Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy

全基因组关联研究 肥厚性心肌病 医学 孟德尔随机化 遗传学 遗传关联 心肌病 基因 内科学 单核苷酸多态性 生物 遗传变异 基因型 心力衰竭
作者
Rafik Tadros,Sean Zheng,Christopher Grace,Paloma Jordà,Catherine Francis,Sean J. Jurgens,Kate Thomson,Andrew R. Harper,Arthur A.M. Wilde,Iacopo Olivotto,Arnon Adler,Anuj Goel,James S. Ware,Connie R. Bezzina,Hugh Watkins
出处
期刊:European Heart Journal [Oxford University Press]
卷期号:44 (Supplement_2) 被引量:9
标识
DOI:10.1093/eurheartj/ehad655.3197
摘要

Abstract Background Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Prior genome-wide association studies (GWAS) identified few genomic loci and disease genes due to limited sample size. Purpose To discover novel genetic loci, genes and mechanisms implicated in HCM using a large scale GWAS and multi-trait analysis of GWAS (MTAG). Methods and results We performed the largest HCM GWAS meta-analysis and MTAG to date including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We estimated the heritability of HCM attributable to common genetic variation (h2SNP) to be 0.25±0.02 using genome-based restricted maximum likelihood (GREML), with higher h2SNP in non-sarcomeric (0.29±0.02) compared to sarcomeric HCM (0.16±0.04). We identified a total of 70 loci (50 novel) associated with HCM (Figure 1), and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin. We performed rare variant burden analysis including 1,845 clinically-diagnosed unrelated HCM cases and 37,481 controls and demonstrated a 10.5-fold (95% CI: 4.1-26.8; P=0.0000002) excess burden of SVIL loss of function (LoF) variants in HCM cases. Two-sample mendelian randomization analyses using LV contractility as exposure and obstructive (oHCM) and non-obstructive HCM (nHCM) as outcomes support a causal role of increased LV contractility in both oHCM and nHCM (Figure 2), suggesting common disease mechanisms and anticipating shared response to therapy. Conclusion We identify 50 novel genomic loci associated with HCM. Our data suggest that LoF variants in SVIL are a cause of HCM, and that increased contractility mediate both nHCM and oHCM. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.Figure 1Figure 2
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