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

被引：109

作者：

Surendran, Praveen ^{[1
,2
,3
,4
,5
]}

Feofanova, Elena, V ^{[6
]}

Lahrouchi, Najim ^{[7
,8
,9
]}

Ntalla, Ioanna ^{[10
]}

Karthikeyan, Savita ^{[1
]}

Cook, James ^{[11
]}

Chen, Lingyan ^{[1
]}

Mifsud, Borbala ^{[10
,12
]}

Yao, Chen ^{[13
,14
]}

Kraja, Aldi T. ^{[15
,16
]}

Cartwright, James H. ^{[10
]}

Hellwege, Jacklyn N. ^{[17
]}

Giri, Ayush ^{[17
,18
]}

Tragante, Vinicius ^{[19
,20
]}

Thorleifsson, Gudmar ^{[20
]}

Liu, Dajiang J. ^{[21
]}

Prins, Bram P. ^{[1
]}

Stewart, Isobel D. ^{[22
]}

Cabrera, Claudia P. ^{[10
,23
]}

Eales, James M. ^{[24
]}

Akbarov, Artur ^{[24
]}

Auer, Paul L. ^{[25
]}

Bielak, Lawrence F. ^{[26
]}

Bis, Joshua C. ^{[27
]}

Braithwaite, Vickie S. ^{[22
,28
,29
]}

Brody, Jennifer A. ^{[27
]}

Daw, E. Warwick ^{[15
,16
]}

Warren, Helen R. ^{[10
,23
]}

Drenos, Fotios ^{[30
,31
]}

Nielsen, Sune Fallgaard ^{[32
]}

Faul, Jessica D. ^{[33
]}

Fauman, Eric B. ^{[34
]}

Fava, Cristiano ^{[35
,36
]}

Ferreira, Teresa ^{[37
]}

Foley, Christopher N. ^{[1
,38
]}

Franceschini, Nora ^{[39
]}

Gao, He ^{[40
,41
]}

Giannakopoulou, Olga ^{[10
,42
,43
]}

Giulianini, Franco ^{[44
]}

Gudbjartsson, Daniel F. ^{[20
,45
]}

Guo, Xiuqing ^{[46
]}

Harris, Sarah E. ^{[47
,48
]}

Havulinna, Aki S. ^{[48
,49
]}

Helgadottir, Anna ^{[20
]}

Huffman, Jennifer E. ^{[50
]}

Hwang, Shih-Jen ^{[51
,52
,53
]}

Kanoni, Stavroula ^{[10
,54
]}

Kontto, Jukka ^{[49
]}

Larson, Martin G. ^{[52
,53
,55
]}

Li-Gao, Ruifang ^{[56
]}

机构：

[1] Univ Cambridge, British Heart Fdn, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England

[2] Univ Cambridge, British Heart Fdn, Ctr Res Excellence, Cambridge, England

[3] Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England

[4] Univ Cambridge, Cambridge, England

[5] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[6] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA

[7] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[8] Massachusetts Gen Hosp, Ctr Genom Med, Cardiovasc Res Ctr, Boston, MA 02114 USA

[9] Univ Amsterdam, Heart Ctr, Dept Clin & Expt Cardiol, Amsterdam Cardiovasc Sci Amsterdam,Amsterdam UMC, Amsterdam, Netherlands

[10] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England

[11] Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England

[12] Hamad Bin Khalifa Univ, Coll Hlth & Life Sci, Doha, Qatar

[13] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[14] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA

[15] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

[16] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63110 USA

[17] Vanderbilt Univ, Med Ctr, Div Epidemiol,Dept Med,Inst Med & Publ Hlth, Vanderbilt Genet Inst,Tennessee Valley Healthcare, Nashville, TN USA

[18] Vanderbilt Univ, Div Quantitat Sci, Dept Obstet & Gynecol, Vanderbilt Genet Inst,Med Ctr,Tennessee Valley He, Nashville, TN USA

[19] Univ Utrecht, Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands

[20] Amgen Inc, deCODE Genet, Reykjavik, Iceland

[21] Penn State Coll Med, Inst Personalized Med, Hershey, PA USA

[22] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge, England

[23] Queen Mary Univ London, Natl Inst Hlth Res, Barts Cardiovasc Biomed Res Ctr, London, England

[24] Univ Manchester, Fac Med Biol & Hlth, Div Cardiovasc Sci, Manchester, Lancs, England

[25] Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA

[26] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA

[27] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[28] Univ Cambridge, MRC Nutr & Bone Hlth Grp, Cambridge, England

[29] London Sch Hyg & Trop Med, MRC Unit Gambia, Banjul, Gambia

[30] Brunel Univ London, Coll Hlth & Life Sci, Dept Life Sci, London, England

[31] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England

[32] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark

[33] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA

[34] Pfizer, Internal Med Res Unit, Cambridge, MA USA

[35] Univ Verona, Dept Med, Verona, Italy

[36] Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden

[37] Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Big Data Inst, Oxford, England

[38] Univ Cambridge, MRC Biostat Unit, Cambridge, England

[39] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA

[40] Imperial Coll London, MRC Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[41] Imperial Coll London, Natl Inst Hlth Res NIHR, Imperial Biomed Res Ctr, London, England

[42] Queen Mary Univ London, Ctr Genom Hlth, London, England

[43] UCL, Div Psychiat, London, England

[44] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA

[45] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

[46] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Pediat, Lundquist Inst Biomed Innovat, Torrance, CA 90509 USA

[47] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[48] Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland

[49] Finnish Inst Hlth & Welf, Dept Publ Hlth Solut, Helsinki, Finland

[50] Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

来源：

NATURE GENETICS | 2020年 / 52卷 / 12期

基金：

英国医学研究理事会; 英国惠康基金; 欧盟地平线“2020”; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; MENDELIAN RANDOMIZATION; COMMON VARIANTS; IDENTIFIES COMMON; LOCI; RISK; FREQUENCY; TRAITS; HYPERTENSION; GENETICS;

D O I：

10.1038/s41588-020-00713-x

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 similar 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 x 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 similar to 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.

引用

页码：1314 / 1332

页数：19

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