Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.
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DOI：
10.1038/s41588-020-00762-2
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发表时间：
2021-03
期刊：
影响因子：
30.8
通讯作者：
Bezzina CR
中科院分区：
文献类型：
--
作者：
Tadros R;Francis C;Xu X;Vermeer AMC;Harper AR;Huurman R;Kelu Bisabu K;Walsh R;Hoorntje ET;Te Rijdt WP;Buchan RJ;van Velzen HG;van Slegtenhorst MA;Vermeulen JM;Offerhaus JA;Bai W;de Marvao A;Lahrouchi N;Beekman L;Karper JC;Veldink JH;Kayvanpour E;Pantazis A;Baksi AJ;Whiffin N;Mazzarotto F;Sloane G;Suzuki H;Schneider-Luftman D;Elliott P;Richard P;Ader F;Villard E;Lichtner P;Meitinger T;Tanck MWT;van Tintelen JP;Thain A;McCarty D;Hegele RA;Roberts JD;Amyot J;Dubé MP;Cadrin-Tourigny J;Giraldeau G;L'Allier PL;Garceau P;Tardif JC;Boekholdt SM;Lumbers RT;Asselbergs FW;Barton PJR;Cook SA;Prasad SK;O'Regan DP;van der Velden J;Verweij KJH;Talajic M;Lettre G;Pinto YM;Meder B;Charron P;de Boer RA;Christiaans I;Michels M;Wilde AAM;Watkins H;Matthews PM;Ware JS;Bezzina CR
肥厚性心肌病（HCM）和扩张性心肌病（DCM）是年轻健康个体猝死和心力衰竭的主要原因。我们对19,260名心脏结构正常的英国生物银行参与者进行了HCM（1,733例）、DCM（5,521例）和9个左心室（LV）特征的全基因组关联研究（GWAS）和多特征分析。我们确定了16个与HCM相关的位点，13个与DCM相关的位点，23个与LV相关的位点。我们发现LV性状和心肌病之间存在很强的遗传相关性，在HCM和DCM中具有相反的作用。双样本孟德尔随机化支持一种因果关系，即收缩力增加与HCM风险相关。多基因风险评分（PRS）解释了导致HCM罕见变异的携带者中表型变异的重要部分。因此，我们的研究结果提供了证据，PRS可能占孟德尔疾病的变异性。更广泛地说，我们提供了遗传途径如何通过相反的遗传效应导致不同的疾病的见解。
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 (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 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 contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS 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.