Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
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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 M; 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 B; Fava, Cristiano; Ferreira, Teresa; Foley, Christopher N; Franceschini, Nora; Gao, He; Giannakopoulou, Olga; Giulianini, Franco; Gudbjartsson, Daniel F; Guo, Xiuqing; Harris, Sarah E; 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; Stanáková, Alena; Sulem, Patrick; Thériault, Sébastien; Thorsteinsdottir, 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; Zhao, Jing-Hua; Zhao, Wei; 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; Connell, John; Mutsert, Renée de; Dominiczak, Anna F; Dörr, Marcus; Eiriksdottir, Gudny; Farmaki, Aliki-Eleni; Gaziano, J Michael; Grarup, Niels; Grove, 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; Neville, Matt J; Palmer, Colin N A; Papanicolaou, George J; Pedersen, Oluf; Peters, James; Poulter, Neil; Rasheed, Asif; Rasmussen, Katrine L; Rayner, N William; Mägi, Reedik; Renström, Frida; Rettig, Rainer; Rossouw, Jacques; Schreiner, Pamela J; Sever, Peter S; Sigurdsson, Emil L; Skaaby, Tea; Sun, Yan V; Sundstrom, Johan; Thorgeirsson, Gudmundur; Esko, Tõnu; 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; Aliya, Naheed; Almgren, Peter; Amouyel, Philippe; Asselbergs, Folkert W; Barnes, Michael R; Blakemore, Alexandra I; Boehnke, Michael; Bots, Michiel L; Bottinger, Erwin P; Buring, Julie E; Chambers, John C; Chen, Yii-Der Ida; Chowdhury, Rajiv; Conen, David; Correa, Adolfo; Davey Smith, George; Boer, Rudolf A de; Deary, Ian J; Dedoussis, George; Deloukas, Panos; Di Angelantonio, Emanuele; Elliott, 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; Järvelin, Marjo-Riitta; Jukema, J Wouter; Kardia, Sharon L R; Kee, Frank; Kooner, Jaspal S; Kooperberg, Charles; Launer, Lenore J; Lind, Lars; Loos, Ruth J F; Majumder, Abdulla Al Shafi; 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 J; 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; Sheu, Wayne H-H; Smith, Blair H; Soranzo, Nicole; Spector, Timothy D; Starr, John M; 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 J; 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; Munroe, Patricia B; Howson, Joanna M M; LifeLines Cohort Study.
In: NAT GENET, Vol. 52, No. 12, 12.2020, p. 1314-1332.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 M
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 B
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 E
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 - Stanáková, Alena
AU - Sulem, Patrick
AU - Thériault, Sébastien
AU - Thorsteinsdottir, 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 - Zhao, Jing-Hua
AU - Zhao, Wei
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 - Connell, John
AU - Mutsert, Renée de
AU - Dominiczak, Anna F
AU - Dörr, Marcus
AU - Eiriksdottir, Gudny
AU - Farmaki, Aliki-Eleni
AU - Gaziano, J Michael
AU - Grarup, Niels
AU - Grove, 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
AU - Neville, Matt J
AU - Palmer, Colin N A
AU - Papanicolaou, George J
AU - Pedersen, Oluf
AU - Peters, James
AU - Poulter, Neil
AU - Rasheed, Asif
AU - Rasmussen, Katrine L
AU - Rayner, N William
AU - Mägi, Reedik
AU - Renström, Frida
AU - Rettig, Rainer
AU - Rossouw, Jacques
AU - Schreiner, Pamela J
AU - Sever, Peter S
AU - Sigurdsson, Emil L
AU - Skaaby, Tea
AU - Sun, Yan V
AU - Sundstrom, Johan
AU - Thorgeirsson, Gudmundur
AU - Esko, Tõnu
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 - Aliya, Naheed
AU - Almgren, Peter
AU - Amouyel, Philippe
AU - Asselbergs, Folkert W
AU - Barnes, Michael R
AU - Blakemore, Alexandra I
AU - Boehnke, Michael
AU - Bots, Michiel L
AU - Bottinger, Erwin P
AU - Buring, Julie E
AU - Chambers, John C
AU - Chen, Yii-Der Ida
AU - Chowdhury, Rajiv
AU - Conen, David
AU - Correa, Adolfo
AU - Davey Smith, George
AU - Boer, Rudolf A de
AU - Deary, Ian J
AU - Dedoussis, George
AU - Deloukas, Panos
AU - Di Angelantonio, Emanuele
AU - Elliott, 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 - Järvelin, Marjo-Riitta
AU - Jukema, J Wouter
AU - Kardia, Sharon L R
AU - Kee, Frank
AU - Kooner, Jaspal S
AU - Kooperberg, Charles
AU - Launer, Lenore J
AU - Lind, Lars
AU - Loos, Ruth J F
AU - Majumder, Abdulla Al Shafi
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 J
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 - Sheu, Wayne H-H
AU - Smith, Blair H
AU - Soranzo, Nicole
AU - Spector, Timothy D
AU - Starr, John M
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 J
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
AU - Munroe, Patricia B
AU - Howson, Joanna M M
AU - LifeLines Cohort Study
PY - 2020/12
Y1 - 2020/12
N2 - Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants 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 (for example, GATA5 and 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 > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants 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 (for example, GATA5 and 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.
KW - Blood Pressure/genetics
KW - GATA5 Transcription Factor/genetics
KW - Gene Frequency/genetics
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study
KW - Genotype
KW - Humans
KW - Hypertension/genetics
KW - Mutation/genetics
KW - Phospholipase C beta/genetics
KW - Polymorphism, Single Nucleotide/genetics
U2 - 10.1038/s41588-020-00713-x
DO - 10.1038/s41588-020-00713-x
M3 - SCORING: Journal article
C2 - 33230300
VL - 52
SP - 1314
EP - 1332
JO - NAT GENET
JF - NAT GENET
SN - 1061-4036
IS - 12
ER -