%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.

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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 Nat Genet %D 2020 %T Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. %A Surendran, Praveen %A Feofanova, Elena V %A Lahrouchi, Najim %A Ntalla, Ioanna %A Karthikeyan, Savita %A Cook, James %A Chen, Lingyan %A Mifsud, Borbala %A Yao, Chen %A Kraja, Aldi T %A Cartwright, James H %A Hellwege, Jacklyn N %A Giri, Ayush %A Tragante, Vinicius %A Thorleifsson, Gudmar %A Liu, Dajiang J %A Prins, Bram P %A Stewart, Isobel D %A Cabrera, Claudia P %A Eales, James M %A Akbarov, Artur %A Auer, Paul L %A Bielak, Lawrence F %A Bis, Joshua C %A Braithwaite, Vickie S %A Brody, Jennifer A %A Daw, E Warwick %A Warren, Helen R %A Drenos, Fotios %A Nielsen, Sune Fallgaard %A Faul, Jessica D %A Fauman, Eric B %A Fava, Cristiano %A Ferreira, Teresa %A Foley, Christopher N %A Franceschini, Nora %A Gao, He %A Giannakopoulou, Olga %A Giulianini, Franco %A Gudbjartsson, Daniel F %A Guo, Xiuqing %A Harris, Sarah E %A Havulinna, Aki S %A Helgadottir, Anna %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Kanoni, Stavroula %A Kontto, Jukka %A Larson, Martin G %A Li-Gao, Ruifang %A Lindström, Jaana %A Lotta, Luca A %A Lu, Yingchang %A Luan, Jian'an %A Mahajan, Anubha %A Malerba, Giovanni %A Masca, Nicholas G D %A Mei, Hao %A Menni, Cristina %A Mook-Kanamori, Dennis O %A Mosen-Ansorena, David %A Müller-Nurasyid, Martina %A Paré, Guillaume %A Paul, Dirk S %A Perola, Markus %A Poveda, Alaitz %A Rauramaa, Rainer %A Richard, Melissa %A Richardson, Tom G %A Sepúlveda, Nuno %A Sim, Xueling %A Smith, Albert V %A Smith, Jennifer A %A Staley, James R %A Stanáková, Alena %A Sulem, Patrick %A Thériault, Sébastien %A Thorsteinsdottir, Unnur %A Trompet, Stella %A Varga, Tibor V %A Velez Edwards, Digna R %A Veronesi, Giovanni %A Weiss, Stefan %A Willems, Sara M %A Yao, Jie %A Young, Robin %A Yu, Bing %A Zhang, Weihua %A Zhao, Jing-Hua %A Zhao, Wei %A Zhao, Wei %A Evangelou, Evangelos %A Aeschbacher, Stefanie %A Asllanaj, Eralda %A Blankenberg, Stefan %A Bonnycastle, Lori L %A Bork-Jensen, Jette %A Brandslund, Ivan %A Braund, Peter S %A Burgess, Stephen %A Cho, Kelly %A Christensen, Cramer %A Connell, John %A Mutsert, Renée de %A Dominiczak, Anna F %A Dörr, Marcus %A Eiriksdottir, Gudny %A Farmaki, Aliki-Eleni %A Gaziano, J Michael %A Grarup, Niels %A Grove, Megan L %A Hallmans, Goran %A Hansen, Torben %A Have, Christian T %A Heiss, Gerardo %A Jørgensen, Marit E %A Jousilahti, Pekka %A Kajantie, Eero %A Kamat, Mihir %A Käräjämäki, Annemari %A Karpe, Fredrik %A Koistinen, Heikki A %A Kovesdy, Csaba P %A Kuulasmaa, Kari %A Laatikainen, Tiina %A Lannfelt, Lars %A Lee, I-Te %A Lee, Wen-Jane %A Linneberg, Allan %A Martin, Lisa W %A Moitry, Marie %A Nadkarni, Girish %A Neville, Matt J %A Palmer, Colin N A %A Papanicolaou, George J %A Pedersen, Oluf %A Peters, James %A Poulter, Neil %A Rasheed, Asif %A Rasmussen, Katrine L %A Rayner, N