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Abstract
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (e.g. GATA5, PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
| Original language | English |
|---|---|
| Journal | Nature Genetics |
| Early online date | 23 Nov 2020 |
| DOIs | |
| Publication status | E-pub ahead of print - 23 Nov 2020 |
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Generation Scotland
Porteous, D.
UK central government bodies/local authorities, health and hospital authorities
1/04/11 → 31/03/14
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Surendran, P., Feofanova, E. V., Lahrouchi, N., Ntalla, I., Karthikeyan, S., Cook, J., Chen, L., Mifsud, B., Yao, C., Kraja, A. T., Cartwright, J. H., Hellwege, J. N., Giri, A., Tragante, V., Thorleifsson, G., Liu, D. J., Prins, B. P., Stewart, I. D., Cabrera, C. P., ... Howson, J. M. M. (2020). Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. Nature Genetics. https://doi.org/10.1038/s41588-020-00713-x
Surendran, Praveen ; Feofanova, Elena V ; Lahrouchi, Najim ; Ntalla, Ioanna ; Karthikeyan, Savita ; Cook, James ; Chen, Lingyan ; Mifsud, Borbala ; Yao, Chen ; Kraja, Aldi T ; Cartwright, James H ; Hellwege, Jacklyn N ; Giri, Ayush ; Tragante, Vinicius ; Thorleifsson, Gudmar ; Liu, Dajiang J. ; Prins, Bram P ; Stewart, Isobel D. ; Cabrera, Claudia P ; Eales, James ; Akbarov, Artur ; Auer, Paul L. ; Bielak, Lawrence F. ; Bis, Joshua C. ; Braithwaite, Vickie S ; Brody, Jennifer A. ; Daw, E. Warwick ; Warren, Helen R ; Drenos, Fotios ; Nielsen, Sune Fallgaard ; Faul, Jessica D ; Fauman, Eric ; Fava, Cristiano ; Ferreira, Teresa ; Foley, Christopher N ; Franceschini, Nora ; Gao, He ; Giannakopoulou, Olga ; Giulianini, Franco ; Gudbjartsson, Daniel F ; Guo, Xiuqing ; Harris, Sarah ; Havulinna, Aki S ; Helgadottir, Anna ; Huffman, Jennifer E ; Hwang, Shih-Jen ; Kanoni, Stavroula ; Kontto, Jukka ; Larson, Martin G. ; Li-Gao, Ruifang ; Lindström, Jaana ; Lotta, Luca A ; Lu, Yingchang ; Luan, Jian'an ; Mahajan, Anubha ; Malerba, Giovanni ; Masca, Nicholas G D ; Mei, Hao ; Menni, Cristina ; Mook-Kanamori, Dennis O ; Mosen-Ansorena, David ; Müller-Nurasyid, Martina ; Paré, Guillaume ; Paul, Dirk S ; Perola, Markus ; Poveda, Alaitz ; Rauramaa, Rainer ; Richard, Melissa ; Richardson, Tom G. ; Sepúlveda, Nuno ; Sim, Xueling ; Smith, Albert V ; Smith, Jennifer A. ; Staley, James R. ; Stančáková, Alena ; Sulem, Patrick ; Thériault, Sébastien ; Thorstensdottir, Unnur ; Trompet, Stella ; Varga, Tibor V ; Velez Edwards, Digna R ; Veronesi, Giovanni ; Weiss, Stefan ; Willems, Sara M ; Yao, Jie ; Young, Robin ; Yu, Bing ; Zhang, Weihua ; Hua Zhao, Jing ; Zhao, Wei ; Evangelou, Evangelos ; Aeschbacher, Stefanie ; Asllanaj, Eralda ; Blankenberg, Stefan ; Bonnycastle, Lori L. ; Bork-Jensen, Jette ; Brandslund, Ivan ; Braund, Peter S ; Burgess, Stephen ; Cho, Kelly ; Christensen, Cramer ; Connelly, John ; de Mutsert, Renée ; Dominiczak, Anna F. ; Dörr, Marcus ; Eiriksdottir, Gudny ; Farmaki, Aliki-Eleni ; Gaziano, J Michael ; Grarup, Niels ; Grove-Gaona, Megan L ; Hallmans, Göran ; Hansen, Torben ; Have, Christian T ; Heiss, Gerardo ; Jørgensen, Marit E ; Jousilahti, Pekka ; Kajantie, Eero ; Kamat, Mihir ; Käräjämäki, AnneMari ; Karpe, Fredrik ; Koistinen, Heikki A ; Kovesdy, Csaba P ; Kuulasmaa, Kari ; Laatikainen, Tiina ; Lannfelt, Lars ; Lee, I-te ; Lee, Wen-jane ; Linneberg, Allan ; Martin, Lisa W ; Moitry, Marie ; Nadkarni, Girish N ; Neville, Matt J. ; Palmer, Colin N. A. ; Papanicolau, George J. ; Pederson, Oluf ; Peters, James ; Poulter, Neil ; Rasheed, Asif ; Rasmussen, Katrine L ; William Rayner, N. ; Mägi, Reedik ; Renström, Frida ; Rettig, Rainer ; Rossouw, Jacques ; Schreiner, Pamela J ; Sever, Peter J. ; Sigurdsson, Emil L ; Skaaby, Tea ; Sun, Yan V ; Sundstrom, Johan ; Thorgeirsson, Gudmundur ; Esko, Tonu ; Trabetti, Elisabetta ; Tsao, Philip S ; Tuomi, Tiinamaija ; Turner, Stephen T ; Tzoulaki, Ioanna ; Vaartjes, Ilonca ; Vergnaud, Anne-Claire ; Willer, Cristen J. ; Wilson, Peter W F ; Witte, Daniel R. ; Yonova-Doing, Ekaterina ; Zhang, He ; Naheed, Aliya ; Almgren, Peter ; Amouyel, Philippe ; Asselbergs, Folkert W. ; Barnes, Michael R ; Blakemore, Alexandra I F ; Boehnke, Michael ; Bots, Michiel L ; Bottinger, Erwin P ; Buring, Julie E ; Chambers, John C. ; Ida Chen, Yii-Der ; Chowdry, Rajiv ; Conen, David ; Correa, Adolfo ; Smith, George Davey ; De Boer, Rudolf A. ; Deary, Ian ; Dedoussis, George ; Deloukas, Panos ; Di Angelantonio, Emanuele ; Elliot, Paul ; Felix, Stephan B. ; Ferrières, Jean ; Ford, Ian ; Fornage, Myriam ; Franks, Paul W. ; Franks, Stephen ; Frossard, Philippe ; Gambaro, Giovanni ; Gaunt, Tom R ; Groop, Leif ; Gudnason, Vilmundur ; Harris, Tamara B. ; Hayward, Caroline ; Hennig, Branwen J. ; Herzig, Karl-Heinz ; Ingelsson, Erik ; Tuomilehto, Jaakko ; Jarvelin, Mario-Riitta ; Wouter Jukema, J. ; Kardia, Sharon L R ; Kee, Frank ; Kooner, Jaspal S. ; Kooperberg, Charles ; Lenore, Launer J ; Lind, Lars ; Loos, Ruth J. F. ; al Shafi Majumder, Abdulla ; Laakso, Markku ; McCarthy, Mark I ; Melander, Olle ; Mohlke, Karen L. ; Murray, Alison D ; Nordestgaard, Børge Grønne ; Orho-Melander, Marju ; Packard, Chris J ; Padmanabhan, Sandosh ; Palmas, Walter ; Polasek, Ozren ; Porteous, David John ; Prentice, Andrew M. ; Province, Michael A. ; Relton, Caroline L. ; Rice, Kenneth ; Ridker, Paul M. ; Rolandsson, Olov ; Rosendaal, Frits R. ; Rotter, Jerome I ; Rudan, Igor ; Salomaa, Veikko ; Samani, Nilesh J ; Sattar, Naveed ; H-H Sheu, Wayne ; Smith, Blair H ; Soranzo, Nicole ; Spector, Timothy D. ; Starr, John ; Sebert, Sylvain ; Taylor, Kent D ; Lakka, Timo A ; Timpson, Nicholas J. ; Tobin, Martin D. ; van der Harst, Pim ; van der Meer, Peter ; Ramachandran, Vasan S ; Verweij, Niek ; Virtamo, Jarmo ; Völker, Uwe ; Weir, David R ; Zeggini, Eleftheria ; Charchar, Fadi J ; Wareham, Nicholas J. ; Langenberg, Claudia ; Tomaszewski, Maciej ; Butterworth, Adam S ; Caulfield, Mark ; Danesh, John ; Edwards, Todd L ; Holm, Hilma ; Hung, Adriana M ; Lindgren, Cecilia M ; Liu, Chunyu ; Manning, Alisa K ; Morris, Andrew P. ; Morrison, Alanna C. ; O'Donnell, Christopher J. ; Psaty, Bruce M. ; Saleheen, Danish ; Stefansson, Kari ; Boerwinkle, Eric ; Chasman, Daniel I ; Levy, Daniel ; Newton-Cheh, Christopher H ; Munroe, Patricia B ; Howson, Joanna M M. / Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. In: Nature Genetics. 2020.
