Integrating Genetic, Transcriptional, and Functional Analyses to Identify 5 Novel Genes for Atrial Fibrillation

被引：156

作者：

Sinner, Moritz F. ^{[1
]}

Tucker, Nathan R. ^{[2
]}

Lunetta, Kathryn L. ^{[3
,4
,5
]}

Ozaki, Kouichi ^{[6
]}

Smith, J. Gustav ^{[7
,8
]}

Trompet, Stella ^{[9
]}

Bis, Joshua C. ^{[10
,11
]}

Lin, Honghuang ^{[4
,5
,12
]}

Chung, Mina K. ^{[13
,14
]}

Nielsen, Jonas B. ^{[15
,16
]}

Lubitz, Steven A. ^{[2
,17
]}

Krijthe, Bouwe P. ^{[18
,19
]}

Magnani, Jared W. ^{[20
]}

Ye, Jiangchuan ^{[2
]}

Gollob, Michael H. ^{[21
]}

Tsunoda, Tatsuhiko ^{[22
]}

Mueller-Nurasyid, Martina ^{[1
,23
,24
]}

Lichtner, Peter ^{[25
]}

Peters, Annette ^{[26
,27
]}

Dolmatova, Elena ^{[2
]}

Kubo, Michiaki ^{[28
]}

Smith, Jonathan D. ^{[13
,29
]}

Psaty, Bruce M. ^{[10
,11
,30
,31
,32
]}

Smith, Nicholas L. ^{[10
,30
,31
,33
]}

Jukema, Wouter ^{[9
,34
]}

Chasman, Daniel I. ^{[35
,36
]}

Albert, Christine M. ^{[35
,36
]}

Ebana, Yusuke ^{[37
]}

Furukawa, Tetsushi ^{[37
]}

MacFarlane, Peter W. ^{[38
]}

Harris, Tamara B. ^{[39
]}

Darbar, Dawood ^{[40
]}

Doerr, Marcus ^{[41
]}

Holst, Anders G. ^{[15
,16
]}

Svendsen, Jesper H. ^{[15
,16
,42
]}

Hofman, Albert ^{[18
,19
]}

Uitterlinden, Andre G. ^{[18
,19
,43
]}

Gudnason, Vilmundur ^{[44
,45
]}

Isobe, Mitsuaki ^{[46
]}

Malik, Rainer ^{[47
]}

Dichgans, Martin ^{[47
,48
]}

Rosand, Jonathan ^{[49
,50
,51
]}

Van Wagoner, David R. ^{[13
,14
]}

Benjamin, Emelia J. ^{[4
,5
,20
,52
,53
]}

Milan, David J. ^{[2
,17
]}

Melander, Olle ^{[54
]}

Heckbert, Susan R. ^{[10
,30
,31
]}

Ford, Ian ^{[55
]}

Liu, Yongmei ^{[56
]}

Barnard, John ^{[57
]}

机构：

[1] Univ Munich, Dept Med 1, Univ Hosp Munich, D-80336 Munich, Germany

[2] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA

[3] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[4] NHLBI, Framingham, MA USA

[5] Boston Univ, Framingham Heart Study, Framingham, MA USA

[6] RIKEN Ctr Integrat Med Sci, Lab Cardiovasc Dis, Yokohama, Kanagawa, Japan

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

[8] Lund Univ, Dept Cardiol, Lund, Sweden

[9] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands

[10] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[11] Univ Washington, Dept Med, Seattle, WA USA

[12] Boston Univ, Sch Med, Dept Med, Computat Biomed Sect, Boston, MA 02118 USA

[13] Cleveland Clin, Dept Cardiovasc Med, Heart & Vasc Inst, Cleveland, OH 44106 USA

[14] Cleveland Clin, Dept Mol Cardiol, Lerner Res Inst, Cleveland, OH 44106 USA

[15] Danish Natl Res Fdn, Ctr Cardiac Arrhythmia, Copenhagen, Denmark

[16] Univ Copenhagen, Rigshosp, Mol Cardiol Lab, Ctr Heart, DK-2100 Copenhagen, Denmark

[17] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA

[18] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[19] NCHA, Rotterdam, Netherlands

[20] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA

[21] Univ Ottawa, Inst Heart, Arrhythmia Res Lab, Ottawa, ON, Canada

[22] RIKEN Ctr Integrat Med Sci, Lab Med Sci Math, Yokohama, Kanagawa, Japan

[23] German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany

[24] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[25] German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany

[26] Deutsches Zentrum Herz Kreislaufforsch eV DZHK, Partner Site Munich Heart Alliance, Munich, Germany

[27] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany

[28] RIKEN Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan

[29] Cleveland Clin, Dept Cellular & Mol Med, Lerner Res Inst, Cleveland, OH 44106 USA

[30] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA

[31] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[32] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[33] Dept Vet Affairs, Epidemiol Res & Informat Ctr, Off Res & Dev, Seattle, WA USA

[34] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands

[35] Harvard Univ, Sch Med, Boston, MA USA

[36] Brigham & Womens Hosp, Div Prevent Med, Div Cardiovasc, Boston, MA 02115 USA

[37] Tokyo Med & Dent Univ, Med Res Inst, Dept Bioinformat Pharmacol, Tokyo, Japan

[38] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland

[39] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA

[40] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA

[41] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med B, Greifswald, Germany

[42] Univ Copenhagen, Dept Clin Med, Fac Hlth Sci, Copenhagen, Denmark

[43] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[44] Iceland Heart Assoc, Res Inst, Kopavogur, Iceland

[45] Univ Iceland, Reykjavik, Iceland

[46] Tokyo Med & Dent Univ, Dept Cardiovasc Med, Tokyo, Japan

[47] Univ Munich, Inst Stroke & Dementia Res, Univ Hosp Munich, Munich, Germany

[48] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[49] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[50] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

来源：

CIRCULATION | 2014年 / 130卷 / 15期

基金：

英国医学研究理事会; 新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

atrial fibrillation; epidemiology; genetics; gene expression; polymorphism; single nucleotide; zebrafish; GENOME-WIDE ASSOCIATION; RISK-FACTORS; VARIANTS; ONSET; LOCI; METAANALYSIS; PRAVASTATIN; UBIQUITIN; PROTEIN; NKX2-5;

D O I：

10.1161/CIRCULATIONAHA.114.009892

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. Methods and Results-To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5x10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2x10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7x10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8x10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0x10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9x10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6x10(-19)), GJA1 (P=2.66x10(-6)), and TBX5 (P=1.36x10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). Conclusions-We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

引用

页码：1225 / +

页数：48

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