, Graciela %A Chen, Lin Y %A Chen, Yii-Der Ida %A Sandhu, Roopinder K %A Li, Man %A Eric Boerwinkle %A Eisele, Lewin %A Lannfelt, Lars %A Rost, Natalia %A Anderson, Christopher D %A Taylor, Kent D %A Campbell, Archie %A Magnusson, Patrik K %A Porteous, David %A Hocking, Lynne J %A Vlachopoulou, Efthymia %A Pedersen, Nancy L %A Nikus, Kjell %A Orho-Melander, Marju %A Hamsten, Anders %A Heeringa, Jan %A Denny, Joshua C %A Kriebel, Jennifer %A Darbar, Dawood %A Newton-Cheh, Christopher %A Shaffer, Christian %A Macfarlane, Peter W %A Heilmann-Heimbach, Stefanie %A Almgren, Peter %A Huang, Paul L %A Sotoodehnia, Nona %A Soliman, Elsayed Z %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Völker, Uwe %A Jöckel, Karl-Heinz %A Sinner, Moritz F %A Lin, Henry J %A Guo, Xiuqing %A Dichgans, Martin %A Ingelsson, Erik %A Kooperberg, Charles %A Melander, Olle %A Loos, Ruth J F %A Laurikka, Jari %A Conen, David %A Rosand, Jonathan %A van der Harst, Pim %A Lokki, Marja-Liisa %A Kathiresan, Sekar %A Pereira, Alexandre %A Jukema, J Wouter %A Hayward, Caroline %A Rotter, Jerome I %A Marz, Winfried %A Lehtimäki, Terho %A Stricker, Bruno H %A Chung, Mina K %A Felix, Stephan B %A Gudnason, Vilmundur %A Alonso, Alvaro %A Roden, Dan M %A Kääb, Stefan %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Tanaka, Toshihiro %A Lunetta, Kathryn L %A Lubitz, Steven A %A Ellinor, Patrick T %K Atrial Fibrillation %K Black or African American %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Quantitative Trait Loci %K White People %X

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

%B Nat Genet %V 49 %P 946-952 %8 2017 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/28416818?dopt=Abstract %R 10.1038/ng.3843 %0 Journal Article %J Aging (Albany NY) %D 2016 %T DNA methylation-based measures of biological age: meta-analysis predicting time to death. %A Chen, Brian H %A Marioni, Riccardo E %A Colicino, Elena %A Peters, Marjolein J %A Ward-Caviness, Cavin K %A Tsai, Pei-Chien %A Roetker, Nicholas S %A Just, Allan C %A Demerath, Ellen W %A Guan, Weihua %A Bressler, Jan %A Fornage, Myriam %A Studenski, Stephanie %A Vandiver, Amy R %A Moore, Ann Zenobia %A Tanaka, Toshiko %A Kiel, Douglas P %A Liang, Liming %A Vokonas, Pantel %A Schwartz, Joel %A Lunetta, Kathryn L %A Murabito, Joanne M %A Bandinelli, Stefania %A Hernandez, Dena G %A Melzer, David %A Nalls, Michael %A Pilling, Luke C %A Price, Timothy R %A Singleton, Andrew B %A Gieger, Christian %A Holle, Rolf %A Kretschmer, Anja %A Kronenberg, Florian %A Kunze, Sonja %A Linseisen, Jakob %A Meisinger, Christine %A Rathmann, Wolfgang %A Waldenberger, Melanie %A Visscher, Peter M %A Shah, Sonia %A Wray, Naomi R %A McRae, Allan F %A Franco, Oscar H %A Hofman, Albert %A Uitterlinden, André G %A Absher, Devin %A Assimes, Themistocles %A Levine, Morgan E %A Lu, Ake T %A Tsao, Philip S %A Hou, Lifang %A Manson, JoAnn E %A Carty, Cara L %A LaCroix, Andrea Z %A Reiner, Alexander P %A Spector, Tim D %A Feinberg, Andrew P %A Levy, Daniel %A Baccarelli, Andrea %A van Meurs, Joyce %A Bell, Jordana T %A Peters, Annette %A Deary, Ian J %A Pankow, James S %A Ferrucci, Luigi %A Horvath, Steve %K Aging %K DNA Methylation %K Epigenesis, Genetic %K Female %K Humans %K Logistic Models %K Male %K Mortality %K Racial Groups %K Risk Factors %K Survival Analysis %K T-Lymphocyte Subsets %X

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10, independent of chronological age, even after adjusting for additional risk factors (p<5.4x10, and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.