@article{1aaf570bf14a435fa6d7bf4385cb79a9,
title = "Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals",
abstract = "Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (e.g. GATA5, PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.",
author = "Praveen Surendran and Feofanova, {Elena V} and Najim Lahrouchi and Ioanna Ntalla and Savita Karthikeyan and James Cook and Lingyan Chen and Borbala Mifsud and Chen Yao and Kraja, {Aldi T} and Cartwright, {James H} and Hellwege, {Jacklyn N} and Ayush Giri and Vinicius Tragante and Gudmar Thorleifsson and Liu, {Dajiang J.} and Prins, {Bram P} and Stewart, {Isobel D.} and Cabrera, {Claudia P} and James Eales and Artur Akbarov and Auer, {Paul L.} and Bielak, {Lawrence F.} and Bis, {Joshua C.} and Braithwaite, {Vickie S} and Brody, {Jennifer A.} and Daw, {E. Warwick} and Warren, {Helen R} and Fotios Drenos and Nielsen, {Sune Fallgaard} and Faul, {Jessica D} and Eric Fauman and Cristiano Fava and Teresa Ferreira and Foley, {Christopher N} and Nora Franceschini and He Gao and Olga Giannakopoulou and Franco Giulianini and Gudbjartsson, {Daniel F} and Xiuqing Guo and Sarah Harris and Havulinna, {Aki S} and Anna Helgadottir and Huffman, {Jennifer E} and Shih-Jen Hwang and Stavroula Kanoni and Jukka Kontto and Larson, {Martin G.} and Ruifang Li-Gao and Jaana Lindstr{\"o}m and Lotta, {Luca A} and Yingchang Lu and Jian'an Luan and Anubha Mahajan and Giovanni Malerba and Masca, {Nicholas G D} and Hao Mei and Cristina Menni and Mook-Kanamori, {Dennis O} and David Mosen-Ansorena and Martina M{\"u}ller-Nurasyid and Guillaume Par{\'e} and Paul, {Dirk S} and Markus Perola and Alaitz Poveda and Rainer Rauramaa and Melissa Richard and Richardson, {Tom G.} and Nuno Sep{\'u}lveda and Xueling Sim and Smith, {Albert V} and Smith, {Jennifer A.} and Staley, {James R.} and Alena Stan{\v c}{\'a}kov{\'a} and Patrick Sulem and S{\'e}bastien Th{\'e}riault and Unnur Thorstensdottir and Stella Trompet and Varga, {Tibor V} and {Velez Edwards}, {Digna R} and Giovanni Veronesi and Stefan Weiss and Willems, {Sara M} and Jie Yao and Robin Young and Bing Yu and Weihua Zhang and {Hua Zhao}, Jing and Wei Zhao and Evangelos Evangelou and Stefanie Aeschbacher and Eralda Asllanaj and Stefan Blankenberg and Bonnycastle, {Lori L.} and Jette Bork-Jensen and Ivan Brandslund and Braund, {Peter S} and Stephen Burgess and Kelly Cho and Cramer Christensen and John Connelly and {de Mutsert}, Ren{\'e}e and Dominiczak, {Anna F.} and Marcus D{\"o}rr and Gudny Eiriksdottir and Aliki-Eleni Farmaki and Gaziano, {J Michael} and Niels Grarup and Grove-Gaona, {Megan L} and G{\"o}ran Hallmans and Torben Hansen and Have, {Christian T} and Gerardo Heiss and J{\o}rgensen, {Marit E} and Pekka Jousilahti and Eero Kajantie and Mihir Kamat and AnneMari K{\"a}r{\"a}j{\"a}m{\"a}ki and Fredrik Karpe and Koistinen, {Heikki A} and Kovesdy, {Csaba P} and Kari Kuulasmaa and Tiina Laatikainen and Lars Lannfelt and I-te Lee and Wen-jane Lee and Allan Linneberg and Martin, {Lisa W} and Marie Moitry and Nadkarni, {Girish N} and Neville, {Matt J.} and Palmer, {Colin N. A.} and Papanicolau, {George J.} and Oluf Pederson and James Peters and Neil Poulter and Asif Rasheed and Rasmussen, {Katrine L} and {William Rayner}, N. and Reedik M{\"a}gi and Frida Renstr{\"o}m and Rainer Rettig and Jacques Rossouw and Schreiner, {Pamela J} and Sever, {Peter J.} and Sigurdsson, {Emil L} and Tea Skaaby and Sun, {Yan V} and Johan Sundstrom and Gudmundur Thorgeirsson and Tonu Esko and Elisabetta Trabetti and Tsao, {Philip S} and Tiinamaija Tuomi and Turner, {Stephen T} and Ioanna Tzoulaki and Ilonca Vaartjes and Anne-Claire Vergnaud and Willer, {Cristen J.