Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and Show more
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management. Show less
Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited. In this study, we performed Show more
Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited. In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry. We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1 [sulfotransferase 1A1], SH2B3 [SH2B adapter protein 3], SERPINE2 [serpin family E member 2], RGS18 [regulator of G-protein signaling 18], PZP [pregnancy zone protein], NOTUM [notum, palmitoleoyl-protein carboxylesterase], METAP1 [methionyl aminopeptidase 1], MANEA [mannosidase endo-alpha], jun-D [JunD proto-oncogene], GDF15 [growth differentiation factor 15], FGL1 [fibrinogen like 1], FGF5 [fibroblast growth factor 5], FES [FES proto-oncogene], APOBR [apolipoprotein B receptor], ANP [natriuretic peptide A], ALDH-E2 [aldehyde dehydrogenase 2 family member], ADAMTS13 [ADAM metallopeptidase with thrombospondin type 1 motif 13], and 3MG [N-methylpurine DNA glycosylase]), among which 11 were either directly or indirectly supported by gene expression data, 9 were supported by Bayesian colocalization analyses, and 5 (SERPINE2, PZP, FGF5, FES, and ANP) were supported by all lines of evidence examined. Protein interaction mapping identified potential shared biological pathways through natriuretic peptide signaling, blood pressure regulation, immune tolerance, and thrombin activity regulation. This investigation identified multiple targetable proteins linked to cardiovascular, inflammatory, and coagulation pathways, with SERPINE2, PZP, FGF5, FES, and ANP identified as pivotal proteins with likely causal roles in the development of preeclampsia. The identification of these potential targets may guide the development of targeted therapies for preeclampsia. Show less
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 Show more
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. Show less