%B Aging (Albany NY) %V 8 %P 1844-1865 %8 2016 Sep 28 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/27690265?dopt=Abstract %R 10.18632/aging.101020 %0 Journal Article %J Sci Transl Med %D 2016 %T A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. %A Scott, Robert A %A Freitag, Daniel F %A Li, Li %A Chu, Audrey Y %A Surendran, Praveen %A Young, Robin %A Grarup, Niels %A Stančáková, Alena %A Chen, Yuning %A Varga, Tibor V %A Yaghootkar, Hanieh %A Luan, Jian'an %A Zhao, Jing Hua %A Willems, Sara M %A Wessel, Jennifer %A Wang, Shuai %A Maruthur, Nisa %A Michailidou, Kyriaki %A Pirie, Ailith %A van der Lee, Sven J %A Gillson, Christopher %A Al Olama, Ali Amin %A Amouyel, Philippe %A Arriola, Larraitz %A Arveiler, Dominique %A Aviles-Olmos, Iciar %A Balkau, Beverley %A Barricarte, Aurelio %A Barroso, Inês %A Garcia, Sara Benlloch %A Bis, Joshua C %A Blankenberg, Stefan %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Borecki, Ingrid B %A Bork-Jensen, Jette %A Bowden, Sarah %A Caldas, Carlos %A Caslake, Muriel %A Cupples, L Adrienne %A Cruchaga, Carlos %A Czajkowski, Jacek %A den Hoed, Marcel %A Dunn, Janet A %A Earl, Helena M %A Ehret, Georg B %A Ferrannini, Ele %A Ferrieres, Jean %A Foltynie, Thomas %A Ford, Ian %A Forouhi, Nita G %A Gianfagna, Francesco %A Gonzalez, Carlos %A Grioni, Sara %A Hiller, Louise %A Jansson, Jan-Håkan %A Jørgensen, Marit E %A Jukema, J Wouter %A Kaaks, Rudolf %A Kee, Frank %A Kerrison, Nicola D %A Key, Timothy J %A Kontto, Jukka %A Kote-Jarai, Zsofia %A Kraja, Aldi T %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Linneberg, Allan %A Liu, Chunyu %A Marenne, Gaëlle %A Mohlke, Karen L %A Morris, Andrew P %A Muir, Kenneth %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Navarro, Carmen %A Nielsen, Sune F %A Nilsson, Peter M %A Nordestgaard, Børge G %A Packard, Chris J %A Palli, Domenico %A Panico, Salvatore %A Peloso, Gina M %A Perola, Markus %A Peters, Annette %A Poole, Christopher J %A Quirós, J Ramón %A Rolandsson, Olov %A Sacerdote, Carlotta %A Salomaa, Veikko %A Sánchez, María-José %A Sattar, Naveed %A Sharp, Stephen J %A Sims, Rebecca %A Slimani, Nadia %A Smith, Jennifer A %A Thompson, Deborah J %A Trompet, Stella %A Tumino, Rosario %A van der A, Daphne L %A van der Schouw, Yvonne T %A Virtamo, Jarmo %A Walker, Mark %A Walter, Klaudia %A Abraham, Jean E %A Amundadottir, Laufey T %A Aponte, Jennifer L %A Butterworth, Adam S %A Dupuis, Josée %A Easton, Douglas F %A Eeles, Rosalind A %A Erdmann, Jeanette %A Franks, Paul W %A Frayling, Timothy M %A Hansen, Torben %A Howson, Joanna M M %A Jørgensen, Torben %A Kooner, Jaspal %A Laakso, Markku %A Langenberg, Claudia %A McCarthy, Mark I %A Pankow, James S %A Pedersen, Oluf %A Riboli, Elio %A Rotter, Jerome I %A Saleheen, Danish %A Samani, Nilesh J %A Schunkert, Heribert %A Vollenweider, Peter %A O'Rahilly, Stephen %A Deloukas, Panos %A Danesh, John %A Goodarzi, Mark O %A Kathiresan, Sekar %A Meigs, James B %A Ehm, Margaret G %A Wareham, Nicholas J %A Waterworth, Dawn M %K Alleles %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Dipeptidyl Peptidase 4 %K Genotype %K Glucagon-Like Peptide-1 Receptor %K Humans %K Obesity %K Receptor, Cannabinoid, CB2 %K Receptor, Serotonin, 5-HT2C %K Receptors, Somatostatin %K Sodium-Glucose Transporter 1 %X