} and Wilson, {Peter W F} and Witte, {Daniel R.} and Ekaterina Yonova-Doing and He Zhang and Aliya Naheed and Peter Almgren and Philippe Amouyel and Asselbergs, {Folkert W.} and Barnes, {Michael R} and Blakemore, {Alexandra I F} and Michael Boehnke and Bots, {Michiel L} and Bottinger, {Erwin P} and Buring, {Julie E} and Chambers, {John C.} and {Ida Chen}, Yii-Der and Rajiv Chowdry and David Conen and Adolfo Correa and Smith, {George Davey} and {De Boer}, {Rudolf A.} and Ian Deary and George Dedoussis and Panos Deloukas and {Di Angelantonio}, Emanuele and Paul Elliot and Felix, {Stephan B.} and Jean Ferri{\`e}res and Ian Ford and Myriam Fornage and Franks, {Paul W.} and Stephen Franks and Philippe Frossard and Giovanni Gambaro and Gaunt, {Tom R} and Leif Groop and Vilmundur Gudnason and Harris, {Tamara B.} and Caroline Hayward and Hennig, {Branwen J.} and Karl-Heinz Herzig and Erik Ingelsson and Jaakko Tuomilehto and Mario-Riitta Jarvelin and {Wouter Jukema}, J. and Kardia, {Sharon L R} and Frank Kee and Kooner, {Jaspal S.} and Charles Kooperberg and Lenore, {Launer J} and Lars Lind and Loos, {Ruth J. F.} and {al Shafi Majumder}, Abdulla and Markku Laakso and McCarthy, {Mark I} and Olle Melander and Mohlke, {Karen L.} and Murray, {Alison D} and Nordestgaard, {B{\o}rge Gr{\o}nne} and Marju Orho-Melander and Packard, {Chris J} and Sandosh Padmanabhan and Walter Palmas and Ozren Polasek and Porteous, {David John} and Prentice, {Andrew M.} and Province, {Michael A.} and Relton, {Caroline L.} and Kenneth Rice and Ridker, {Paul M.} and Olov Rolandsson and Rosendaal, {Frits R.} and Rotter, {Jerome I} and Igor Rudan and Veikko Salomaa and Samani, {Nilesh J} and Naveed Sattar and {H-H Sheu}, Wayne and Smith, {Blair H} and Nicole Soranzo and Spector, {Timothy D.} and John Starr and Sylvain Sebert and Taylor, {Kent D} and Lakka, {Timo A} and Timpson, {Nicholas J.} and Tobin, {Martin D.} and {van der Harst}, Pim and {van der Meer}, Peter and Ramachandran, {Vasan S} and Niek Verweij and Jarmo Virtamo and Uwe V{\"o}lker and Weir, {David R} and Eleftheria Zeggini and Charchar, {Fadi J} and Wareham, {Nicholas J.} and Claudia Langenberg and Maciej Tomaszewski and Butterworth, {Adam S} and Mark Caulfield and John Danesh and Edwards, {Todd L} and Hilma Holm and Hung, {Adriana M} and Lindgren, {Cecilia M} and Chunyu Liu and Manning, {Alisa K} and Morris, {Andrew P.} and Morrison, {Alanna C.} and O'Donnell, {Christopher J.} and Psaty, {Bruce M.} and Danish Saleheen and Kari Stefansson and Eric Boerwinkle and Chasman, {Daniel I} and Daniel Levy and Newton-Cheh, {Christopher H} and Munroe, {Patricia B} and Howson, {Joanna M M}",
year = "2020",
month = nov,
day = "23",
doi = "10.1038/s41588-020-00713-x",
language = "English",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
}
Surendran, P, Feofanova, EV, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, J, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, E, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, S, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindström, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Müller-Nurasyid, M, Paré, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepúlveda, N, Sim, X, Smith, AV, Smith, JA, Staley, JR, Stančáková, A, Sulem, P, Thériault, S, Thorstensdottir, U, Trompet, S, Varga, TV, Velez Edwards, DR, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Hua Zhao, J, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connelly, J, de