Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity

被引：223

作者：

Harper, Andrew R. ^{[1
,2
]}

Goel, Anuj ^{[1
,2
]}

Grace, Christopher ^{[1
,2
]}

Thomson, Kate L. ^{[1
,2
,3
]}

Petersen, Steffen E. ^{[4
]}

Xu, Xiao ^{[5
]}

Waring, Adam ^{[2
]}

Ormondroyd, Elizabeth ^{[1
,2
]}

Kramer, Christopher M. ^{[6
]}

Ho, Carolyn Y. ^{[7
]}

Neubauer, Stefan ^{[1
]}

Tadros, Rafik ^{[8
]}

Ware, James S. ^{[5
]}

Bezzina, Connie R. ^{[9
]}

Farrall, Martin ^{[1
,2
]}

Watkins, Hugh ^{[1
,2
,10
]}

机构：

[1] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England

[2] Univ Oxford, Wellcome Ctr Human Genet, Oxford, England

[3] Churchill Hosp, Oxford Med Genet Labs, Oxford, England

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

[5] Imperial Coll London, Natl Heart & Lung Inst, London, England

[6] Univ Virginia Hlth Syst, Charlottesville, VA USA

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

[8] Montreal Heart Inst, Cardiovasc Genet Ctr, Montreal, PQ, Canada

[9] Amsterdam UMC, AMC Heart Ctr, Amsterdam, Netherlands

[10] Oxford Univ Hosp NHS Fdn Trust, John Radcliffe Hosp, NIHR Oxford Biomed Res Ctr, Oxford, England

来源：

NATURE GENETICS | 2021年 / 53卷 / 02期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

D O I：

10.1038/s41588-020-00764-0

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h(g)(2) = 0.34 +/- 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.

引用

页码：135 / +

页数：14

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