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

%B Sci Transl Med %V 8 %P 341ra76 %8 2016 Jun 01 %G eng %N 341 %1 https://www.ncbi.nlm.nih.gov/pubmed/27252175?dopt=Abstract %R 10.1126/scitranslmed.aad3744 %0 Journal Article %J Nat Genet %D 2015 %T A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. %A Nikpay, Majid %A Goel, Anuj %A Won, Hong-Hee %A Hall, Leanne M %A Willenborg, Christina %A Kanoni, Stavroula %A Saleheen, Danish %A Kyriakou, Theodosios %A Nelson, Christopher P %A Hopewell, Jemma C %A Webb, Thomas R %A Zeng, Lingyao %A Dehghan, Abbas %A Alver, Maris %A Armasu, Sebastian M %A Auro, Kirsi %A Bjonnes, Andrew %A Chasman, Daniel I %A Chen, Shufeng %A Ford, Ian %A Franceschini, Nora %A Gieger, Christian %A Grace, Christopher %A Gustafsson, Stefan %A Huang, Jie %A Hwang, Shih-Jen %A Kim, Yun Kyoung %A Kleber, Marcus E %A Lau, King Wai %A Lu, Xiangfeng %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mihailov, Evelin %A Morrison, Alanna C %A Pervjakova, Natalia %A Qu, Liming %A Rose, Lynda M %A Salfati, Elias %A Saxena, Richa %A Scholz, Markus %A Smith, Albert V %A Tikkanen, Emmi %A Uitterlinden, Andre %A Yang, Xueli %A Zhang, Weihua %A Zhao, Wei %A de Andrade, Mariza %A de Vries, Paul S %A Van Zuydam, Natalie R %A Anand, Sonia S %A Bertram, Lars %A Beutner, Frank %A Dedoussis, George %A Frossard, Philippe %A Gauguier, Dominique %A Goodall, Alison H %A Gottesman, Omri %A Haber, Marc %A Han, Bok-Ghee %A Huang, Jianfeng %A Jalilzadeh, Shapour %A Kessler, Thorsten %A König, Inke R %A Lannfelt, Lars %A Lieb, Wolfgang %A Lind, Lars %A Lindgren, Cecilia M %A Lokki, Marja-Liisa %A Magnusson, Patrik K %A Mallick, Nadeem H %A Mehra, Narinder %A Meitinger, Thomas %A Memon, Fazal-Ur-Rehman %A Morris, Andrew P %A Nieminen, Markku S %A Pedersen, Nancy L %A Peters, Annette %A Rallidis, Loukianos S %A Rasheed, Asif %A Samuel, Maria %A Shah, Svati H %A Sinisalo, Juha %A Stirrups, Kathleen E %A Trompet, Stella %A Wang, Laiyuan %A Zaman, Khan S %A Ardissino, Diego %A Eric Boerwinkle %A Borecki, Ingrid B %A Bottinger, Erwin P %A Buring, Julie E %A Chambers, John C %A Collins, Rory %A Cupples, L Adrienne %A Danesh, John %A Demuth, Ilja %A Elosua, Roberto %A Epstein, Stephen E %A Esko, Tõnu %A Feitosa, Mary F %A Franco, Oscar H %A Franzosi, Maria Grazia %A Granger, Christopher B %A Gu, Dongfeng %A Gudnason, Vilmundur %A Hall, Alistair S %A Hamsten, Anders %A Harris, Tamara B %A Hazen, Stanley L %A Hengstenberg, Christian %A Hofman, Albert %A Ingelsson, Erik %A Iribarren, Carlos %A Jukema, J Wouter %A Karhunen, Pekka J %A Kim, Bong-Jo %A Kooner, Jaspal S %A Kullo, Iftikhar J %A Lehtimäki, Terho %A Loos, Ruth J F %A Melander, Olle %A Metspalu, Andres %A Marz, Winfried %A Palmer, Colin N %A Perola, Markus %A Quertermous, Thomas %A Rader, Daniel J %A Ridker, Paul M %A Ripatti, Samuli %A Roberts, Robert %A Salomaa, Veikko %A Sanghera, Dharambir K %A Schwartz, Stephen M %A Seedorf, Udo %A Stewart, Alexandre F %A Stott, David J %A Thiery, Joachim %A Zalloua, Pierre A %A O'Donnell, Christopher J %A Reilly, Muredach P %A Assimes, Themistocles L %A Thompson, John R %A Erdmann, Jeanette %A Clarke, Robert %A Watkins, Hugh %A Kathiresan, Sekar %A McPherson, Ruth %A Deloukas, Panos %A Schunkert, Heribert %A Samani, Nilesh J %A Farrall, Martin %K Coronary Artery Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Phenotype %X