Mutsert, R, Dominiczak, AF, Dörr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove-Gaona, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jørgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Käräjämäki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, T, Lannfelt, L, Lee, I, Lee, W, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, GN, Neville, MJ, Palmer, CNA, Papanicolau, GJ, Pederson, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, William Rayner, N, Mägi, R, Renström, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PJ, Sigurdsson, EL, Skaaby, T, Sun, YV, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Naheed, A, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, AIF, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Ida Chen, Y-D, Chowdry, R, Conen, D, Correa, A, Smith, GD, De Boer, RA, Deary, I, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliot, P, Felix, SB, Ferrières, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Wouter Jukema, J, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Lenore, LJ, Lind, L, Loos, RJF, al Shafi Majumder, A, Laakso, M, McCarthy, MI, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, JI, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, H-H Sheu, W, Smith, BH, Soranzo, N, Spector, TD, Starr, J, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, van der Harst, P, van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Völker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, M, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, DI, Levy, D, Newton-Cheh, CH, Munroe, PB & Howson, JMM 2020, 'Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals', Nature Genetics. https://doi.org/10.1038/s41588-020-00713-x
Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. / Surendran, Praveen; Feofanova, Elena V; Lahrouchi, Najim; Ntalla, Ioanna; Karthikeyan, Savita; Cook, James; Chen, Lingyan; Mifsud, Borbala; Yao, Chen ; Kraja, Aldi T; Cartwright, James H; Hellwege, Jacklyn N ; Giri, Ayush; Tragante, Vinicius; Thorleifsson, Gudmar; Liu, Dajiang J.; Prins, Bram P; Stewart, Isobel D.; Cabrera, Claudia P; Eales, James; Akbarov, Artur; Auer, Paul L.; Bielak, Lawrence F.; Bis, Joshua C.; Braithwaite, Vickie S; Brody, Jennifer A.; Daw, E. Warwick; Warren, Helen R; Drenos, Fotios; Nielsen, Sune Fallgaard; Faul, Jessica D; Fauman, Eric; Fava, Cristiano; Ferreira, Teresa; Foley, Christopher N; Franceschini, Nora; Gao, He; Giannakopoulou, Olga; Giulianini, Franco; Gudbjartsson, Daniel F; Guo, Xiuqing; Harris, Sarah; Havulinna, Aki S; Helgadottir, Anna; Huffman, Jennifer E; Hwang, Shih-Jen; Kanoni, Stavroula; Kontto, Jukka; Larson, Martin G.; Li-Gao, Ruifang; Lindström, Jaana; Lotta, Luca A; Lu, Yingchang; Luan, Jian'an; Mahajan, Anubha; Malerba, Giovanni; Masca, Nicholas G D; Mei, Hao; Menni, Cristina; Mook-Kanamori, Dennis O; Mosen-Ansorena, David; Müller-Nurasyid, Martina; Paré, Guillaume; Paul, Dirk S; Perola, Markus; Poveda, Alaitz; Rauramaa, Rainer; Richard, Melissa; Richardson, Tom G.; Sepúlveda, Nuno; Sim, Xueling; Smith, Albert V; Smith, Jennifer A.; Staley, James R.; Stančáková, Alena; Sulem, Patrick; Thériault, Sébastien; Thorstensdottir, Unnur; Trompet, Stella; Varga, Tibor V; Velez Edwards, Digna R; Veronesi, Giovanni; Weiss, Stefan; Willems, Sara M; Yao, Jie; Young, Robin; Yu, Bing; Zhang, Weihua; Hua Zhao, Jing; Zhao, Wei; Evangelou, Evangelos; Aeschbacher, Stefanie; Asllanaj, Eralda; Blankenberg, Stefan; Bonnycastle, Lori L.; Bork-Jensen, Jette; Brandslund, Ivan; Braund, Peter S; Burgess, Stephen; Cho, Kelly; Christensen, Cramer; Connelly, John; de Mutsert, Renée; Dominiczak, Anna F.; Dörr, Marcus; Eiriksdottir, Gudny; Farmaki, Aliki-Eleni; Gaziano, J Michael; Grarup, Niels; Grove-Gaona, Megan L; Hallmans, Göran; Hansen, Torben; Have, Christian T; Heiss, Gerardo; Jørgensen, Marit