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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 > 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.

SUBMITTER: Surendran P 

PROVIDER: S-EPMC7610439 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Surendran Praveen P   Feofanova Elena V EV   Lahrouchi Najim N   Ntalla Ioanna I   Karthikeyan Savita S   Cook James J   Chen Lingyan L   Mifsud Borbala B   Yao Chen C   Kraja Aldi T AT   Cartwright James H JH   Hellwege Jacklyn N JN   Giri Ayush A   Tragante Vinicius V   Thorleifsson Gudmar G   Liu Dajiang J DJ   Prins Bram P BP   Stewart Isobel D ID   Cabrera Claudia P CP   Eales James M JM   Akbarov Artur A   Auer Paul L PL   Bielak Lawrence F LF   Bis Joshua C JC   Braithwaite Vickie S VS   Brody Jennifer A JA   Daw E Warwick EW   Warren Helen R HR   Drenos Fotios F   Nielsen Sune Fallgaard SF   Faul Jessica D JD   Fauman Eric B EB   Fava Cristiano C   Ferreira Teresa T   Foley Christopher N CN   Franceschini Nora N   Gao He H   Giannakopoulou Olga O   Giulianini Franco F   Gudbjartsson Daniel F DF   Guo Xiuqing X   Harris Sarah E SE   Havulinna Aki S AS   Helgadottir Anna A   Huffman Jennifer E JE   Hwang Shih-Jen SJ   Kanoni Stavroula S   Kontto Jukka J   Larson Martin G MG   Li-Gao Ruifang R   Lindström Jaana J   Lotta Luca A LA   Lu Yingchang Y   Luan Jian'an J   Mahajan Anubha A   Malerba Giovanni G   Masca Nicholas G D NGD   Mei Hao H   Menni Cristina C   Mook-Kanamori Dennis O DO   Mosen-Ansorena David D   Müller-Nurasyid Martina M   Paré Guillaume G   Paul Dirk S DS   Perola Markus M   Poveda Alaitz A   Rauramaa Rainer R   Richard Melissa M   Richardson Tom G TG   Sepúlveda Nuno N   Sim Xueling X   Smith Albert V AV   Smith Jennifer A JA   Staley James R JR   Stanáková Alena A   Sulem Patrick P   Thériault Sébastien S   Thorsteinsdottir Unnur U   Trompet Stella S   Varga Tibor V TV   Velez Edwards Digna R DR   Veronesi Giovanni G   Weiss Stefan S   Willems Sara M SM   Yao Jie J   Young Robin R   Yu Bing B   Zhang Weihua W   Zhao Jing-Hua JH   Zhao Wei W   Zhao Wei W   Evangelou Evangelos E   Aeschbacher Stefanie S   Asllanaj Eralda E   Blankenberg Stefan S   Bonnycastle Lori L LL   Bork-Jensen Jette J   Brandslund Ivan I   Braund Peter S PS   Burgess Stephen S   Cho Kelly K   Christensen Cramer C   Connell John J   Mutsert Renée de R   Dominiczak Anna F AF   Dörr Marcus M   Eiriksdottir Gudny G   Farmaki Aliki-Eleni AE   Gaziano J Michael JM   Grarup Niels N   Grove Megan L ML   Hallmans Göran G   Hansen Torben T   Have Christian T CT   Heiss Gerardo G   Jørgensen Marit E ME   Jousilahti Pekka P   Kajantie Eero E   Kamat Mihir M   Käräjämäki AnneMari A   Karpe Fredrik F   Koistinen Heikki A HA   Kovesdy Csaba P CP   Kuulasmaa Kari K   Laatikainen Tiina T   Lannfelt Lars L   Lee I-Te IT   Lee Wen-Jane WJ   Linneberg Allan A   Martin Lisa W LW   Moitry Marie M   Nadkarni Girish G   Neville Matt J MJ   Palmer Colin N A CNA   Papanicolaou George J GJ   Pedersen Oluf O   Peters James J   Poulter Neil N   Rasheed Asif A   Rasmussen Katrine L KL   Rayner N William NW   Mägi Reedik R   Renström