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

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

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/30224653?dopt=Abstract %R 10.1038/s41588-018-0205-x %0 Journal Article %J Am J Hum Genet %D 2018 %T A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. %A Sung, Yun J %A Winkler, Thomas W %A de Las Fuentes, Lisa %A Bentley, Amy R %A Brown, Michael R %A Kraja, Aldi T %A Schwander, Karen %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Noordam, Raymond %A Aslibekyan, Stella %A Aschard, Hugues %A Bartz, Traci M %A Dorajoo, Rajkumar %A Liu, Yongmei %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Warren, Helen R %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 Pires %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Kuhnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A 'an Luan, Jian %A McKenzie, Colin A %A Meian, He %A Nelson, Christopher P %A Rauramaa, Rainer %A Schupf, Nicole %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 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 %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cabrera, Claudia P %A Cade, Brian %A Caizheng, Yu %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Chauhan, Ganesh %A Christensen, Kaare %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Debette, Stéphanie %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Fisher, Virginia A %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Graff, Misa %A Gu, C Charles %A Gu, Dongfeng %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven %A Irvin, Marguerite R %A Jia, Yucheng %A Joehanes, Roby %A Justice, Anne E %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Komulainen, Pirjo %A Kooperberg, Charles %A Krieger, Jose E %A Kubo, Michiaki %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Kiang %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Long, Jirong %A Louie, Tin %A Mägi, Reedik %A Mahajan, Anubha %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Morris, Andrew P %A Mosley, Thomas H %A Munson, Peter %A Murray, Alison D %A Nalls, Mike A %A Nasri, Ubaydah %A Norris, Jill M %A North, Kari %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %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 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 Seshadri, Sudha %A Sever, Peter %A Sitlani, Colleen M %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 X %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %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 de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost B %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Newman, Anne B %A Oldehinkel, Albertine J %A Pereira, Alexandre C %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 Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Levy, Daniel %A O'Connell, Jeff R %A Psaty, Bruce M %A van Dam, Rob M %A Sims, Mario %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A Fornage, Myriam %A Rotimi, Charles N %A Province, Michael A %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Caulfield, Mark J %A Elliott, Paul %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Cupples, L Adrienne %A Rao, Dabeeru C %A Chasman, Daniel I %K Blood Pressure %K Cohort Studies %K Continental Population Groups %K Diastole %K Epistasis, Genetic %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Reproducibility of Results %K Smoking %K Systole %X

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

%B Am J Hum Genet %V 102 %P 375-400 %8 2018 03 01 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29455858?dopt=Abstract %R 10.1016/j.ajhg.2018.01.015 %0 Journal Article %J PLoS One %D 2018 %T Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. %A Feitosa, Mary F %A Kraja, Aldi T %A Chasman, Daniel I %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Bentley, Amy R %A Brown, Michael R %A Schwander, Karen %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Wojczynski, Mary K %A Alver, Maris %A Boissel, Mathilde %A Cai, Qiuyin %A Campbell, Archie %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Laguzzi, Federica %A Luan, Jian'an %A Matoba, Nana %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Riaz, Muhammad %A Rueedi, Rico %A Robino, Antonietta %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Vitart, Veronique %A Wang, Yajuan %A Ware, Erin B %A Warren, Helen R %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Boerwinkle, Eric %A Borecki, Ingrid %A Broeckel, Ulrich %A Brown, Morris %A Brumat, Marco %A Burke, Gregory L %A Canouil, Mickaël %A Chakravarti, Aravinda %A Charumathi, Sabanayagam %A Ida Chen, Yii-Der %A Connell, John M %A Correa, Adolfo %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Deng, Xuan %A Ding, Jingzhong %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Eppinga, Ruben N %A Evangelou, Evangelos %A Faul, Jessica D %A Felix, Stephan B %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gigante, Bruna %A Gu, C Charles %A Gu, Dongfeng %A Hagenaars, Saskia P %A Hallmans, Goran %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Howard, Barbara V %A Ikram, M Arfan %A John, Ulrich %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lin, Shiow %A Liu, Jianjun %A Liu, Jingmin %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Nalls, Mike A %A Nelson, Christopher P %A Sotoodehnia, Nona %A Norris, Jill M %A O'Connell, Jeff R %A Palmer, Nicholette D %A Perls, Thomas %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Roll, Kathryn %A Rose, Lynda M %A Rosendaal, Frits R %A Rotter, Jerome I %A Schmidt, Carsten O %A Schreiner, Pamela J %A Schupf, Nicole %A Scott, William R %A Sever, Peter S %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Turner, Stephen T %A Uitterlinden, André G %A Vollenweider, Peter %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Williams, Christine %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Kutalik, Zoltán %A Laakso, Markku %A Laurie, Cathy C %A Leander, Karin %A Lehtimäki, Terho %A Study, Lifelines Cohort %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Polasek, Ozren %A Porteous, David J %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Bouchard, Claude %A Christensen, Kaare %A Evans, Michele K %A Gudnason, Vilmundur %A Horta, Bernardo L %A Kardia, Sharon L R %A Liu, Yongmei %A Pereira, Alexandre C %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Gauderman, W James %A Zhu, Xiaofeng %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Rotimi, Charles N %A Cupples, L Adrienne %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Kooperberg, Charles %A Palmas, Walter %A Rice, Kenneth %A Morrison, Alanna C %A Elliott, Paul %A Caulfield, Mark J %A Munroe, Patricia B %A Rao, Dabeeru C %A Province, Michael A %A Levy, Daniel %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Alcohol Drinking %K Blood Pressure %K Cohort Studies %K Continental Population Groups %K Female %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Pedigree %K Polymorphism, Single Nucleotide %K Young Adult %X

