%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 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 Nat Genet %D 2019 %T Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. %A Justice, Anne E %A Karaderi, Tugce %A Highland, Heather M %A Young, Kristin L %A Graff, Mariaelisa %A Lu, Yingchang %A Turcot, Valérie %A Auer, Paul L %A Fine, Rebecca S %A Guo, Xiuqing %A Schurmann, Claudia %A Lempradl, Adelheid %A Marouli, Eirini %A Mahajan, Anubha %A Winkler, Thomas W %A Locke, Adam E %A Medina-Gomez, Carolina %A Esko, Tõnu %A Vedantam, Sailaja %A Giri, Ayush %A Lo, Ken Sin %A Alfred, Tamuno %A Mudgal, Poorva %A Ng, Maggie C Y %A Heard-Costa, Nancy L %A Feitosa, Mary F %A Manning, Alisa K %A Willems, Sara M %A Sivapalaratnam, Suthesh %A Abecasis, Goncalo %A Alam, Dewan S %A Allison, Matthew %A Amouyel, Philippe %A Arzumanyan, Zorayr %A Balkau, Beverley %A Bastarache, Lisa %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Böger, Carsten A %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Broer, Linda %A Burt, Amber A %A Butterworth, Adam S %A Caulfield, Mark J %A Cesana, Giancarlo %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Collins, Francis S %A Cook, James P %A Cox, Amanda J %A Crosslin, David S %A Danesh, John %A de Bakker, Paul I W %A Denus, Simon de %A Mutsert, Renée de %A Dedoussis, George %A Demerath, Ellen W %A Dennis, Joe G %A Denny, Josh C %A Di Angelantonio, Emanuele %A Dörr, Marcus %A Drenos, Fotios %A Dube, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Feng, Shuang %A Ferrannini, Ele %A Ferrieres, Jean %A Florez, Jose C %A Fornage, Myriam %A Fox, Caroline S %A Franks, Paul W %A Friedrich, Nele %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Girotto, Giorgia %A Gorski, Mathias %A Grallert, Harald %A Grarup, Niels %A Grove, Megan L %A Gustafsson, Stefan %A Haessler, Jeff %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Heid, Iris M %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Hung, Yi-Jen %A Hveem, Kristian %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jarvik, Gail P %A Jia, Yucheng %A Jørgensen, Torben %A Jousilahti, Pekka %A Justesen, Johanne M %A Kahali, Bratati %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kee, Frank %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Kovacs, Peter %A Krämer, Bernhard K %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Leslie A %A Langenberg, Claudia %A Larson, Eric B %A Lee, Nanette R %A Lee, Wen-Jane %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A MacGregor, Stuart %A Mägi, Reedik %A Männistö, Satu %A Marenne, Gaëlle %A Marten, Jonathan %A Masca, Nicholas G D %A McCarthy, Mark I %A Meidtner, Karina %A Mihailov, Evelin %A Moilanen, Leena %A Moitry, Marie %A Mook-Kanamori, Dennis O %A Morgan, Anna %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Ntalla, Ioanna %A O'Connell, Jeffrey R %A Owen, Katharine R %A Pedersen, Oluf %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Ewing, Ailith %A Polasek, Ozren %A Raitakari, Olli T %A Rasheed, Asif %A Raulerson, Chelsea K %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Ridker, Paul M %A Rivas, Manuel A %A Robertson, Neil R %A Robino, Antonietta %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Smith, Blair H %A Smith, Jennifer A %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen E %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swart, Karin M A %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Torres, Mina %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vanhala, Mauno %A Varma, Rohit %A Vermeulen, Sita H %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wareham, Nicholas J %A Warren, Helen R %A Waterworth, Dawn M %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Wood, Andrew R %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zheng, He %A Zhou, Wei %A Zillikens, M Carola %A Rivadeneira, Fernando %A Borecki, Ingrid B %A Pospisilik, J Andrew %A Deloukas, Panos %A Frayling, Timothy M %A Lettre, Guillaume %A Mohlke, Karen L %A Rotter, Jerome I %A Kutalik, Zoltán %A Hirschhorn, Joel N %A Cupples, L Adrienne %A Loos, Ruth J F %A North, Kari E %A Lindgren, Cecilia M %K Animals %K Body Fat Distribution %K Body Mass Index %K Case-Control Studies %K Drosophila %K Exome %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Homeostasis %K Humans %K Lipids %K Male %K Proteins %K Risk Factors %K Waist-Hip Ratio %X

