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共享遗传途径通过相反作用增加了肥厚性和扩张型心肌病的发病风险
2021-01-26 16:35

共享遗传途径通过相反作用增加了肥大性和扩张性心肌病的发病风险,这一成果由荷兰阿姆斯特丹大学 Connie R. Bezzina和加拿大蒙特利尔大学Rafik Tadros研究组合作经过不懈努力而取得。2021年1月25日出版的《自然-遗传学》杂志发表了这一最新研究成果。

研究人员对来自19,260名英国Biobank心脏结构正常参与者中肥厚性心肌病(HCM)(1,733例)、扩张型心肌病(DCM)(5,521例)和9个左心室(LV)性状的数据进行了全基因组关联研究和多特征分析。研究揭示了与HCM相关的16个基因座、与DCM相关的13个基因座和与LV性状相关的23个基因座。

研究人员发现LV性状和心肌病之间存在显著的遗传相关性,而在HCM和DCM中则具有相反的作用。对两个样本进行孟德尔随机抽样的数据支持这种因果联系,并将左室收缩增强与HCM发病风险关联起来。多基因风险评分解释了大部分HCM罕见变异携带者的表型异质性。因此,该研究提供的证据表明多基因风险评分可能解释了孟德尔方式遗传病的变异性。更广泛地说,该研究提供了有关遗传途径如何通过相反遗传效应导致不同疾病发生的原因。

据了解,HCM和DCM是造成年轻人突然死亡和心力衰竭的主要原因。

附:英文原文

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

Author: Rafik Tadros, Catherine Francis, Xiao Xu, Alexa M. C. Vermeer, Andrew R. Harper, Roy Huurman, Ken Kelu Bisabu, Roddy Walsh, Edgar T. Hoorntje, Wouter P. te Rijdt, Rachel J. Buchan, Hannah G. van Velzen, Marjon A. van Slegtenhorst, Jentien M. Vermeulen, Joost Allard Offerhaus, Wenjia Bai, Antonio de Marvao, Najim Lahrouchi, Leander Beekman, Jacco C. Karper, Jan H. Veldink, Elham Kayvanpour, Antonis Pantazis, A. John Baksi, Nicola Whiffin, Francesco Mazzarotto, Geraldine Sloane, Hideaki Suzuki, Deborah Schneider-Luftman, Paul Elliott, Pascale Richard, Flavie Ader, Eric Villard, Peter Lichtner, Thomas Meitinger, Michael W. T. Tanck, J. Peter van Tintelen, Andrew Thain, David McCarty, Robert A. Hegele, Jason D. Roberts, Julie Amyot, Marie-Pierre Dub, Julia Cadrin-Tourigny, Genevive Giraldeau, Philippe L. LAllier, Patrick Garceau, Jean-Claude Tardif, S. Matthijs Boekholdt, R. Thomas Lumbers, Folkert W. Asselbergs, Paul J. R. Barton, Stuart A. Cook, Sanjay K. Prasad, Declan P. ORegan, Jolanda van der Velden, Karin J. H. Verweij, Mario Talajic

Issue&Volume: 2021-01-25

Abstract: 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.

DOI: 10.1038/s41588-020-00762-2

Source: https://www.nature.com/articles/s41588-020-00762-2

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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