William %A Mägi, Reedik %A Renstrom, Frida %A Rettig, Rainer %A Rossouw, Jacques %A Schreiner, Pamela J %A Sever, Peter S %A Sigurdsson, Emil L %A Skaaby, Tea %A Sun, Yan V %A Sundström, Johan %A Thorgeirsson, Gudmundur %A Esko, Tõnu %A Trabetti, Elisabetta %A Tsao, Philip S %A Tuomi, Tiinamaija %A Turner, Stephen T %A Tzoulaki, Ioanna %A Vaartjes, Ilonca %A Vergnaud, Anne-Claire %A Willer, Cristen J %A Wilson, Peter W F %A Witte, Daniel R %A Yonova-Doing, Ekaterina %A Zhang, He %A Aliya, Naheed %A Almgren, Peter %A Amouyel, Philippe %A Asselbergs, Folkert W %A Barnes, Michael R %A Blakemore, Alexandra I %A Boehnke, Michael %A Bots, Michiel L %A Bottinger, Erwin P %A Buring, Julie E %A Chambers, John C %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Conen, David %A Correa, Adolfo %A Davey Smith, George %A Boer, Rudolf A de %A Deary, Ian J %A Dedoussis, George %A Deloukas, Panos %A Di Angelantonio, Emanuele %A Elliott, Paul %A Felix, Stephan B %A Ferrieres, Jean %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Franks, Stephen %A Frossard, Philippe %A Gambaro, Giovanni %A Gaunt, Tom R %A Groop, Leif %A Gudnason, Vilmundur %A Harris, Tamara B %A Hayward, Caroline %A Hennig, Branwen J %A Herzig, Karl-Heinz %A Ingelsson, Erik %A Tuomilehto, Jaakko %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kardia, Sharon L R %A Kee, Frank %A Kooner, Jaspal S %A Kooperberg, Charles %A Launer, Lenore J %A Lind, Lars %A Loos, Ruth J F %A Majumder, Abdulla Al Shafi %A Laakso, Markku %A McCarthy, Mark I %A Melander, Olle %A Mohlke, Karen L %A Murray, Alison D %A Nordestgaard, Børge Grønne %A Orho-Melander, Marju %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmas, Walter %A Polasek, Ozren %A Porteous, David J %A Prentice, Andrew M %A Province, Michael A %A Relton, Caroline L %A Rice, Kenneth %A Ridker, Paul M %A Rolandsson, Olov %A Rosendaal, Frits R %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sattar, Naveed %A Sheu, Wayne H-H %A Smith, Blair H %A Soranzo, Nicole %A Spector, Timothy D %A Starr, John M %A Sebert, Sylvain %A Taylor, Kent D %A Lakka, Timo A %A Timpson, Nicholas J %A Tobin, Martin D %A van der Harst, Pim %A van der Meer, Peter %A Ramachandran, Vasan S %A Verweij, Niek %A Virtamo, Jarmo %A Völker, Uwe %A Weir, David R %A Zeggini, Eleftheria %A Charchar, Fadi J %A Wareham, Nicholas J %A Langenberg, Claudia %A Tomaszewski, Maciej %A Butterworth, Adam S %A Caulfield, Mark J %A Danesh, John %A Edwards, Todd L %A Holm, Hilma %A Hung, Adriana M %A Lindgren, Cecilia M %A Liu, Chunyu %A Manning, Alisa K %A Morris, Andrew P %A Morrison, Alanna C %A O'Donnell, Christopher J %A Psaty, Bruce M %A Saleheen, Danish %A Stefansson, Kari %A Eric Boerwinkle %A Chasman, Daniel I %A Levy, Daniel %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Howson, Joanna M M %K Blood Pressure %K GATA5 Transcription Factor %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Hypertension %K Mutation %K Phospholipase C beta %K Polymorphism, Single Nucleotide %X