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

%B Nat Genet %V 51 %P 452-469 %8 2019 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30778226?dopt=Abstract %R 10.1038/s41588-018-0334-2 %0 Journal Article %J Nat Genet %D 2019 %T Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Esko, Tõnu %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Manning, Alisa K %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Winkler, Thomas W %A Abecasis, Goncalo %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Allison, Matthew %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Butterworth, Adam S %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der I %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Galbany, Jordi Corominas %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Davies, Gail %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A Heijer, Martin %A Hollander, Anneke I %A Ruijter, Hester M %A Dennis, Joe G %A Denny, Josh C %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dube, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Faul, Jessica D %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrieres, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grabe, Hans-Jörgen %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeff %A Hakonarson, Hakon %A Hammerschlag, Anke R %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Have, Christian T %A Hayward, Caroline %A He, Liang %A Heard-Costa, Nancy L %A Heath, Andrew C %A Heid, Iris M %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Kiemeney, Lambertus A %A Kim, Eric %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Kooperberg, Charles %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Lange, Leslie A %A Langenberg, Claudia %A Larson, Eric B %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Liu, Yongmei %A Lo, Ken S %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Medland, Sarah E %A Meidtner, Karina %A Milani, Lili %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Nyholt, Dale R %A O'Connel, Jeffrey R %A O'Donoghue, Michelle L %A Loohuis, Loes M Olde %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Polderman, Tinca J %A Puolijoki, Hannu %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Robertson, Neil R %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati H %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Smith, Albert V %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen E %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Edwards, Digna R Velez %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Ware, Erin B %A Wareham, Nicholas J %A Warren, Helen R %A Waterworth, Dawn M %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Witte, Daniel R %A Wood, Andrew R %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhao, Wei %A Zhou, Wei %A Zondervan, Krina T %A Rotter, Jerome I %A Pospisilik, John A %A Rivadeneira, Fernando %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Lettre, Guillaume %A North, Kari E %A Lindgren, Cecilia M %A Hirschhorn, Joel N %A Loos, Ruth J F %X

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

%B Nat Genet %V 51 %P 1191-1192 %8 2019 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/31160809?dopt=Abstract %R 10.1038/s41588-019-0447-2 %0 Journal Article %J Nat Genet %D 2018 %T Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Esko, Tõnu %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Manning, Alisa K %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Winkler, Thomas W %A Abecasis, Goncalo %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Allison, Matthew %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Butterworth, Adam S %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der I %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Corominas Galbany, Jordi %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Davies, Gail %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A Heijer, Martin %A Hollander, Anneke I %A Ruijter, Hester M %A Dennis, Joe G %A Denny, Josh C %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dube, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Faul, Jessica D %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrieres, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grabe, Hans-Jörgen %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeff %A Hakonarson, Hakon %A Hammerschlag, Anke R %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Have, Christian T %A Hayward, Caroline %A He, Liang %A Heard-Costa, Nancy L %A Heath, Andrew C %A Heid, Iris M %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Kiemeney, Lambertus A %A Kim, Eric %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Kooperberg, Charles %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Lange, Leslie A %A Langenberg, Claudia %A Larson, Eric B %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Liu, Yongmei %A Lo, Ken S %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Medland, Sarah E %A Meidtner, Karina %A Milani, Lili %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Nyholt, Dale R %A O'Connel, Jeffrey R %A O'Donoghue, Michelle L %A Olde Loohuis, Loes M %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Polderman, Tinca J %A Puolijoki, Hannu %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Robertson, Neil R %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati H %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Smith, Albert V %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen E %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Velez Edwards, Digna R %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Ware, Erin B %A Wareham, Nicholas J %A Warren, Helen R %A Waterworth, Dawn M %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Witte, Daniel R %A Wood, Andrew R %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhao, Wei %A Zhou, Wei %A Zondervan, Krina T %A Rotter, Jerome I %A Pospisilik, John A %A Rivadeneira, Fernando %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Lettre, Guillaume %A North, Kari E %A Lindgren, Cecilia M %A Hirschhorn, Joel N %A Loos, Ruth J F %K Adult %K Animals %K Body Mass Index %K Drosophila %K Energy Intake %K Energy Metabolism %K Female %K Gene Frequency %K Genetic Variation %K Humans %K Male %K Obesity %K Proteins %K Syndrome %X