Frida F   Rettig Rainer R   Rossouw Jacques J   Schreiner Pamela J PJ   Sever Peter S PS   Sigurdsson Emil L EL   Skaaby Tea T   Sun Yan V YV   Sundstrom Johan J   Thorgeirsson Gudmundur G   Esko Tõnu T   Trabetti Elisabetta E   Tsao Philip S PS   Tuomi Tiinamaija T   Turner Stephen T ST   Tzoulaki Ioanna I   Vaartjes Ilonca I   Vergnaud Anne-Claire AC   Willer Cristen J CJ   Wilson Peter W F PWF   Witte Daniel R DR   Yonova-Doing Ekaterina E   Zhang He H   Aliya Naheed N   Almgren Peter P   Amouyel Philippe P   Asselbergs Folkert W FW   Barnes Michael R MR   Blakemore Alexandra I AI   Boehnke Michael M   Bots Michiel L ML   Bottinger Erwin P EP   Buring Julie E JE   Chambers John C JC   Chen Yii-Der Ida YI   Chowdhury Rajiv R   Conen David D   Correa Adolfo A   Davey Smith George G   Boer Rudolf A de RA   Deary Ian J IJ   Dedoussis George G   Deloukas Panos P   Di Angelantonio Emanuele E   Elliott Paul P   Felix Stephan B SB   Ferrières Jean J   Ford Ian I   Fornage Myriam M   Franks Paul W PW   Franks Stephen S   Frossard Philippe P   Gambaro Giovanni G   Gaunt Tom R TR   Groop Leif L   Gudnason Vilmundur V   Harris Tamara B TB   Hayward Caroline C   Hennig Branwen J BJ   Herzig Karl-Heinz KH   Ingelsson Erik E   Tuomilehto Jaakko J   Järvelin Marjo-Riitta MR   Jukema J Wouter JW   Kardia Sharon L R SLR   Kee Frank F   Kooner Jaspal S JS   Kooperberg Charles C   Launer Lenore J LJ   Lind Lars L   Loos Ruth J F RJF   Majumder Abdulla Al Shafi AAS   Laakso Markku M   McCarthy Mark I MI   Melander Olle O   Mohlke Karen L KL   Murray Alison D AD   Nordestgaard Børge Grønne BG   Orho-Melander Marju M   Packard Chris J CJ   Padmanabhan Sandosh S   Palmas Walter W   Polasek Ozren O   Porteous David J DJ   Prentice Andrew M AM   Province Michael A MA   Relton Caroline L CL   Rice Kenneth K   Ridker Paul M PM   Rolandsson Olov O   Rosendaal Frits R FR   Rotter Jerome I JI   Rudan Igor I   Salomaa Veikko V   Samani Nilesh J NJ   Sattar Naveed N   Sheu Wayne H-H WH   Smith Blair H BH   Soranzo Nicole N   Spector Timothy D TD   Starr John M JM   Sebert Sylvain S   Taylor Kent D KD   Lakka Timo A TA   Timpson Nicholas J NJ   Tobin Martin D MD   van der Harst Pim P   van der Meer Peter P   Ramachandran Vasan S VS   Verweij Niek N   Virtamo Jarmo J   Völker Uwe U   Weir David R DR   Zeggini Eleftheria E   Charchar Fadi J FJ   Wareham Nicholas J NJ   Langenberg Claudia C   Tomaszewski Maciej M   Butterworth Adam S AS   Caulfield Mark J MJ   Danesh John J   Edwards Todd L TL   Holm Hilma H   Hung Adriana M AM   Lindgren Cecilia M CM   Liu Chunyu C   Manning Alisa K AK   Morris Andrew P AP   Morrison Alanna C AC   O'Donnell Christopher J CJ   Psaty Bruce M BM   Saleheen Danish D   Stefansson Kari K   Boerwinkle Eric E   Chasman Daniel I DI   Levy Daniel D   Newton-Cheh Christopher C   Munroe Patricia B PB   Howson Joanna M M JMM  

Nature genetics 20201123 12


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<sup>-8</sup>), 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%  ...[more]

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2017-01-12 | GSE93421 | GEO