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Nature genetics · 2021

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

СтатьяМетаанализПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Tadros Rafik, Francis Catherine, Xu Xiao, Vermeer Alexa M C, Harper Andrew R, Huurman Roy, Kelu Bisabu Ken, Walsh Roddy, Hoorntje Edgar T, Te Rijdt Wouter P, Buchan Rachel J, van Velzen Hannah G, van Slegtenhorst Marjon A, Vermeulen Jentien M, Offerhaus Joost Allard, Bai Wenjia, de Marvao Antonio, Lahrouchi Najim, Beekman Leander, Karper Jacco C, Veldink Jan H, Kayvanpour Elham, Pantazis Antonis, Baksi A John, Whiffin Nicola, Mazzarotto Francesco, Sloane Geraldine, Suzuki Hideaki, Schneider-Luftman Deborah, Elliott Paul, Richard Pascale, Ader Flavie, Villard Eric, Lichtner Peter, Meitinger Thomas, Tanck Michael W T, van Tintelen J Peter, Thain Andrew, McCarty David, Hegele Robert A, Roberts Jason D, Amyot Julie, Dubé Marie-Pierre, Cadrin-Tourigny Julia, Giraldeau Geneviève, L'Allier Philippe L, Garceau Patrick, Tardif Jean-Claude, Boekholdt S Matthijs, Lumbers R Thomas, Asselbergs Folkert W, Barton Paul J R, Cook Stuart A, Prasad Sanjay K, O'Regan Declan P, van der Velden Jolanda, Verweij Karin J H, Talajic Mario, Lettre Guillaume, Pinto Yigal M, Meder Benjamin, Charron Philippe, de Boer Rudolf A, Christiaans Imke, Michels Michelle, Wilde Arthur A M, Watkins Hugh, Matthews Paul M, Ware James S, Bezzina Connie R

Аннотация

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.

Предметные рубрики MeSH

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

Реквизиты и контакты