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 -1/4155,063 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.
Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension / P. Surendran, F. Drenos, R. Young, H. Warren, J. Cook, A. Manning, N. Grarup, X. Sim, D. Barnes, K. Witkowska, J. Staley, V. Tragante, T. Tukiainen, H. Yaghootkar, N. Masca, D. Freitag, T. Ferreira, O. Giannakopoulou, A. Tinker, M. Harakalova, E. Mihailov, C. Liu, A. Kraja, S. Nielsen, A. Rasheed, M. Samue, W. Zhao, L. Bonnycastle, A. Jackson, N. Narisu, A. Swift, L. Southam, J. Marten, J. Huyghe, A. Stancakova, C. Fava, T. Ohlsson, A. Matchan, K. Stirrups, J. Bork-Jensen, A. Gjesing, J. Kontto, M. Perola, S. Shaw-Hawkins, A. Havulinna, H. Zhang, L. Donnelly, C. Groves, N. Rayner, M. Neville, N. Robertson, A. Yiorkas, K. Herzig, E. Kajantie, W. Zhang, S. Willems, L. Lannfelt, G. Malerba, N. Soranzo, E. Trabetti, N. Verweij, E. Evangelou, A. Moayyeri, A. Vergnaud, C. Nelson, A. Poveda, T. Varga, M. Caslake, A. de Craen, S. Trompet, J. Luan, R. Scott, S. Harris, D. Liewald, R. Marioni, C. Menni, A. Farmaki, G. Hallmans, F. Renstrom, J. Huffman, M. Hassinen, S. Burgess, R. Vasan, J. Felix, M. Uria-Nickelsen, A. Malarstign, D. Reilly, M. Hoek, T. Vogt, H. Lin, W. Lieb, M. Traylor, H. Markus, H. Highland, A. Justice, E. Marouli, J. Lindstrom, M. Uusitupa, P. Komulainen, T. Lakka, R. Rauramaa, O. Polasek, I. Rudan, O. Rolandsson, P. Franks, G. Dedoussis, T. Spector, P. Jousilahti, S. Mannisto, I. Deary, J. Starr, C. Langenberg, N. Wareham, M. Brown, A. Dominiczak, J. Connell, J. Jukema, N. Sattar, I. Ford, C. Packard, T. Esko, R. Magi, A. Metspalu, R. de Boer, P. van der Meer, P. van der Harst, G. Gambaro, E. Ingelsson, L. Lind, P. de Bakker, M. Numans, I. Brandslund, C. Christensen, E. Petersen, E. Korpi-Hyovalti, H. Oksa, J. Chambers, J. Kooner, A. Blakemore, S. Franks, M. Jarvelin, L. Husemoen, A. Linneberg, T. Skaaby, B. Thuesen, F. Karpe, J. Tuomilehto, A. Doney, A. Morris, C. Palmer, O. Holmen, K. Hveem, C. Willer, T. Tuomi, L. Groop, A. Karajamaki, A. Palotie, S. Ripatti, V. Salomaa, D. Alam, A. Majmnder, E. Di Angelantonio, R. Chowdhury, M. Mccarthy, N. Poulter, A. Stanton, P. Sever, P. Amouyel, D. Arveiler, S. Blankenberg, J. Ferrieres, F. Kee, K. Kuulasmaa, M. Muller-Nurasyid, G. Veronesi, J. Virtamo, P. Deloukas, P. Elliott, E. Zeggini, S. Kathiresan, O. Melander, J. Kuusisto, M. Laakso, S. Padmanabhan, D. Porteous, C. Hayward, G. Scotland, F. Collins, K. Mohlke, T. Hansen, O. Pedersen, M. Boehnke, H. Stringham, P. Frossard, C. Newton-Cheh, M. Tobin, B. Nordestgaard, M. Caulfield, A. Mahajan, A. Morris, M. Tomaszewski, N. Samani, D. Saleheen, F. Asselbergs, C. Lindgren, J. Danesh, L. Wain, A. Butterworth, J. Howson, P. Munroe. - In: NATURE GENETICS. - ISSN 1061-4036. - 48:10(2016), pp. 1151-1161. [10.1038/ng.3654]
Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension
C. Menni;
2016
Abstract
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 -1/4155,063 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.
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