Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.
Rafik TadrosCatherine FrancisXiao XuAlexa M C VermeerAndrew R HarperRoy HuurmanKen Kelu BisabuRoddy WalshEdgar T HoorntjeWouter P Te RijdtRachel J BuchanHannah G van VelzenMarjon A van SlegtenhorstJentien M VermeulenJoost Allard OfferhausWenjia BaiAntonio de MarvaoNajim LahrouchiLeander BeekmanJacco C KarperJan Herman VeldinkElham KayvanpourAntonis PantazisA John BaksiNicola WhiffinFrancesco MazzarottoGeraldine SloaneHideaki SuzukiDeborah Schneider-LuftmanPaul ElliottPascale RichardFlavie AderEric VillardPeter LichtnerThomas MeitingerMichael W T Tanckvan J Peter TintelenAndrew ThainDavid McCartyRobert A HegeleJason D RobertsJulie AmyotMarie-Pierre DubéJulia Cadrin-TourignyGeneviève GiraldeauPhilippe L L'AllierPatrick GarceauJean-Claude TardifS Matthijs BoekholdtR Thomas LumbersFolkert W. AsselbergsPaul J R BartonStuart A CookSanjay K PrasadDeclan P O'ReganJolanda van der VeldenKarin J H VerweijMario TalajicGuillaume LettreYigal M PintoBenjamin MederPhilippe CharronRudolf A de BoerImke ChristiaansMichelle MichelsArthur A M WildeHugh C WatkinsPaul M MatthewsJames Simon WareConnie R BezzinaPublished in: Nature genetics (2021)
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.
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