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

%B Nat Genet %V 47 %P 1121-1130 %8 2015 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/26343387?dopt=Abstract %R 10.1038/ng.3396 %0 Journal Article %J Nat Genet %D 2015 %T Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. %A Gaulton, Kyle J %A Ferreira, Teresa %A Lee, Yeji %A Raimondo, Anne %A Mägi, Reedik %A Reschen, Michael E %A Mahajan, Anubha %A Locke, Adam %A Rayner, N William %A Robertson, Neil %A Scott, Robert A %A Prokopenko, Inga %A Scott, Laura J %A Green, Todd %A Sparso, Thomas %A Thuillier, Dorothee %A Yengo, Loic %A Grallert, Harald %A Wahl, Simone %A Frånberg, Mattias %A Strawbridge, Rona J %A Kestler, Hans %A Chheda, Himanshu %A Eisele, Lewin %A Gustafsson, Stefan %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Qi, Lu %A Karssen, Lennart C %A van Leeuwen, Elisabeth M %A Willems, Sara M %A Li, Man %A Chen, Han %A Fuchsberger, Christian %A Kwan, Phoenix %A Ma, Clement %A Linderman, Michael %A Lu, Yingchang %A Thomsen, Soren K %A Rundle, Jana K %A Beer, Nicola L %A van de Bunt, Martijn %A Chalisey, Anil %A Kang, Hyun Min %A Voight, Benjamin F %A Abecasis, Gonçalo R %A Almgren, Peter %A Baldassarre, Damiano %A Balkau, Beverley %A Benediktsson, Rafn %A Blüher, Matthias %A Boeing, Heiner %A Bonnycastle, Lori L %A Bottinger, Erwin P %A Burtt, Noël P %A Carey, Jason %A Charpentier, Guillaume %A Chines, Peter S %A Cornelis, Marilyn C %A Couper, David J %A Crenshaw, Andrew T %A van Dam, Rob M %A Doney, Alex S F %A Dorkhan, Mozhgan %A Edkins, Sarah %A Eriksson, Johan G %A Esko, Tõnu %A Eury, Elodie %A Fadista, João %A Flannick, Jason %A Fontanillas, Pierre %A Fox, Caroline %A Franks, Paul W %A Gertow, Karl %A Gieger, Christian %A Gigante, Bruna %A Gottesman, Omri %A Grant, George B %A Grarup, Niels %A Groves, Christopher J %A Hassinen, Maija %A Have, Christian T %A Herder, Christian %A Holmen, Oddgeir L %A Hreidarsson, Astradur B %A Humphries, Steve E %A Hunter, David J %A Jackson, Anne U %A Jonsson, Anna %A Jørgensen, Marit E %A Jørgensen, Torben %A Kao, Wen-Hong L %A Kerrison, Nicola D %A Kinnunen, Leena %A Klopp, Norman %A Kong, Augustine %A Kovacs, Peter %A Kraft, Peter %A Kravic, Jasmina %A Langford, Cordelia %A Leander, Karin %A Liang, Liming %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindholm, Eero %A Linneberg, Allan %A Liu, Ching-Ti %A Lobbens, Stéphane %A Luan, Jian'an %A Lyssenko, Valeriya %A Männistö, Satu %A McLeod, Olga %A Meyer, Julia %A Mihailov, Evelin %A Mirza, Ghazala %A Mühleisen, Thomas W %A Müller-Nurasyid, Martina %A Navarro, Carmen %A Nöthen, Markus M %A Oskolkov, Nikolay N %A Owen, Katharine R %A Palli, Domenico %A Pechlivanis, Sonali %A Peltonen, Leena %A Perry, John R B %A Platou, Carl G P %A Roden, Michael %A Ruderfer, Douglas %A Rybin, Denis %A van der Schouw, Yvonne T %A Sennblad, Bengt %A Sigurðsson, Gunnar %A Stančáková, Alena %A Steinbach, Gerald %A Storm, Petter %A Strauch, Konstantin %A Stringham, Heather M %A Sun, Qi %A Thorand, Barbara %A Tikkanen, Emmi %A Tonjes, Anke %A Trakalo, Joseph %A Tremoli, Elena %A Tuomi, Tiinamaija %A Wennauer, Roman %A Wiltshire, Steven %A Wood, Andrew R %A Zeggini, Eleftheria %A Dunham, Ian %A Birney, Ewan %A Pasquali, Lorenzo %A Ferrer, Jorge %A Loos, Ruth J F %A Dupuis, Josée %A Florez, Jose C %A Eric Boerwinkle %A Pankow, James S %A van Duijn, Cornelia %A Sijbrands, Eric %A Meigs, James B %A Hu, Frank B %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A Lakka, Timo A %A Rauramaa, Rainer %A Stumvoll, Michael %A Pedersen, Nancy L %A Lind, Lars %A Keinanen-Kiukaanniemi, Sirkka M %A Korpi-Hyövälti, Eeva %A Saaristo, Timo E %A Saltevo, Juha %A Kuusisto, Johanna %A Laakso, Markku %A Metspalu, Andres %A Erbel, Raimund %A Jöcke, Karl-Heinz %A Moebus, Susanne %A Ripatti, Samuli %A Salomaa, Veikko %A Ingelsson, Erik %A Boehm, Bernhard O %A Bergman, Richard N %A Collins, Francis S %A Mohlke, Karen L %A Koistinen, Heikki %A Tuomilehto, Jaakko %A Hveem, Kristian %A Njølstad, Inger %A Deloukas, Panagiotis %A Donnelly, Peter J %A Frayling, Timothy M %A Hattersley, Andrew T %A de Faire, Ulf %A Hamsten, Anders %A Illig, Thomas %A Peters, Annette %A Cauchi, Stephane %A Sladek, Rob %A Froguel, Philippe %A Hansen, Torben %A Pedersen, Oluf %A Morris, Andrew D %A Palmer, Collin N A %A Kathiresan, Sekar %A Melander, Olle %A Nilsson, Peter M %A Groop, Leif C %A Barroso, Inês %A Langenberg, Claudia %A Wareham, Nicholas J %A O'Callaghan, Christopher A %A Gloyn, Anna L %A Altshuler, David %A Boehnke, Michael %A Teslovich, Tanya M %A McCarthy, Mark I %A Morris, Andrew P %K Binding Sites %K Case-Control Studies %K Chromatin Immunoprecipitation %K Chromosome Mapping %K Diabetes Mellitus, Type 2 %K Gene Expression Regulation %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Hepatocyte Nuclear Factor 3-beta %K Humans %K Islets of Langerhans %K Liver %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Receptor, Melatonin, MT2 %X