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

%B PLoS One %V 13 %P e0198166 %8 2018 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/29912962?dopt=Abstract %R 10.1371/journal.pone.0198166 %0 Journal Article %J Nat Genet %D 2017 %T Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. %A Day, Felix R %A Thompson, Deborah J %A Helgason, Hannes %A Chasman, Daniel I %A Finucane, Hilary %A Sulem, Patrick %A Ruth, Katherine S %A Whalen, Sean %A Sarkar, Abhishek K %A Albrecht, Eva %A Altmaier, Elisabeth %A Amini, Marzyeh %A Barbieri, Caterina M %A Boutin, Thibaud %A Campbell, Archie %A Demerath, Ellen %A Giri, Ayush %A He, Chunyan %A Hottenga, Jouke J %A Karlsson, Robert %A Kolcic, Ivana %A Loh, Po-Ru %A Lunetta, Kathryn L %A Mangino, Massimo %A Marco, Brumat %A McMahon, George %A Medland, Sarah E %A Nolte, Ilja M %A Noordam, Raymond %A Nutile, Teresa %A Paternoster, Lavinia %A Perjakova, Natalia %A Porcu, Eleonora %A Rose, Lynda M %A Schraut, Katharina E %A Segrè, Ayellet V %A Smith, Albert V %A Stolk, Lisette %A Teumer, Alexander %A Andrulis, Irene L %A Bandinelli, Stefania %A Beckmann, Matthias W %A Benitez, Javier %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bojesen, Stig E %A Bolla, Manjeet K %A Brand, Judith S %A Brauch, Hiltrud %A Brenner, Hermann %A Broer, Linda %A Brüning, Thomas %A Buring, Julie E %A Campbell, Harry %A Catamo, Eulalia %A Chanock, Stephen %A Chenevix-Trench, Georgia %A Corre, Tanguy %A Couch, Fergus J %A Cousminer, Diana L %A Cox, Angela %A Crisponi, Laura %A Czene, Kamila %A Davey Smith, George %A de Geus, Eco J C N %A de Mutsert, Renée %A De Vivo, Immaculata %A Dennis, Joe %A Devilee, Peter %A Dos-Santos-Silva, Isabel %A Dunning, Alison M %A Eriksson, Johan G %A Fasching, Peter A %A Fernández-Rhodes, Lindsay %A Ferrucci, Luigi %A Flesch-Janys, Dieter %A Franke, Lude %A Gabrielson, Marike %A Gandin, Ilaria %A Giles, Graham G %A Grallert, Harald %A Gudbjartsson, Daniel F %A Guenel, Pascal %A Hall, Per %A Hallberg, Emily %A Hamann, Ute %A Harris, Tamara B %A Hartman, Catharina A %A Heiss, Gerardo %A Hooning, Maartje J %A Hopper, John L %A Hu, Frank %A Hunter, David J %A Ikram, M Arfan %A Im, Hae Kyung %A Järvelin, Marjo-Riitta %A Joshi, Peter K %A Karasik, David %A Kellis, Manolis %A Kutalik, Zoltán %A LaChance, Genevieve %A Lambrechts, Diether %A Langenberg, Claudia %A Launer, Lenore J %A Laven, Joop S E %A Lenarduzzi, Stefania %A Li, Jingmei %A Lind, Penelope A %A Lindström, Sara %A Liu, Yongmei %A Luan, Jian'an %A Mägi, Reedik %A Mannermaa, Arto %A Mbarek, Hamdi %A McCarthy, Mark I %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Metspalu, Andres %A Michailidou, Kyriaki %A Milani, Lili %A Milne, Roger L %A Montgomery, Grant W %A Mulligan, Anna M %A Nalls, Mike A %A Navarro, Pau %A Nevanlinna, Heli %A Nyholt, Dale R %A Oldehinkel, Albertine J %A O'Mara, Tracy A %A Padmanabhan, Sandosh %A Palotie, Aarno %A Pedersen, Nancy %A Peters, Annette %A Peto, Julian %A Pharoah, Paul D P %A Pouta, Anneli %A Radice, Paolo %A Rahman, Iffat %A Ring, Susan M %A Robino, Antonietta %A Rosendaal, Frits R %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Sala, Cinzia F %A Schmidt, Marjanka K %A Scott, Robert A %A Shah, Mitul %A Sorice, Rossella %A Southey, Melissa C %A Sovio, Ulla %A Stampfer, Meir %A Steri, Maristella %A Strauch, Konstantin %A Tanaka, Toshiko %A Tikkanen, Emmi %A Timpson, Nicholas J %A Traglia, Michela %A Truong, Therese %A Tyrer, Jonathan P %A Uitterlinden, André G %A Edwards, Digna R Velez %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Wang, Qin %A Widen, Elisabeth %A van Dijk, Ko Willems %A Willemsen, Gonneke %A Winqvist, Robert %A Wolffenbuttel, Bruce H R %A Zhao, Jing Hua %A Zoledziewska, Magdalena %A Zygmunt, Marek %A Alizadeh, Behrooz Z %A Boomsma, Dorret I %A Ciullo, Marina %A Cucca, Francesco %A Esko, Tõnu %A Franceschini, Nora %A Gieger, Christian %A Gudnason, Vilmundur %A Hayward, Caroline %A Kraft, Peter %A Lawlor, Debbie A %A Magnusson, Patrik K E %A Martin, Nicholas G %A Mook-Kanamori, Dennis O %A Nohr, Ellen A %A Polasek, Ozren %A Porteous, David %A Price, Alkes L %A Ridker, Paul M %A Snieder, Harold %A Spector, Tim D %A Stöckl, Doris %A Toniolo, Daniela %A Ulivi, Sheila %A Visser, Jenny A %A Völzke, Henry %A Wareham, Nicholas J %A Wilson, James F %A Spurdle, Amanda B %A Thorsteindottir, Unnur %A Pollard, Katherine S %A Easton, Douglas F %A Tung, Joyce Y %A Chang-Claude, Jenny %A Hinds, David %A Murray, Anna %A Murabito, Joanne M %A Stefansson, Kari %A Ong, Ken K %A Perry, John R B %K Adolescent %K Age Factors %K Body Mass Index %K Databases, Genetic %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomic Imprinting %K Humans %K Intercellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Menarche %K Neoplasms %K Polymorphism, Single Nucleotide %K Puberty %K Quantitative Trait Loci %K Ribonucleoproteins %K Risk Factors %X