E; Jousilahti, Pekka; Kajantie, Eero; Kamat, Mihir; Käräjämäki, AnneMari; Karpe, Fredrik; Koistinen, Heikki A; Kovesdy, Csaba P; Kuulasmaa, Kari; Laatikainen, Tiina; Lannfelt, Lars; Lee, I-te; Lee, Wen-jane; Linneberg, Allan; Martin, Lisa W; Moitry, Marie; Nadkarni, Girish N; Neville, Matt J.; Palmer, Colin N. A.; Papanicolau, George J.; Pederson, Oluf; Peters, James; Poulter, Neil; Rasheed, Asif; Rasmussen, Katrine L; William Rayner, N.; Mägi, Reedik; Renström, Frida; Rettig, Rainer; Rossouw, Jacques; Schreiner, Pamela J; Sever, Peter J.; Sigurdsson, Emil L; Skaaby, Tea; Sun, Yan V; Sundstrom, Johan; Thorgeirsson, Gudmundur; Esko, Tonu; Trabetti, Elisabetta; Tsao, Philip S; Tuomi, Tiinamaija; Turner, Stephen T; Tzoulaki, Ioanna; Vaartjes, Ilonca; Vergnaud, Anne-Claire; Willer, Cristen J.; Wilson, Peter W F; Witte, Daniel R.; Yonova-Doing, Ekaterina; Zhang, He; Naheed, Aliya; Almgren, Peter; Amouyel, Philippe; Asselbergs, Folkert W.; Barnes, Michael R; Blakemore, Alexandra I F; Boehnke, Michael; Bots, Michiel L; Bottinger, Erwin P; Buring, Julie E; Chambers, John C.; Ida Chen, Yii-Der; Chowdry, Rajiv; Conen, David; Correa, Adolfo; Smith, George Davey; De Boer, Rudolf A.; Deary, Ian; Dedoussis, George ; Deloukas, Panos; Di Angelantonio, Emanuele; Elliot, Paul; Felix, Stephan B.; Ferrières, Jean; Ford, Ian; Fornage, Myriam; Franks, Paul W.; Franks, Stephen; Frossard, Philippe; Gambaro, Giovanni; Gaunt, Tom R; Groop, Leif ; Gudnason, Vilmundur; Harris, Tamara B.; Hayward, Caroline; Hennig, Branwen J.; Herzig, Karl-Heinz; Ingelsson, Erik; Tuomilehto, Jaakko; Jarvelin, Mario-Riitta; Wouter Jukema, J.; Kardia, Sharon L R; Kee, Frank; Kooner, Jaspal S.; Kooperberg, Charles; Lenore, Launer J; Lind, Lars; Loos, Ruth J. F.; al Shafi Majumder, Abdulla; Laakso, Markku; McCarthy, Mark I; Melander, Olle; Mohlke, Karen L.; Murray, Alison D; Nordestgaard, Børge Grønne; Orho-Melander, Marju; Packard, Chris J; Padmanabhan, Sandosh; Palmas, Walter; Polasek, Ozren; Porteous, David John; Prentice, Andrew M.; Province, Michael A.; Relton, Caroline L.; Rice, Kenneth; Ridker, Paul M.; Rolandsson, Olov; Rosendaal, Frits R.; Rotter, Jerome I; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Sattar, Naveed; H-H Sheu, Wayne; Smith, Blair H; Soranzo, Nicole; Spector, Timothy D.; Starr, John; Sebert, Sylvain; Taylor, Kent D; Lakka, Timo A; Timpson, Nicholas J.; Tobin, Martin D.; van der Harst, Pim; van der Meer, Peter; Ramachandran, Vasan S; Verweij, Niek; Virtamo, Jarmo; Völker, Uwe; Weir, David R; Zeggini, Eleftheria; Charchar, Fadi J; Wareham, Nicholas J.; Langenberg, Claudia ; Tomaszewski, Maciej; Butterworth, Adam S; Caulfield, Mark; Danesh, John; Edwards, Todd L; Holm, Hilma; Hung, Adriana M; Lindgren, Cecilia M; Liu, Chunyu; Manning, Alisa K; Morris, Andrew P.; Morrison, Alanna C.; O'Donnell, Christopher J.; Psaty, Bruce M.; Saleheen, Danish; Stefansson, Kari; Boerwinkle, Eric; Chasman, Daniel I; Levy, Daniel; Newton-Cheh, Christopher H; Munroe, Patricia B; Howson, Joanna M M.
In: Nature Genetics, 23.11.2020.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
AU - Surendran, Praveen
AU - Feofanova, Elena V
AU - Lahrouchi, Najim
AU - Ntalla, Ioanna
AU - Karthikeyan, Savita
AU - Cook, James
AU - Chen, Lingyan
AU - Mifsud, Borbala
AU - Yao, Chen
AU - Kraja, Aldi T
AU - Cartwright, James H
AU - Hellwege, Jacklyn N
AU - Giri, Ayush
AU - Tragante, Vinicius
AU - Thorleifsson, Gudmar
AU - Liu, Dajiang J.
AU - Prins, Bram P
AU - Stewart, Isobel D.
AU - Cabrera, Claudia P
AU - Eales, James
AU - Akbarov, Artur
AU - Auer, Paul L.
AU - Bielak, Lawrence F.
AU - Bis, Joshua C.
AU - Braithwaite, Vickie S
AU - Brody, Jennifer A.
