The impact of common and rare genetic variants on bradyarrhythmia development

被引：1

作者：

Weng, Lu-Chen ^{[1
,2
,3
]}

Raemoe, Joel T. ^{[4
,5
]}

Jurgens, Sean J. ^{[2
,6
]}

Khurshid, Shaan ^{[1
,2
,7
]}

Chaffin, Mark ^{[2
]}

Hall, Amelia Weber ^{[8
]}

Morrill, Valerie N. ^{[2
]}

Wang, Xin ^{[2
]}

Nauffal, Victor ^{[2
,3
,9
]}

Sun, Yan V. ^{[10
,11
]}

Beer, Dominik ^{[12
]}

Lee, Simon ^{[13
]}

Nadkarni, Girish N. ^{[13
]}

Duong, ThuyVy ^{[14
]}

Wang, Biqi ^{[15
]}

Czuba, Tomasz ^{[16
,17
]}

Austin, Thomas R. ^{[18
,19
]}

Yoneda, Zachary T. ^{[20
]}

Friedman, Daniel J. ^{[21
]}

Clayton, Anne ^{[22
]}

Hyman, Matthew C. ^{[23
]}

Judy, Renae L. ^{[24
]}

Skanes, Allan C. ^{[25
]}

Orland, Kate M. ^{[26
]}

Treu, Timothy M. ^{[3
]}

Oetjens, Matthew T. ^{[27
]}

Alonso, Alvaro ^{[28
]}

Soliman, Elsayed Z. ^{[29
]}

Lin, Honghuang ^{[15
]}

Lunetta, Kathryn L. ^{[30
]}

van der Pals, Jesper ^{[31
,32
]}

Issa, Tariq Z. ^{[33
]}

Nafissi, Navid A. ^{[21
]}

May, Heidi T. ^{[22
]}

Leong-Sit, Peter ^{[25
]}

Roselli, Carolina ^{[2
,34
]}

Choi, Seung Hoan ^{[2
]}

Khan, Habib R. ^{[35
]}

Knight, Stacey ^{[22
,36
]}

Linner, Richard Karlsson ^{[27
,37
]}

Bezzina, Connie R. ^{[38
]}

Ripatti, Samuli ^{[39
]}

Heckbert, Susan R. ^{[18
,19
]}

Gaziano, J. Michael ^{[3
,40
,41
]}

Loos, Ruth J. F. ^{[42
,43
]}

Psaty, Bruce M. ^{[18
,44
,45
,46
]}

Smith, J. Gustav ^{[16
,17
,31
,32
,47
,48
]}

Benjamin, Emelia J. ^{[49
,50
,51
]}

Arking, Dan E. ^{[14
]}

Rader, Daniel J. ^{[52
,53
]}

机构：

[1] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[2] Broad Inst MIT & Harvard, Cardiovasc Dis Initiat, Cambridge, MA USA

[3] VA Boston Healthcare Syst, Boston, MA USA

[4] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki Inst Life Sci HiLIFE, Helsinki, Finland

[5] Broad Inst MIT & Harvard, Cambridge, MA USA

[6] Univ Amsterdam, Amsterdam UMC, Dept Expt Cardiol, Amsterdam, Netherlands

[7] Massachusetts Gen Hosp, Telemachus & Irene Demoulas Family Fdn Ctr Cardia, Boston, MA 02114 USA

[8] Broad Inst MIT & Harvard, Gene Regulat Observ, Cambridge, MA USA

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

[10] VA Atlanta Healthcare Syst, Decatur, GA USA

[11] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA

[12] Geisinger, Heart Inst, Danville, PA USA

[13] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[14] Johns Hopkins Univ, Sch Med, Dept Med Genet, McKusick Nathans Inst, Baltimore, MD USA

[15] Univ Massachusetts, Chan Med Sch, Dept Med, Worcester, MA 01605 USA

[16] Gothenburg Univ, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden

[17] Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden

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

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

[20] Vanderbilt Univ, Med Ctr, Dept Med, Div Cardiovasc Med, Nashville, TN USA

[21] Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA

[22] Intermt Med Ctr, Intermt Heart Inst, Murray, UT USA

[23] Univ Penn, Hosp Univ Penn, Div Cardiac Electrophysiol, Philadelphia, PA 19104 USA

[24] Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA

[25] Western Univ, Dept Med, Div Cardiol, Sect Cardiac Electrophysiol, London, ON, Canada

[26] Univ Wisconsin, Dept Med, Div Cardiovasc Med, Madison, WI USA

[27] Geisinger, Autism & Dev Med Inst, Lewisburg, PA USA

[28] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA

[29] Wake Forest Sch Med, Dept Med, Epidemiol Cardiol Res Ctr, Sect Cardiovasc Med, Winston Salem, NC 27101 USA

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

[31] Lund Univ, Clin Sci, Dept Cardiol, Lund, Sweden

[32] Skane Univ Hosp, Lund, Sweden

[33] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

[34] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands

[35] Western Univ, Sect Cardiac Electrophysiol, London, ON, Canada

[36] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA

[37] Leiden Univ, Leiden Law Sch, Dept Econ, Leiden, Netherlands

[38] Univ Amsterdam, Amsterdam Univ Med Ctr, Amsterdam Cardiovasc Sci, Dept Expt Cardiol,Heart Ctr, Amsterdam, Netherlands

[39] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[40] Harvard Med Sch, Boston, MA 02115 USA

[41] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA

[42] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[43] Univ Copenhagen, Dept Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark

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

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

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

[47] Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden

[48] Lund Univ, Ctr Diabet, Lund, Sweden

[49] Boston Univ, Chobanian & Avedisian Sch Med, Dept Med, Boston, MA 02215 USA

[50] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

来源：

NATURE GENETICS | 2025年 / 57卷 / 01期

基金：

瑞典研究理事会; 欧洲研究理事会; 美国国家卫生研究院; 芬兰科学院;

关键词：

QT INTERVAL DURATION; CARDIAC CONDUCTION; HEART-RATE; LOCI; MUTATIONS; IDENTIFICATION; HERITABILITY; METAANALYSIS; STATEMENT;

D O I：

10.1038/s41588-024-01978-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (r(g)=0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias. G

引用

页码：53 / 64

页数：22

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