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

%B Nat Genet %V 50 %P 26-41 %8 2018 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29273807?dopt=Abstract %R 10.1038/s41588-017-0011-x %0 Journal Article %J Nat Genet %D 2018 %T Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Esko, Tõnu %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Manning, Alisa K %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Winkler, Thomas W %A Abecasis, Goncalo %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Allison, Matthew %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Butterworth, Adam S %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der I %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Corominas Galbany, Jordi %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Davies, Gail %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A Heijer, Martin %A Hollander, Anneke I %A Ruijter, Hester M %A Dennis, Joe G %A Denny, Josh C %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dube, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Faul, Jessica D %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrieres, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grabe, Hans-Jörgen %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeff %A Hakonarson, Hakon %A Hammerschlag, Anke R %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Have, Christian T %A Hayward, Caroline %A He, Liang %A Heard-Costa, Nancy L %A Heath, Andrew C %A Heid, Iris M %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Kiemeney, Lambertus A %A Kim, Eric %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Kooperberg, Charles %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Lange, Leslie A %A Langenberg, Claudia %A Larson, Eric B %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Liu, Yongmei %A Lo, Ken S %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Medland, Sarah E %A Meidtner, Karina %A Milani, Lili %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Nyholt, Dale R %A O'Connel, Jeffrey R %A O'Donoghue, Michelle L %A Olde Loohuis, Loes M %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Polderman, Tinca J %A Puolijoki, Hannu %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Robertson, Neil R %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati H %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Smith, Albert V %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen E %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Velez Edwards, Digna R %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Ware, Erin B %A Wareham, Nicholas J %A Warren, Helen R %A Waterworth, Dawn M %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Witte, Daniel R %A Wood, Andrew R %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhao, Wei %A Zhou, Wei %A Zondervan, Krina T %A Rotter, Jerome I %A Pospisilik, John A %A Rivadeneira, Fernando %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Lettre, Guillaume %A North, Kari E %A Lindgren, Cecilia M %A Hirschhorn, Joel N %A Loos, Ruth J F %X

