TY - JOUR
T1 - Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity
AU - HCMR Investigators
AU - Harper, Andrew R.
AU - Goel, Anuj
AU - Grace, Christopher
AU - Thomson, Kate L.
AU - Petersen, Steffen E.
AU - Xu, Xiao
AU - Waring, Adam
AU - Ormondroyd, Elizabeth
AU - Kramer, Christopher M.
AU - Ho, Carolyn Y.
AU - Neubauer, Stefan
AU - Kolm, Paul
AU - Kwong, Raymond
AU - Dolman, Sarahfaye F.
AU - Desvigne-Nickens, Patrice
AU - Dimarco, John P.
AU - Geller, Nancy
AU - Kim, Dong Yun
AU - Zhang, Cheng
AU - Weintraub, William
AU - Abraham, Theodore
AU - Anderson, Lisa
AU - Appelbaum, Evan
AU - Autore, Camillo
AU - Berry, Colin
AU - Biagini, Elena
AU - Bradlow, William
AU - Bucciarelli-Ducci, Chiara
AU - Chiribiri, Amedeo
AU - Choudhury, Lubna
AU - Crean, Andrew
AU - Dawson, Dana
AU - Desai, Milind Y.
AU - Elstein, Eleanor
AU - Flett, Andrew
AU - Friedrich, Matthias
AU - Heitner, Stephen
AU - Helms, Adam
AU - Jacoby, Daniel L.
AU - Kim, Han
AU - Kim, Bette
AU - Larose, Eric
AU - Mahmod, Masliza
AU - Mahrholdt, Heiko
AU - Maron, Martin
AU - McCann, Gerry
AU - Michels, Michelle
AU - Mohiddin, Saidi
AU - Nagueh, Sherif
AU - Newby, David
N1 - Publisher Copyright:
© 2021, Crown.
PY - 2021/2
Y1 - 2021/2
N2 - 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; h2g = 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.
AB - 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; h2g = 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.
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U2 - 10.1038/s41588-020-00764-0
DO - 10.1038/s41588-020-00764-0
M3 - Article
C2 - 33495597
AN - SCOPUS:85099771026
SN - 1061-4036
VL - 53
SP - 135
EP - 142
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -