PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

被引：62

作者：

van Setten, Jessica ^{[1
]}

Brody, Jennifer A. ^{[2
]}

Jamshidi, Yalda ^{[3
]}

Swenson, Brenton R. ^{[2
,4
]}

Butler, Anne M. ^{[5
]}

Campbell, Harry ^{[6
]}

Del Greco, Fabiola M. ^{[7
]}

Evans, Daniel S. ^{[8
]}

Gibson, Quince ^{[9
]}

Gudbjartsson, Daniel F. ^{[10
,11
]}

Kerr, Kathleen F. ^{[12
]}

Krijthe, Bouwe P. ^{[13
]}

Lyytikainen, Leo-Pekka ^{[14
,15
]}

Mueller, Christian ^{[16
,17
]}

Mueller-Nurasyid, Martina ^{[18
,19
,20
,21
]}

Nolte, Ilja M. ^{[21
]}

Padmanabhan, Sandosh ^{[22
]}

Ritchie, Marylyn D. ^{[23
]}

Robino, Antonietta ^{[24
]}

Smith, Albert V. ^{[25
,26
,27
]}

Steri, Maristella ^{[28
]}

Tanaka, Toshiko ^{[29
]}

Teumer, Alexander ^{[30
,31
]}

Trompet, Stella ^{[32
,33
]}

Ulivi, Sheila ^{[24
]}

Verweij, Niek ^{[34
]}

Yin, Xiaoyan ^{[35
]}

Arnar, David O. ^{[10
,26
,36
]}

Asselbergs, Folkert W. ^{[1
,37
,38
,39
,40
]}

Bader, Joel S. ^{[41
]}

Barnard, John ^{[42
]}

Bis, Josh ^{[16
,17
]}

Blankenberg, Stefan ^{[17
,18
]}

Boerwinkle, Eric ^{[43
]}

Bradford, Yuki ^{[23
]}

Buckley, Brendan M. ^{[44
]}

Chung, Mina K. ^{[45
,46
]}

Crawford, Dana ^{[47
]}

den Hoed, Marcel ^{[48
,49
]}

Denny, Josh C. ^{[50
]}

Dominiczak, Anna F. ^{[22
]}

Ehret, Georg B. ^{[51
]}

Eijgelsheim, Mark ^{[13
,52
]}

Ellinor, Patrick T. ^{[53
,54
,55
]}

Felix, Stephan B. ^{[31
,56
]}

Franco, Oscar H. ^{[13
]}

Franke, Lude ^{[57
]}

Harris, Tamara B. ^{[58
]}

Holm, Hilma ^{[10
]}

Ilaria, Gandin ^{[59
]}

机构：

[1] Univ Utrecht, Univ Med Ctr Utrecht, Dept Cardiol, NL-3584 CX Utrecht, Netherlands

[2] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[3] St Georges Univ London, Cardiogenet Lab, Mol & Clin Sci Res Inst, London SW17 0RE, England

[4] Univ Washington, Inst Publ Hlth Genet, Sch Publ Hlth, Seattle, WA 98195 USA

[5] Washington Univ, Sch Med, Div Infect Dis, St Louis, MO 63110 USA

[6] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh EH8 9YL, Midlothian, Scotland

[7] Univ Lubeck, Inst Biomed, Affiliated Inst, Eurac Res, I-39100 Bolzano, Italy

[8] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA

[9] Univ Alabama Birmingham Hosp, Dept Surg, Birmingham, AL 35233 USA

[10] DeCODE Genet Amgen Inc, IS-101 Reykjavik, Iceland

[11] Univ Iceland, Sch Engn & Nat Sci, IS-101 Reykjavik, Iceland

[12] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA

[13] Erasmus MC, Dept Epidemiol, NL-3015 GD Rotterdam, Netherlands

[14] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland

[15] Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Dept Clin Chem, Tampere 33014, Finland

[16] Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, D-20251 Hamburg, Germany

[17] DZHK German Ctr Cardiovasc Res, Partner Site, Hamburg, Germany

[18] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany

[19] Hosp Ludwig Maximilians Univ LMU Munich, Dept Internal Med Cardiol 1, D-81377 Munich, Germany

[20] DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80802 Munich, Germany

[21] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9713GZ Groningen, Netherlands

[22] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland

[23] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA

[24] IRCCS Burlo Garofolo, Inst Maternal & Child Health, I-34137 Trieste, Italy

[25] Iceland Heart Assoc, IS-201 Kopavogur, Iceland

[26] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

[27] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[28] CNR, Ist Ric Genet & Biomed, I-00185 Cagliari, Italy

[29] NIA, Translat Gerontol Branch, Bethesda, MD 20892 USA

[30] Univ Med Greifswald, Inst Community Med, D-17489 Greifswald, Germany

[31] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany

[32] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands

[33] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands

[34] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-7913GZ Groningen, Netherlands

[35] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA

[36] Landspitali Univ Hosp, Dept Med, IS-101 Reykjavik, Iceland

[37] Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands

[38] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London WC1E 6BT, England

[39] UCL, Farr Inst Hlth Informat Res, London WC1E 6BT, England

[40] UCL, Inst Hlth Informat, London WC1E 6BT, England

[41] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA

[42] Cleveland Clin, Lerner Res Inst, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA

[43] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA

[44] Univ Coll Cork, Dept Pharmacol & Therapeut, Cork T12 K8AF, Ireland

[45] Cleveland Clin, Heart & Vasc Inst, Dept Cardiovasc Med, Cleveland, OH 44195 USA

[46] Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44195 USA

[47] Case Western Reserve Univ, Inst Computat Biol, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA

[48] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75105 Uppsala, Sweden

[49] Uppsala Univ, Sci Life Lab, SE-75105 Uppsala, Sweden

[50] Vanderbilt Univ, Biomed Informat & Med, 221 Kirkland Hall, Nashville, TN 37235 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

COMMON VARIANTS; HEART-RATE; QRS DURATION; CARDIAC CONDUCTION; FIBRILLATION; EPIDEMIOLOGY; COHORTS; RISK; RARE; SNPS;

D O I：

10.1038/s41467-018-04766-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genomewide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are overrepresented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of similar to 105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

引用

页数：11

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