AU - Daw, E. Warwick
AU - Warren, Helen R
AU - Drenos, Fotios
AU - Nielsen, Sune Fallgaard
AU - Faul, Jessica D
AU - Fauman, Eric
AU - Fava, Cristiano
AU - Ferreira, Teresa
AU - Foley, Christopher N
AU - Franceschini, Nora
AU - Gao, He
AU - Giannakopoulou, Olga
AU - Giulianini, Franco
AU - Gudbjartsson, Daniel F
AU - Guo, Xiuqing
AU - Harris, Sarah
AU - Havulinna, Aki S
AU - Helgadottir, Anna
AU - Huffman, Jennifer E
AU - Hwang, Shih-Jen
AU - Kanoni, Stavroula
AU - Kontto, Jukka
AU - Larson, Martin G.
AU - Li-Gao, Ruifang
AU - Lindström, Jaana
AU - Lotta, Luca A
AU - Lu, Yingchang
AU - Luan, Jian'an
AU - Mahajan, Anubha
AU - Malerba, Giovanni
AU - Masca, Nicholas G D
AU - Mei, Hao
AU - Menni, Cristina
AU - Mook-Kanamori, Dennis O
AU - Mosen-Ansorena, David
AU - Müller-Nurasyid, Martina
AU - Paré, Guillaume
AU - Paul, Dirk S
AU - Perola, Markus
AU - Poveda, Alaitz
AU - Rauramaa, Rainer
AU - Richard, Melissa
AU - Richardson, Tom G.
AU - Sepúlveda, Nuno
AU - Sim, Xueling
AU - Smith, Albert V
AU - Smith, Jennifer A.
AU - Staley, James R.
AU - Stančáková, Alena
AU - Sulem, Patrick
AU - Thériault, Sébastien
AU - Thorstensdottir, Unnur
AU - Trompet, Stella
AU - Varga, Tibor V
AU - Velez Edwards, Digna R
AU - Veronesi, Giovanni
AU - Weiss, Stefan
AU - Willems, Sara M
AU - Yao, Jie
AU - Young, Robin
AU - Yu, Bing
AU - Zhang, Weihua
AU - Hua Zhao, Jing
AU - Zhao, Wei
AU - Evangelou, Evangelos
AU - Aeschbacher, Stefanie
AU - Asllanaj, Eralda
AU - Blankenberg, Stefan
AU - Bonnycastle, Lori L.
AU - Bork-Jensen, Jette
AU - Brandslund, Ivan
AU - Braund, Peter S
AU - Burgess, Stephen
AU - Cho, Kelly
AU - Christensen, Cramer
AU - Connelly, John
AU - de Mutsert, Renée
AU - Dominiczak, Anna F.
AU - Dörr, Marcus
AU - Eiriksdottir, Gudny
AU - Farmaki, Aliki-Eleni
AU - Gaziano, J Michael
AU - Grarup, Niels
AU - Grove-Gaona, Megan L
AU - Hallmans, Göran
AU - Hansen, Torben
AU - Have, Christian T
AU - Heiss, Gerardo
AU - Jørgensen, Marit E
AU - Jousilahti, Pekka
AU - Kajantie, Eero
AU - Kamat, Mihir
AU - Käräjämäki, AnneMari
AU - Karpe, Fredrik
AU - Koistinen, Heikki A
AU - Kovesdy, Csaba P
AU - Kuulasmaa, Kari
AU - Laatikainen, Tiina
AU - Lannfelt, Lars
AU - Lee, I-te
AU - Lee, Wen-jane
AU - Linneberg, Allan
AU - Martin, Lisa W
AU - Moitry, Marie
AU - Nadkarni, Girish N
AU - Neville, Matt J.
AU - Palmer, Colin N. A.
AU - Papanicolau, George J.
AU - Pederson, Oluf
AU - Peters, James
AU - Poulter, Neil
AU - Rasheed, Asif
AU - Rasmussen, Katrine L
AU - William Rayner, N.
AU - Mägi, Reedik
AU - Renström, Frida
AU - Rettig, Rainer
AU - Rossouw, Jacques
AU - Schreiner, Pamela J
AU - Sever, Peter J.
AU - Sigurdsson, Emil L
AU - Skaaby, Tea
AU - Sun, Yan V
AU - Sundstrom, Johan
AU - Thorgeirsson, Gudmundur
AU - Esko, Tonu
AU - Trabetti, Elisabetta
AU - Tsao, Philip S
AU - Tuomi, Tiinamaija
AU - Turner, Stephen T
AU - Tzoulaki, Ioanna
AU - Vaartjes, Ilonca
AU - Vergnaud, Anne-Claire
AU - Willer, Cristen J.
AU - Wilson, Peter W F
AU - Witte, Daniel R.
