Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect

• Published in: Nature genetics Vol. 53; no. 2; pp. 128 - 134
• Main Authors: Tadros, Rafik, Francis, Catherine, Xu, Xiao, Vermeer, Alexa M. C., Harper, Andrew R., Huurman, Roy, Kelu Bisabu, Ken, Walsh, Roddy, Hoorntje, Edgar T., te Rijdt, Wouter P., Buchan, Rachel J., van Velzen, Hannah G., van Slegtenhorst, Marjon A., Vermeulen, Jentien M., Offerhaus, Joost Allard, Bai, Wenjia, de Marvao, Antonio, Lahrouchi, Najim, Beekman, Leander, Karper, Jacco C., Veldink, Jan H., Kayvanpour, Elham, Pantazis, Antonis, Baksi, A. John, Whiffin, Nicola, Mazzarotto, Francesco, Sloane, Geraldine, Suzuki, Hideaki, Schneider-Luftman, Deborah, Elliott, Paul, Richard, Pascale, Ader, Flavie, Villard, Eric, Lichtner, Peter, Meitinger, Thomas, Tanck, Michael W. T., van Tintelen, J. Peter, Thain, Andrew, McCarty, David, Hegele, Robert A., Roberts, Jason D., Amyot, Julie, Dubé, Marie-Pierre, Cadrin-Tourigny, Julia, Giraldeau, Geneviève, L’Allier, Philippe L., Garceau, Patrick, Tardif, Jean-Claude, Boekholdt, S. Matthijs, Lumbers, R. Thomas, Asselbergs, Folkert W., Barton, Paul J. R., Cook, Stuart A., Prasad, Sanjay K., O’Regan, Declan P., van der Velden, Jolanda, Verweij, Karin J. H., Talajic, Mario, Lettre, Guillaume, Pinto, Yigal M., Meder, Benjamin, Charron, Philippe, de Boer, Rudolf A., Christiaans, Imke, Michels, Michelle, Wilde, Arthur A. M., Watkins, Hugh, Matthews, Paul M., Ware, James S., Bezzina, Connie R.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-02-2021; Nature Publishing Group
• Subjects: 45; 45/43; 59/57; 631/208/205/2138; 631/208/457; 692/308/2056; 692/699/75/74; 692/700/228/2050/1512; Agriculture; Animal Genetics and Genomics; Biobanks; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cardiac muscle; Cardiomyopathy; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - mortality; Cardiomyopathy, Dilated - physiopathology; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - mortality; Cardiomyopathy, Hypertrophic - physiopathology; Case-Control Studies; Chromosomes; Congestive heart failure; Coronary artery disease; Disease; Gene Frequency; Gene Function; Gene loci; Genetic aspects; Genetic effects; Genetic Predisposition to Disease; Genetic variability; Genome-wide association studies; Genome-Wide Association Study; Genomes; Health aspects; Heart diseases; Heart Ventricles - physiopathology; Human Genetics; Humans; Identification and classification; Kaplan-Meier Estimate; Letter; Life Sciences; Linkage Disequilibrium; Meta-analysis; Muscle contraction; Muscles; Polygenic inheritance; Polymorphism, Single Nucleotide; Population; Quantitative Trait Loci; Risk; Risk factors; Ventricle; Ventricular Function, Left - genetics; Canada; United Kingdom > UK
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-020-00762-2

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
Genome-wide analyses identify multiple loci associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular (LV) traits. Cardiomyopathies exhibit strong genetic correlations with LV traits, with opposing effects in HCM and DCM.