The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Authors: Georg Ehret, Teresa Ferreira, Daniel I. Chasman, Anne Jackson, Ellen M. Schmidt, Toby Johnson, Guðmar Þorleifsson, Jian’an Luan, Louise A Donnelly, Stavroula Kanoni, Ann-Kristin Petersen, Vasyl Pihur, Rona J. Strawbridge, Dmitry Shungin, Maria Hughes, Osorio Meirelles, Marika Kaakinen, Nabila Bouatia‐Naji, Kati Kristiansson, Sonia Shah, Marcus E. Kleber, Xiuqing Guo, Leo‐Pekka Lyytikäinen, Cristiano Fava, Niclas Eriksson, Ilja M. Nolte, Patrik K. E. Magnusson, Elias Salfati, Lοukianos S. Rallidis, Elizabeth Theusch, Andrew J. Smith, Lasse Folkersen, Kate Witkowska, Tune H. Pers, Roby Joehanes, Stuart K. Kim, Lazaros Lataniotis, Rick Jansen, Andrew D. Johnson, Helen R. Warren, Young Jin Kim, Wei Zhao, Ying Wu, Bamidele O. Tayo, Murielle Bochud, Devin Absher, Linda S. Adair, Najaf Amin, Dan E. Arking, Tomas Axelsson, Damiano Baldassarre, Beverley Balkau, Stefania Bandinelli, Michael R. Barnes, Inês Barroso, Steve Bevan, Joshua C Bis, Gyða Björnsdóttir, Michael Boehnke, Eric Boerwinkle, Lori L. Bonnycastle, Dorret I. Boomsma, Stefan R. Bornstein, Morris J. Brown, Michel Burnier, Claudia Cabrera, John C. Chambers, I‐Shou Chang, Ching‐Yu Cheng, Peter S. Chines, Ren-Hua Chung, Francis S. Collins, John Connell, Angela Döring, Jean Dallongeville, John Danesh, Ulf dé Fairé, Graciela Delgado, Anna F. Dominiczak, Alex S. F. Doney, Fotios Drenos, Sarah Edkins, John D. Eicher, Roberto Elosúa, Stefan Enroth, Jeanette Erdmann, Per Eriksson, Tõnu Esko, Εvangelos Εvangelou, Alun Evans, Tove Fall, Martin Farrall, Janine F. Felix, Jean Ferrières, Luigi Ferrucci, Myriam Fornage, Terrence Forrester, Nora Franceschini, Oscar H Franco Duran, Anders Franco‐Cereceda, Ross M. Fraser, Santhi K. Ganesh, He Gao, Karl Gertow, Francesco Gianfagna, Bruna Gigante, Franco Giulianini, Anuj Goel, Alison H. Goodall, Mark O Goodarzi, Mathias Gorski, Jürgen Gräßler, Christopher J. Groves, Vilmundur Guðnason, Ulf Gyllensten, Göran Hallmans, Anna-Liisa Hartikainen, Maija Hassinen, Aki S. Havulinna, Caroline Hayward, Serge Herçberg, Karl-Heinz Herzig, Andrew A. Hicks, Aroon D. Hingorani, Joel N. Hirschhorn, Albert Hofman, Jostein Holmen, Oddgeir L. Holmen, Jouke‐Jan Hottenga, Phil Howard, Chao A. Hsiung, Steven C. Hunt, M. Arfan Ikram, Thomas Illig, Carlos Iribarren, Richard A. Jensen, Mika Kähönen, Hyun Min Kang, Sekar Kathiresan, Brendan J. Keating, Kay‐Tee Khaw, Yun Kyoung Kim, Eric H. Kim, Mika Kivimäki, Norman Klopp, Genovefa Kolovou, Pirjo Komulainen, Jaspal S. Kooner, Gülüm Kosova, Ronald M. Krauss, Diana Kuh, Zoltán Kutalik, Johanna Kuusisto, Kirsti Kvaløy, Timo A. Lakka, Sang Lee, I‐Te Lee, Wen‐Jane Lee, Daniel