AU - Yonova-Doing, Ekaterina
AU - Zhang, He
AU - Naheed, Aliya
AU - Almgren, Peter
AU - Amouyel, Philippe
AU - Asselbergs, Folkert W.
AU - Barnes, Michael R
AU - Blakemore, Alexandra I F
AU - Boehnke, Michael
AU - Bots, Michiel L
AU - Bottinger, Erwin P
AU - Buring, Julie E
AU - Chambers, John C.
AU - Ida Chen, Yii-Der
AU - Chowdry, Rajiv
AU - Conen, David
AU - Correa, Adolfo
AU - Smith, George Davey
AU - De Boer, Rudolf A.
AU - Deary, Ian
AU - Dedoussis, George
AU - Deloukas, Panos
AU - Di Angelantonio, Emanuele
AU - Elliot, Paul
AU - Felix, Stephan B.
AU - Ferrières, Jean
AU - Ford, Ian
AU - Fornage, Myriam
AU - Franks, Paul W.
AU - Franks, Stephen
AU - Frossard, Philippe
AU - Gambaro, Giovanni
AU - Gaunt, Tom R
AU - Groop, Leif
AU - Gudnason, Vilmundur
AU - Harris, Tamara B.
AU - Hayward, Caroline
AU - Hennig, Branwen J.
AU - Herzig, Karl-Heinz
AU - Ingelsson, Erik
AU - Tuomilehto, Jaakko
AU - Jarvelin, Mario-Riitta
AU - Wouter Jukema, J.
AU - Kardia, Sharon L R
AU - Kee, Frank
AU - Kooner, Jaspal S.
AU - Kooperberg, Charles
AU - Lenore, Launer J
AU - Lind, Lars
AU - Loos, Ruth J. F.
AU - al Shafi Majumder, Abdulla
AU - Laakso, Markku
AU - McCarthy, Mark I
AU - Melander, Olle
AU - Mohlke, Karen L.
AU - Murray, Alison D
AU - Nordestgaard, Børge Grønne
AU - Orho-Melander, Marju
AU - Packard, Chris J
AU - Padmanabhan, Sandosh
AU - Palmas, Walter
AU - Polasek, Ozren
AU - Porteous, David John
AU - Prentice, Andrew M.
AU - Province, Michael A.
AU - Relton, Caroline L.
AU - Rice, Kenneth
AU - Ridker, Paul M.
AU - Rolandsson, Olov
AU - Rosendaal, Frits R.
AU - Rotter, Jerome I
AU - Rudan, Igor
AU - Salomaa, Veikko
AU - Samani, Nilesh J
AU - Sattar, Naveed
AU - H-H Sheu, Wayne
AU - Smith, Blair H
AU - Soranzo, Nicole
AU - Spector, Timothy D.
AU - Starr, John
AU - Sebert, Sylvain
AU - Taylor, Kent D
AU - Lakka, Timo A
AU - Timpson, Nicholas J.
AU - Tobin, Martin D.
AU - van der Harst, Pim
AU - van der Meer, Peter
AU - Ramachandran, Vasan S
AU - Verweij, Niek
AU - Virtamo, Jarmo
AU - Völker, Uwe
AU - Weir, David R
AU - Zeggini, Eleftheria
AU - Charchar, Fadi J
AU - Wareham, Nicholas J.
AU - Langenberg, Claudia
AU - Tomaszewski, Maciej
AU - Butterworth, Adam S
AU - Caulfield, Mark
AU - Danesh, John
AU - Edwards, Todd L
AU - Holm, Hilma
AU - Hung, Adriana M
AU - Lindgren, Cecilia M
AU - Liu, Chunyu
AU - Manning, Alisa K
AU - Morris, Andrew P.
AU - Morrison, Alanna C.
AU - O'Donnell, Christopher J.
AU - Psaty, Bruce M.
AU - Saleheen, Danish
AU - Stefansson, Kari
AU - Boerwinkle, Eric
AU - Chasman, Daniel I
AU - Levy, Daniel
AU - Newton-Cheh, Christopher H
AU - Munroe, Patricia B
AU - Howson, Joanna M M
PY - 2020/11/23
Y1 - 2020/11/23
N2 - Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (e.g. GATA5, PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
AB - Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (e.g. GATA5, PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
UR - https://www.nature.com/ng/volumes
U2 - 10.1038/s41588-020-00713-x
DO - 10.1038/s41588-020-00713-x
M3 - Article
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
ER -
Surendran P, Feofanova EV, Lahrouchi N, Ntalla I, Karthikeyan S, Cook J et al. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. Nature Genetics. 2020 Nov 23. https://doi.org/10.1038/s41588-020-00713-x