TY - JOUR
T1 - Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity
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 - HCMR Investigators
AU - Tadros, Rafik
AU - Ware, James S.
AU - Bezzina, Connie R.
AU - Farrall, Martin
AU - Watkins, Hugh
N1 - Funding Information:
This work was supported by funding from the British Heart Foundation (BHF), the Medical Research Council (MRC), the National Heart, Lung, and Blood Institute (NIH grant U01HL117006-01A1), the Wellcome Trust (201543/B/16/Z), Wellcome Trust core awards (090532/Z/09/Z and 203141/Z/16/Z) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. A.R.H. has received support from the MRC Doctoral Training Partnership. A.G. has received support from the BHF, European Commission (LSHM-CT-2007-037273 and HEALTH-F2-2013-601456) and Tripartite Immunometabolism Consortium (TrIC)-NovoNordisk Foundation (NNF15CC0018486). S.E.P. acknowledges support from the NIHR Barts Biomedical Research Centre. A.W. has received support from the Wellcome Trust. S.N., M.F. and H.W. are members of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). We are grateful for access to the high-performance Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute that is supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. The views expressed are those of the author(s) and do not necessarily reflect those of the NHS, NIHR, Department of Health or Department of Health and Social Care. We thank the NIHR BioResource volunteers for their participation and gratefully acknowledge the NIHR BioResource centers, NHS Trusts and staff for their contribution. We thank the NIHR and NHS Blood and Transplant. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project, which is managed by Genomics England (a wholly owned company of the Department of Health and Social Care) and funded by the NIHR and NHS England with research infrastructure funding from the Wellcome Trust, Cancer Research UK and the MRC. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We acknowledge the contribution of the Oxford Medical Genetics Laboratories.
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.
UR - https://www.scopus.com/pages/publications/85099771026
U2 - 10.1038/s41588-020-00764-0
DO - 10.1038/s41588-020-00764-0
M3 - Article
C2 - 33495597
SN - 1061-4036
VL - 53
SP - 135
EP - 142
JO - Nature genetics
JF - Nature genetics
IS - 2
ER -