Levy, Xiaohui Li, Kae-Woei Liang, Honghuang Lin, Lin Li, Jaana Lindström, Stéphane Lobbens, Satu Männistö, Gabriele Müller, Martina Müller‐Nurasyid, François Mach, Hugh S. Markus, Eirini Marouli, Mark I. McCarthy, Colin A. McKenzie, Pierre Meneton, Cristina Menni, Andres Metspalu, Vladan Mijatovic, Leena Moilanen, May E. Montasser, Andrew D Morris, Alanna C. Morrison, Antonella Mulas, Ramaiah Nagaraja, Narisu Narisu, Kjell Nikus, Christopher J. O’Donnell, Paul F. O’Reilly, Ken K. Ong, Fred Paccaud, Cameron D. Palmer, Afshin Parsa, Nancy L. Pedersen, Brenda W.J.H. Penninx, Markus Perola, Annette Peters, Neil Poulter, Peter P. Pramstaller, Bruce M. Psaty, Thomas Quertermous, Dabeeru C Rao, Asif Rasheed, N. William Rayner, Frida Renström, Rainer Rettig, Kenneth Rice, Robert Roberts, Lynda M. Rose, Jacques Rossouw, Nilesh J. Samani, Serena Sanna, Jouko Saramies, Heribert Schunkert, Sylvain Sebért, Wayne H-H Sheu, Young-Ah Shin, Xueling Sim, Johannes H. Smit, Albert V. Smith, Maria X. Sosa, Tim D. Spector, Alena Stančáková, Alice Stanton, Kathleen Stirrups, Heather M. Stringham, Johan Sundström, Amy J. Swift, Ann‐Christine Syvänen, E Shyong Tai, Toshiko Tanaka, Kirill V. Tarasov, Alexander Teumer, Unnur Thorsteinsdottir, Martin D. Tobin, Elena Tremoli, André G. Uitterlinden, Matti Uusitupa, Ahmad Vaez, Dhananjay Vaidya, Cornelia M. van Duijn, Erik P.A. van Iperen, Ramachandran S. Vasan, Germaine C. Verwoert, Jarmo Virtamo, Véronique Vitart, Benjamin F. Voight, Péter Vollenweider, Aline Wagner, Louise V. Wain, Nicholas J. Wareham, Hugh Watkins, Alan B. Weder, Harm-Jan Westra, Rainford Wilks, Tom Wilsgaard, James F Wilson, Tien Yin Wong, Tsun-Po Yang, Jie Yao, Loïc Yengo, Weihua Zhang, Jing Hua Zhao, Xiaofeng Zhu, Pascal Bovet, Richard S Cooper, Karen L Mohlke, Danish Saleheen, Jong‐Young Lee, Paul Elliott, Hinco J. Gierman, Cristen J. Willer, Lude Franke, G. Kees Hovingh, Kent D. Taylor, George Dedoussis, Peter S. Sever, Andrew Wong, Lars Lind, Themistocles L. Assimes, Inger Njølstad, Peter E. H. Schwarz, Claudia Langenberg, Harold Snieder, Mark J. Caulfield, Olle Melander, Markku Laakso, Juha Saltevo, Rainer Rauramaa, Jaakko Tuomilehto, Erik Ingelsson, Terho Lehtimäki, Kristian Hveem, Walter Palmas, Winfried März, Meena Kumari, Veikko Salomaa, Yii‐Der I. Chen, Jerome I. Rotter, Philippe Froguel, Marjo‐Riitta Järvelin, Edward G. Lakatta, Kari Kuulasmaa, Paul W. Franks, Anders Hamsten, H-Erich Wichmann, Colin N A Palmer, Kāri Stefánsson, Paul M. Ridker, Ruth J. F. Loos, Aravinda Chakravarti, Panos Deloukas, Andrew P. Morris, Christopher Newton‐Cheh, Patricia B. Munroe - Nature Genetics 2016 cited by 438

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.