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

%B Nat Genet %V 52 %P 1314-1332 %8 2020 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/33230300?dopt=Abstract %R 10.1038/s41588-020-00713-x %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 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 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 J Med Genet %D 2016 %T Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels. %A van Leeuwen, Elisabeth M %A Sabo, Aniko %A Bis, Joshua C %A Huffman, Jennifer E %A Manichaikul, Ani %A Smith, Albert V %A Feitosa, Mary F %A Demissie, Serkalem %A Joshi, Peter K %A Duan, Qing %A Marten, Jonathan %A van Klinken, Jan B %A Surakka, Ida %A Nolte, Ilja M %A Zhang, Weihua %A Mbarek, Hamdi %A Li-Gao, Ruifang %A Trompet, Stella %A Verweij, Niek %A Evangelou, Evangelos %A Lyytikäinen, Leo-Pekka %A Tayo, Bamidele O %A Deelen, Joris %A van der Most, Peter J %A van der Laan, Sander W %A Arking, Dan E %A Morrison, Alanna %A Dehghan, Abbas %A Franco, Oscar H %A Hofman, Albert %A Rivadeneira, Fernando %A Sijbrands, Eric J %A Uitterlinden, André G %A Mychaleckyj, Josyf C %A Campbell, Archie %A Hocking, Lynne J %A Padmanabhan, Sandosh %A Brody, Jennifer A %A Rice, Kenneth M %A White, Charles C %A Harris, Tamara %A Isaacs, Aaron %A Campbell, Harry %A Lange, Leslie A %A Rudan, Igor %A Kolcic, Ivana %A Navarro, Pau %A Zemunik, Tatijana %A Salomaa, Veikko %A Kooner, Angad S %A Kooner, Jaspal S %A Lehne, Benjamin %A Scott, William R %A Tan, Sian-Tsung %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda W J H %A Willemsen, Gonneke %A de Mutsert, Renée %A Ford, Ian %A Gansevoort, Ron T %A Segura-Lepe, Marcelo P %A Raitakari, Olli T %A Viikari, Jorma S %A Nikus, Kjell %A Forrester, Terrence %A McKenzie, Colin A %A de Craen, Anton J M %A de Ruijter, Hester M %A Pasterkamp, Gerard %A Snieder, Harold %A Oldehinkel, Albertine J %A Slagboom, P Eline %A Cooper, Richard S %A Kähönen, Mika %A Lehtimäki, Terho %A Elliott, Paul %A van der Harst, Pim %A Jukema, J Wouter %A Mook-Kanamori, Dennis O %A Boomsma, Dorret I %A Chambers, John C %A Swertz, Morris %A Ripatti, Samuli %A Willems van Dijk, Ko %A Vitart, Veronique %A Polasek, Ozren %A Hayward, Caroline %A Wilson, James G %A Wilson, James F %A Gudnason, Vilmundur %A Rich, Stephen S %A Psaty, Bruce M %A Borecki, Ingrid B %A Boerwinkle, Eric %A Rotter, Jerome I %A Cupples, L Adrienne %A van Duijn, Cornelia M %K Angiopoietin-Like Protein 4 %K Angiopoietins %K Exons %K Fasting %K Female %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.

RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

%B J Med Genet %V 53 %P 441-9 %8 2016 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/27036123?dopt=Abstract %R 10.1136/jmedgenet-2015-103439 %0 Journal Article %J NPJ Aging Mech Dis %D 2015 %T Fine mapping the region reveals a common intronic insertion associated to HDL-C. %A van Leeuwen, Elisabeth M %A Huffman, Jennifer E %A Bis, Joshua C %A Isaacs, Aaron %A Mulder, Monique %A Aniko Sabo %A Smith, Albert V %A Demissie, Serkalem %A Manichaikul, Ani %A Brody, Jennifer A %A Feitosa, Mary F %A Duan, Qing %A Schraut, Katharina E %A Navarro, Pau %A Van Vliet-Ostaptchouk, Jana V %A Zhu, Gu %A Mbarek, Hamdi %A Trompet, Stella %A Verweij, Niek %A Lyytikäinen, Leo-Pekka %A Deelen, Joris %A Nolte, Ilja M %A van der Laan, Sander W %A Davies, Gail %A Vermeij-Verdoold, Andrea Jm %A van Oosterhout, Andy Alj %A Vergeer-Drop, Jeannette M %A Arking, Dan E %A Trochet, Holly %A Medina-Gomez, Carolina %A Rivadeneira, Fernando %A Uitterlinden, André G %A Dehghan, Abbas %A Franco, Oscar H %A Sijbrands, Eric J %A Hofman, Albert %A White, Charles C %A Mychaleckyj, Josyf C %A Peloso, Gina M %A Swertz, Morris A %A Willemsen, Gonneke %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda Wjh %A Ford, Ian %A Buckley, Brendan M %A de Craen, Anton Jm %A Starr, John M %A Deary, Ian J %A Pasterkamp, Gerard %A Oldehinkel, Albertine J %A Snieder, Harold %A Slagboom, P Eline %A Nikus, Kjell %A Kähönen, Mika %A Lehtimäki, Terho %A Viikari, Jorma S %A Raitakari, Olli T %A van der Harst, Pim %A Jukema, J Wouter %A Hottenga, Jouke-Jan %A Boomsma, Dorret I %A Whitfield, John B %A Montgomery, Grant %A Martin, Nicholas G %A Polasek, Ozren %A Vitart, Veronique %A Hayward, Caroline %A Kolcic, Ivana %A Wright, Alan F %A Rudan, Igor %A Joshi, Peter K %A Wilson, James F %A Lange, Leslie A %A Wilson, James G %A Gudnason, Vilmundur %A Harris, Tamar B %A Morrison, Alanna C %A Borecki, Ingrid B %A Rich, Stephen S %A Padmanabhan, Sandosh %A Psaty, Bruce M %A Rotter, Jerome I %A Smith, Blair H %A Eric Boerwinkle %A Cupples, L Adrienne %A van Duijn, Cornelia %X

BACKGROUND: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein ( gene. In this study, we investigate the association of and HDL-C further to identify novel, independent variants associated with HDL-C in humans.

METHODS: We performed a meta-analysis of HDL-C within the region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.

RESULTS: The meta-analysis of HDL-C within the region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (=3.179 mg/dl ( value=5.25×10), =0.859 mg/dl ( value=9.51×10)), and this finding suggests that these five novel variants may partly explain the association of with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.

CONCLUSIONS: The causal variants in that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

%B NPJ Aging Mech Dis %V 1 %P 15011 %8 2015 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/28721259?dopt=Abstract %R 10.1038/npjamd.2015.11 %0 Journal Article %J Nat Genet %D 2015 %T Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. %A Day, Felix R %A Ruth, Katherine S %A Thompson, Deborah J %A Lunetta, Kathryn L %A Pervjakova, Natalia %A Chasman, Daniel I %A Stolk, Lisette %A Finucane, Hilary K %A Sulem, Patrick %A Bulik-Sullivan, Brendan %A Esko, Tõnu %A Johnson, Andrew D %A Elks, Cathy E %A Franceschini, Nora %A He, Chunyan %A Altmaier, Elisabeth %A Brody, Jennifer A %A Franke, Lude L %A Huffman, Jennifer E %A Keller, Margaux F %A McArdle, Patrick F %A Nutile, Teresa %A Porcu, Eleonora %A Robino, Antonietta %A Rose, Lynda M %A Schick, Ursula M %A Smith, Jennifer A %A Teumer, Alexander %A Traglia, Michela %A Vuckovic, Dragana %A Yao, Jie %A Zhao, Wei %A Albrecht, Eva %A Amin, Najaf %A Corre, Tanguy %A Hottenga, Jouke-Jan %A Mangino, Massimo %A Smith, Albert V %A Tanaka, Toshiko %A Abecasis, Goncalo %A Andrulis, Irene L %A Anton-Culver, Hoda %A Antoniou, Antonis C %A Arndt, Volker %A Arnold, Alice M %A Barbieri, Caterina %A Beckmann, Matthias W %A Beeghly-Fadiel, Alicia %A Benitez, Javier %A Bernstein, Leslie %A Bielinski, Suzette J %A Blomqvist, Carl %A Boerwinkle, Eric %A Bogdanova, Natalia V %A Bojesen, Stig E %A Bolla, Manjeet K %A Borresen-Dale, Anne-Lise %A Boutin, Thibaud S %A Brauch, Hiltrud %A Brenner, Hermann %A Brüning, Thomas %A Burwinkel, Barbara %A Campbell, Archie %A Campbell, Harry %A Chanock, Stephen J %A Chapman, J Ross %A Chen, Yii-Der Ida %A Chenevix-Trench, Georgia %A Couch, Fergus J %A Coviello, Andrea D %A Cox, Angela %A Czene, Kamila %A Darabi, Hatef %A De Vivo, Immaculata %A Demerath, Ellen W %A Dennis, Joe %A Devilee, Peter %A Dörk, Thilo %A Dos-Santos-Silva, Isabel %A Dunning, Alison M %A Eicher, John D %A Fasching, Peter A %A Faul, Jessica D %A Figueroa, Jonine %A Flesch-Janys, Dieter %A Gandin, Ilaria %A Garcia, Melissa E %A García-Closas, Montserrat %A Giles, Graham G %A Girotto, Giorgia G %A Goldberg, Mark S %A González-Neira, Anna %A Goodarzi, Mark O %A Grove, Megan L %A Gudbjartsson, Daniel F %A Guénel, Pascal %A Guo, Xiuqing %A Haiman, Christopher A %A Hall, Per %A Hamann, Ute %A Henderson, Brian E %A Hocking, Lynne J %A Hofman, Albert %A Homuth, Georg %A Hooning, Maartje J %A Hopper, John L %A Hu, Frank