%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 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 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