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

%B Nat Genet %V 49 %P 834-841 %8 2017 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/28436984?dopt=Abstract %R 10.1038/ng.3841 %0 Journal Article %J Hypertension %D 2017 %T Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. %A Wain, Louise V %A Vaez, Ahmad %A Jansen, Rick %A Joehanes, Roby %A van der Most, Peter J %A Erzurumluoglu, A Mesut %A O'Reilly, Paul F %A Cabrera, Claudia P %A Warren, Helen R %A Rose, Lynda M %A Verwoert, Germaine C %A Hottenga, Jouke-Jan %A Strawbridge, Rona J %A Esko, Tõnu %A Arking, Dan E %A Hwang, Shih-Jen %A Guo, Xiuqing %A Kutalik, Zoltán %A Trompet, Stella %A Shrine, Nick %A Teumer, Alexander %A Ried, Janina S %A Bis, Joshua C %A Smith, Albert V %A Amin, Najaf %A Nolte, Ilja M %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Wareham, Nicholas J %A Hofer, Edith %A Joshi, Peter K %A Kristiansson, Kati %A Traglia, Michela %A Havulinna, Aki S %A Goel, Anuj %A Nalls, Mike A %A Sõber, Siim %A Vuckovic, Dragana %A Luan, Jian'an %A del Greco M, Fabiola %A Ayers, Kristin L %A Marrugat, Jaume %A Ruggiero, Daniela %A Lopez, Lorna M %A Niiranen, Teemu %A Enroth, Stefan %A Jackson, Anne U %A Nelson, Christopher P %A Huffman, Jennifer E %A Zhang, Weihua %A Marten, Jonathan %A Gandin, Ilaria %A Harris, Sarah E %A Zemunik, Tatijana %A Lu, Yingchang %A Evangelou, Evangelos %A Shah, Nabi %A de Borst, Martin H %A Mangino, Massimo %A Prins, Bram P %A Campbell, Archie %A Li-Gao, Ruifang %A Chauhan, Ganesh %A Oldmeadow, Christopher %A Abecasis, Goncalo %A Abedi, Maryam %A Barbieri, Caterina M %A Barnes, Michael R %A Batini, Chiara %A Beilby, John %A Blake, Tineka %A Boehnke, Michael %A Bottinger, Erwin P %A Braund, Peter S %A Brown, Morris %A Brumat, Marco %A Campbell, Harry %A Chambers, John C %A Cocca, Massimiliano %A Collins, Francis %A Connell, John %A Cordell, Heather J %A Damman, Jeffrey J %A Davies, Gail %A de Geus, Eco J %A de Mutsert, Renée %A Deelen, Joris %A Demirkale, Yusuf %A Doney, Alex S F %A Dörr, Marcus %A Farrall, Martin %A Ferreira, Teresa %A Frånberg, Mattias %A Gao, He %A Giedraitis, Vilmantas %A Gieger, Christian %A Giulianini, Franco %A Gow, Alan J %A Hamsten, Anders %A Harris, Tamara B %A Hofman, Albert %A Holliday, Elizabeth G %A Hui, Jennie %A Järvelin, Marjo-Riitta %A Johansson, Åsa %A Johnson, Andrew D %A Jousilahti, Pekka %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Khaw, Kay-Tee %A Kolcic, Ivana %A Koskinen, Seppo %A Langenberg, Claudia %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Mach, François %A Mamasoula, Chrysovalanto %A Menni, Cristina %A Mifsud, Borbala %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew D %A Morrison, Alanna C %A Munson, Peter J %A Nandakumar, Priyanka %A Nguyen, Quang Tri %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A Org, Elin %A Padmanabhan, Sandosh %A Palotie, Aarno %A Paré, Guillaume %A Pattie, Alison %A Penninx, Brenda W J H %A Poulter, Neil %A Pramstaller, Peter P %A Raitakari, Olli T %A Ren, Meixia %A Rice, Kenneth %A Ridker, Paul M %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rotter, Jerome I %A Rudan, Igor %A Saba, Yasaman %A Saint Pierre, Aude %A Sala, Cinzia F %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Scott, Rodney %A Seelen, Marc A %A Shields, Denis C %A Siscovick, David %A Sorice, Rossella %A Stanton, Alice %A Stott, David J %A Sundström, Johan %A Swertz, Morris %A Taylor, Kent D %A Thom, Simon %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, André G %A Völker, Uwe %A Vollenweider, Peter %A Wild, Sarah %A Willemsen, Gonneke %A Wright, Alan F %A Yao, Jie %A Thériault, Sébastien %A Conen, David %A Attia, John %A Sever, Peter %A Debette, Stéphanie %A Mook-Kanamori, Dennis O %A Zeggini, Eleftheria %A Spector, Tim D %A van der Harst, Pim %A Palmer, Colin N A %A Vergnaud, Anne-Claire %A Loos, Ruth J F %A Polasek, Ozren %A Starr, John M %A Girotto, Giorgia %A Hayward, Caroline %A Kooner, Jaspal S %A Lindgren, Cecila M %A Vitart, Veronique %A Samani, Nilesh J %A Tuomilehto, Jaakko %A Gyllensten, Ulf %A Knekt, Paul %A Deary, Ian J %A Ciullo, Marina %A Elosua, Roberto %A Keavney, Bernard D %A Hicks, Andrew A %A Scott, Robert A %A Gasparini, Paolo %A Laan, Maris %A Liu, Yongmei %A Watkins, Hugh %A Hartman, Catharina A %A Salomaa, Veikko %A Toniolo, Daniela %A Perola, Markus %A Wilson, James F %A Schmidt, Helena %A Zhao, Jing Hua %A Lehtimäki, Terho %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Peters, Annette %A Rettig, Rainer %A James, Alan %A Jukema, J Wouter %A Strachan, David P %A Palmas, Walter %A Metspalu, Andres %A Ingelsson, Erik %A Boomsma, Dorret I %A Franco, Oscar H %A Bochud, Murielle %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Elliott, Paul %A Chasman, Daniel I %A Chakravarti, Aravinda %A Knight, Joanne %A Morris, Andrew P %A Levy, Daniel %A Tobin, Martin D %A Snieder, Harold %A Caulfield, Mark J %A Ehret, Georg B %X

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near , , , , , and , and provide new replication evidence for a further 2 signals in and Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

%B Hypertension %8 2017 Jul 24 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28739976?dopt=Abstract %R 10.1161/HYPERTENSIONAHA.117.09438 %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 Ferrières, 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 Tönjes, 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 02 09 %G eng %N 7640 %1 http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract %R 10.1038/nature21039