Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Praveen Surendran, Fotios Drenos, Robin Young, Helen Warren, James P Cook, Alisa K Manning, Niels Grarup, Xueling Sim, Daniel R Barnes, Kate Witkowska, James R Staley, Vinicius Tragante, Taru Tukiainen, Hanieh Yaghootkar, Nicholas Masca, Daniel F Freitag, Teresa Ferreira, Olga Giannakopoulou, Andrew Tinker, Magdalena Harakalova, Evelin Mihailov, Chunyu Liu, Aldi T Kraja, Sune Fallgaard Nielsen, Asif Rasheed, Maria Samuel, Wei Zhao, Lori L Bonnycastle, Anne U Jackson, Narisu Narisu, Amy J Swift, Lorraine Southam, Jonathan Marten, Jeroen R Huyghe, Alena Stančáková, Cristiano Fava, Therese Ohlsson, Angela Matchan, Kathleen E Stirrups, Jette Bork-Jensen, Anette P Gjesing, Jukka Kontto, Markus Perola, Susan Shaw-Hawkins, Aki S Havulinna, He Zhang, Louise A Donnelly, Christopher J Groves, N William Rayner, Matt J Neville, Neil R Robertson, Andrianos M Yiorkas, Karl-Heinz Herzig, Eero Kajantie, Weihua Zhang, Sara M Willems, Lars Lannfelt, Giovanni Malerba, Nicole Soranzo, Elisabetta Trabetti, Niek Verweij, Evangelos Evangelou, Alireza Moayyeri, Anne-Claire Vergnaud, Christopher P Nelson, Alaitz Poveda, Tibor V Varga, Muriel Caslake, Anton J M de Craen, Stella Trompet, Jian’an Luan, Robert A Scott, Sarah E Harris, David C M Liewald, Riccardo Marioni, Cristina Menni, Aliki-Eleni Farmaki, Göran Hallmans, Frida Renström, Jennifer E Huffman, Maija Hassinen, Stephen Burgess, Ramachandran S Vasan, Janine F Felix, Maria Uria-Nickelsen, Anders Malarstig, Dermot F Reilly, Maarten Hoek, Thomas F Vogt, Honghuang Lin, Wolfgang Lieb, Matthew Traylor, Hugh S Markus, Heather M Highland, Anne E Justice, Eirini Marouli, Jaana Lindström, Matti Uusitupa, Pirjo Komulainen, Timo A Lakka, Rainer Rauramaa, Ozren Polasek, Igor Rudan, Olov Rolandsson, Paul W Franks, George Dedoussis, Timothy D Spector, Pekka Jousilahti, Satu Männistö, Ian J Deary, John M Starr, Claudia Langenberg, Nick J Wareham, Morris J Brown, Anna F Dominiczak, John M Connell, J Wouter Jukema, Naveed Sattar, Ian Ford, Chris J Packard, Tõnu Esko, Reedik Mägi, Andres Metspalu, Rudolf A de Boer, Peter van der Meer, Pim van der Harst, Giovanni Gambaro, Erik Ingelsson, Lars Lind, Paul I W de Bakker, Mattijs E Numans, Ivan Brandslund, Cramer Christensen, Eva R B Petersen, Eeva Korpi-Hyövälti, Heikki Oksa, John C Chambers, Jaspal S Kooner, Alexandra I F Blakemore, Steve Franks, Marjo-Riitta Jarvelin, Lise L Husemoen, Allan Linneberg, Tea Skaaby, Betina Thuesen, Fredrik Karpe, Jaakko Tuomilehto, Alex S F Doney, Andrew D Morris, Colin N A Palmer, Oddgeir Lingaas Holmen, Kristian Hveem, Cristen J Willer, Tiinamaija Tuomi, Leif Groop, AnneMari Käräjämäki, Aarno Palotie, Samuli Ripatti, Veikko Salomaa, Dewan S Alam, Abdulla al Shafi Majumder, Emanuele Di Angelantonio, Rajiv Chowdhury, Mark I McCarthy, Neil Poulter, Alice V Stanton, Peter Sever, Philippe Amouyel, Dominique Arveiler, Stefan Blankenberg, Jean Ferrières, Frank Kee, Kari Kuulasmaa, Martina Müller-Nurasyid, Giovanni Veronesi, Jarmo Virtamo, Panos Deloukas, Paul Elliott, Eleftheria Zeggini, Sekar Kathiresan, Olle Melander, Johanna Kuusisto, Markku Laakso, Sandosh Padmanabhan, David J Porteous, Caroline Hayward, Generation Scotland, Francis S Collins, Karen L Mohlke, Torben Hansen, Oluf Pedersen, Michael Boehnke, Heather M Stringham, Philippe Frossard, Christopher Newton-Cheh, Martin D Tobin, Børge Grønne Nordestgaard, Mark J Caulfield, Anubha Mahajan, Andrew P Morris, Maciej Tomaszewski, Nilesh J Samani, Danish Saleheen, Folkert W Asselbergs, Cecilia M Lindgren, John Danesh, Louise V Wain, Adam S Butterworth, Joanna M M Howson, Patricia B Munroe

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.