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

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

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

%B Nat Genet %V 50 %P 765-766 %8 2018 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29549329?dopt=Abstract %R 10.1038/s41588-018-0050-y %0 Journal Article %J Nature %D 2017 %T Rare and low-frequency coding variants alter human adult height. %A Marouli, Eirini %A Graff, Mariaelisa %A Medina-Gomez, Carolina %A Lo, Ken Sin %A Wood, Andrew R %A Kjaer, Troels R %A Fine, Rebecca S %A Lu, Yingchang %A Schurmann, Claudia %A Highland, Heather M %A Rüeger, Sina %A Thorleifsson, Gudmar %A Justice, Anne E %A Lamparter, David %A Stirrups, Kathleen E %A Turcot, Valérie %A Young, Kristin L %A Winkler, Thomas W %A Esko, Tõnu %A Karaderi, Tugce %A Locke, Adam E %A Masca, Nicholas G D %A Ng, Maggie C Y %A Mudgal, Poorva %A Rivas, Manuel A %A Vedantam, Sailaja %A Mahajan, Anubha %A Guo, Xiuqing %A Abecasis, Goncalo %A Aben, Katja K %A Adair, Linda S %A Alam, Dewan S %A Albrecht, Eva %A Allin, Kristine H %A Allison, Matthew %A Amouyel, Philippe %A Appel, Emil V %A Arveiler, Dominique %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Banas, Bernhard %A Bang, Lia E %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bonnycastle, Lori L %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Burt, Amber A %A Butterworth, Adam S %A Carey, David J %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Galbany, Jordi Corominas %A Cox, Amanda J %A Cuellar-Partida, Gabriel %A Danesh, John %A Davies, Gail %A de Bakker, Paul I W %A de Borst, Gert J %A de Denus, Simon %A de Groot, Mark C H %A de Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A den Hollander, Anneke I %A Dennis, Joe G %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dunning, Alison M %A Easton, Douglas F %A Ebeling, Tapani %A Edwards, Todd L %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Faul, Jessica D %A Feitosa, Mary F %A Feng, Shuang %A Ferrannini, Ele %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Giri, Ayush %A Girotto, Giorgia %A Gordon, Scott D %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grarup, Niels %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Hayward, Caroline %A He, Liang %A Heid, Iris M %A Heikkilä, Kauko %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Hocking, Lynne J %A Hollensted, Mette %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hoyng, Carel B %A Huang, Paul L %A Hveem, Kristian %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jhun, Min A %A Jia, Yucheng %A Jiang, Xuejuan %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jousilahti, Pekka %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kee, Frank %A Keeman, Renske %A Kiemeney, Lambertus A %A Kitajima, Hidetoshi %A Kluivers, Kirsten B %A Kocher, Thomas %A Komulainen, Pirjo %A Kontto, Jukka %A Kooner, Jaspal S %A Kooperberg, Charles %A Kovacs, Peter %A Kriebel, Jennifer %A Kuivaniemi, Helena %A Küry, Sébastien %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lakka, Timo A %A Lange, Ethan M %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Larson, Eric B %A Lee, I-Te %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Yeheng %A Liu, Yongmei %A Lophatananon, Artitaya %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Mackey, David A %A Madden, Pamela A F %A Manning, Alisa K %A Männistö, Satu %A Marenne, Gaëlle %A Marten, Jonathan %A Martin, Nicholas G %A Mazul, Angela L %A Meidtner, Karina %A Metspalu, Andres %A Mitchell, Paul %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Morgan, Anna %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Ntalla, Ioanna %A O'Connel, Jeffrey R %A Oksa, Heikki %A Loohuis, Loes M Olde %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Person, Thomas N %A Pirie, Ailith %A Polasek, Ozren %A Posthuma, Danielle %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Ridker, Paul M %A Rioux, John D %A Robertson, Neil %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sandow, Kevin %A Sapkota, Yadav %A Sattar, Naveed %A Schmidt, Marjanka K %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Smith, Albert Vernon %A Smith, Jennifer A %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Steinthorsdottir, Valgerdur %A Stringham, Heather M %A Stumvoll, Michael %A Surendran, Praveen %A 't Hart, Leen M %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Ulivi, Sheila %A van der Laan, Sander W %A Van Der Leij, Andries R %A van Duijn, Cornelia M %A van Schoor, Natasja M %A van Setten, Jessica %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Edwards, Digna R Velez %A Vermeulen, Sita H %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Vozzi, Diego %A Walker, Mark %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Wareham, Nicholas J %A Warren, Helen R %A Wessel, Jennifer %A Willems, Sara M %A Wilson, James G %A Witte, Daniel R %A Woods, Michael O %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhao, Wei %A Zheng, He %A Zhou, Wei %A Rotter, Jerome I %A Boehnke, Michael %A Kathiresan, Sekar %A McCarthy, Mark I %A Willer, Cristen J %A Stefansson, Kari %A Borecki, Ingrid B %A Liu, Dajiang J %A North, Kari E %A Heard-Costa, Nancy L %A Pers, Tune H %A Lindgren, Cecilia M %A Oxvig, Claus %A Kutalik, Zoltán %A Rivadeneira, Fernando %A Loos, Ruth J F %A Frayling, Timothy M %A Hirschhorn, Joel N %A Deloukas, Panos %A Lettre, Guillaume %K ADAMTS Proteins %K Adult %K Alleles %K Body Height %K Cell Adhesion Molecules %K Female %K Gene Frequency %K Genetic Variation %K Genome, Human %K Glycoproteins %K Glycosaminoglycans %K Hedgehog Proteins %K Humans %K Intercellular Signaling Peptides and Proteins %K Interferon Regulatory Factors %K Interleukin-11 Receptor alpha Subunit %K Male %K Multifactorial Inheritance %K NADPH Oxidase 4 %K NADPH Oxidases %K Phenotype %K Pregnancy-Associated Plasma Protein-A %K Procollagen N-Endopeptidase %K Proteoglycans %K Proteolysis %K Receptors, Androgen %K Somatomedins %X

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

%B Nature %V 542 %P 186-190 %8 2017 Feb 09 %G eng %N 7640 %1 https://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract %R 10.1038/nature21039 %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