B %A Huang, Jinyan %A Humphreys, Keith %A Hunter, David J %A Jakubowska, Anna %A Jones, Samuel E %A Kabisch, Maria %A Karasik, David %A Knight, Julia A %A Kolcic, Ivana %A Kooperberg, Charles %A Kosma, Veli-Matti %A Kriebel, Jennifer %A Kristensen, Vessela %A Lambrechts, Diether %A Langenberg, Claudia %A Li, Jingmei %A Li, Xin %A Lindström, Sara %A Liu, Yongmei %A Luan, Jian'an %A Lubinski, Jan %A Mägi, Reedik %A Mannermaa, Arto %A Manz, Judith %A Margolin, Sara %A Marten, Jonathan %A Martin, Nicholas G %A Masciullo, Corrado %A Meindl, Alfons %A Michailidou, Kyriaki %A Mihailov, Evelin %A Milani, Lili %A Milne, Roger L %A Müller-Nurasyid, Martina %A Nalls, Michael %A Neale, Ben M %A Nevanlinna, Heli %A Neven, Patrick %A Newman, Anne B %A Nordestgaard, Børge G %A Olson, Janet E %A Padmanabhan, Sandosh %A Peterlongo, Paolo %A Peters, Ulrike %A Petersmann, Astrid %A Peto, Julian %A Pharoah, Paul D P %A Pirastu, Nicola N %A Pirie, Ailith %A Pistis, Giorgio %A Polasek, Ozren %A Porteous, David %A Psaty, Bruce M %A Pylkäs, Katri %A Radice, Paolo %A Raffel, Leslie J %A Rivadeneira, Fernando %A Rudan, Igor %A Rudolph, Anja %A Ruggiero, Daniela %A Sala, Cinzia F %A Sanna, Serena %A Sawyer, Elinor J %A Schlessinger, David %A Schmidt, Marjanka K %A Schmidt, Frank %A Schmutzler, Rita K %A Schoemaker, Minouk J %A Scott, Robert A %A Seynaeve, Caroline M %A Simard, Jacques %A Sorice, Rossella %A Southey, Melissa C %A Stöckl, Doris %A Strauch, Konstantin %A Swerdlow, Anthony %A Taylor, Kent D %A Thorsteinsdottir, Unnur %A Toland, Amanda E %A Tomlinson, Ian %A Truong, Thérèse %A Tryggvadottir, Laufey %A Turner, Stephen T %A Vozzi, Diego %A Wang, Qin %A Wellons, Melissa %A Willemsen, Gonneke %A Wilson, James F %A Winqvist, Robert %A Wolffenbuttel, Bruce B H R %A Wright, Alan F %A Yannoukakos, Drakoulis %A Zemunik, Tatijana %A Zheng, Wei %A Zygmunt, Marek %A Bergmann, Sven %A Boomsma, Dorret I %A Buring, Julie E %A Ferrucci, Luigi %A Montgomery, Grant W %A Gudnason, Vilmundur %A Spector, Tim D %A van Duijn, Cornelia M %A Alizadeh, Behrooz Z %A Ciullo, Marina %A Crisponi, Laura %A Easton, Douglas F %A Gasparini, Paolo P %A Gieger, Christian %A Harris, Tamara B %A Hayward, Caroline %A Kardia, Sharon L R %A Kraft, Peter %A McKnight, Barbara %A Metspalu, Andres %A Morrison, Alanna C %A Reiner, Alex P %A Ridker, Paul M %A Rotter, Jerome I %A Toniolo, Daniela %A Uitterlinden, André G %A Ulivi, Sheila %A Völzke, Henry %A Wareham, Nicholas J %A Weir, David R %A Yerges-Armstrong, Laura M %A Price, Alkes L %A Stefansson, Kari %A Visser, Jenny A %A Ong, Ken K %A Chang-Claude, Jenny %A Murabito, Joanne M %A Perry, John R B %A Murray, Anna %K Adult %K Age Factors %K Aging %K BRCA1 Protein %K Breast Neoplasms %K DNA Repair %K Female %K Gene Regulatory Networks %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Genotype %K Humans %K Hypothalamus %K Menopause %K Middle Aged %K Models, Genetic %K Phenotype %K Reproduction %K Signal Transduction %X

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

%B Nat Genet %V 47 %P 1294-1303 %8 2015 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract %R 10.1038/ng.3412