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

%B Nat Genet %V 47 %P 1415-25 %8 2015 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/26551672?dopt=Abstract %R 10.1038/ng.3437 %0 Journal Article %J PLoS One %D 2014 %T No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. %A Baumert, Jens %A Huang, Jie %A McKnight, Barbara %A Sabater-Lleal, Maria %A Steri, Maristella %A Chu, Audrey Y %A Trompet, Stella %A Lopez, Lorna M %A Fornage, Myriam %A Teumer, Alexander %A Tang, Weihong %A Rudnicka, Alicja R %A Mälarstig, Anders %A Hottenga, Jouke-Jan %A Kavousi, Maryam %A Lahti, Jari %A Tanaka, Toshiko %A Hayward, Caroline %A Huffman, Jennifer E %A Morange, Pierre-Emmanuel %A Rose, Lynda M %A Basu, Saonli %A Rumley, Ann %A Stott, David J %A Buckley, Brendan M %A de Craen, Anton J M %A Sanna, Serena %A Masala, Marco %A Biffar, Reiner %A Homuth, Georg %A Silveira, Angela %A Sennblad, Bengt %A Goel, Anuj %A Watkins, Hugh %A Müller-Nurasyid, Martina %A Rückerl, Regina %A Taylor, Kent %A Chen, Ming-Huei %A de Geus, Eco J C %A Hofman, Albert %A Witteman, Jacqueline C M %A de Maat, Moniek P M %A Palotie, Aarno %A Davies, Gail %A Siscovick, David S %A Kolcic, Ivana %A Wild, Sarah H %A Song, Jaejoon %A McArdle, Wendy L %A Ford, Ian %A Sattar, Naveed %A Schlessinger, David %A Grotevendt, Anne %A Franzosi, Maria Grazia %A Illig, Thomas %A Waldenberger, Melanie %A Lumley, Thomas %A Tofler, Geoffrey H %A Willemsen, Gonneke %A Uitterlinden, André G %A Rivadeneira, Fernando %A Räikkönen, Katri %A Chasman, Daniel I %A Folsom, Aaron R %A Lowe, Gordon D %A Westendorp, Rudi G J %A Slagboom, P Eline %A Cucca, Francesco %A Wallaschofski, Henri %A Strawbridge, Rona J %A Seedorf, Udo %A Koenig, Wolfgang %A Bis, Joshua C %A Mukamal, Kenneth J %A van Dongen, Jenny %A Widen, Elisabeth %A Franco, Oscar H %A Starr, John M %A Liu, Kiang %A Ferrucci, Luigi %A Polasek, Ozren %A Wilson, James F %A Oudot-Mellakh, Tiphaine %A Campbell, Harry %A Navarro, Pau %A Bandinelli, Stefania %A Eriksson, Johan %A Boomsma, Dorret I %A Dehghan, Abbas %A Clarke, Robert %A Hamsten, Anders %A Eric Boerwinkle %A Jukema, J Wouter %A Naitza, Silvia %A Ridker, Paul M %A Völzke, Henry %A Deary, Ian J %A Reiner, Alexander P %A Trégouët, David-Alexandre %A O'Donnell, Christopher J %A Strachan, David P %A Peters, Annette %A Smith, Nicholas L %K Alcohol Drinking %K Body Mass Index %K Fibrinogen %K Gene-Environment Interaction %K Genomics %K Humans %K Smoking %X

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

%B PLoS One %V 9 %P e111156 %8 2014 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract %R 10.1371/journal.pone.0111156 %0 Journal Article %J Hum Mol Genet %D 2010 %T Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. %A Barbalic, Maja %A Dupuis, Josée %A Dehghan, Abbas %A Bis, Joshua C %A Hoogeveen, Ron C %A Schnabel, Renate B %A Nambi, Vijay %A Bretler, Monique %A Smith, Nicholas L %A Peters, Annette %A Lu, Chen %A Tracy, Russell P %A Aleksic, Nena %A Heeriga, Jan %A Keaney, John F %A Rice, Kenneth %A Lip, Gregory Y H %A Vasan, Ramachandran S %A Glazer, Nicole L %A Larson, Martin G %A Uitterlinden, André G %A Yamamoto, Jennifer %A Durda, Peter %A Haritunians, Talin %A Psaty, Bruce M %A Boerwinkle, Eric %A Hofman, Albert %A Koenig, Wolfgang %A Jenny, Nancy S %A Witteman, Jacqueline C %A Ballantyne, Christie %A Benjamin, Emelia J %K ABO Blood-Group System %K Blood Platelets %K Enzyme-Linked Immunosorbent Assay %K Fluorescence %K Genome-Wide Association Study %K Humans %K Intercellular Adhesion Molecule-1 %K P-Selectin %K White People %X

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

%B Hum Mol Genet %V 19 %P 1863-72 %8 2010 May 01 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/20167578?dopt=Abstract %R 10.1093/hmg/ddq061