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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

ABSTRACT: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

SUBMITTER: Shah S

PROVIDER: S-EPMC6952380 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Shah Sonia S Henry Albert A Roselli Carolina C Lin Honghuang H Sveinbjörnsson Garðar G Fatemifar Ghazaleh G Hedman Åsa K ÅK Wilk Jemma B JB Morley Michael P MP Chaffin Mark D MD Helgadottir Anna A Verweij Niek N Dehghan Abbas A Almgren Peter P Andersson Charlotte C Aragam Krishna G KG Ärnlöv Johan J Backman Joshua D JD Biggs Mary L ML Bloom Heather L HL Brandimarto Jeffrey J Brown Michael R MR Buckbinder Leonard L Carey David J DJ Chasman Daniel I DI Chen Xing X Chen Xu X Chung Jonathan J Chutkow William W Cook James P JP Delgado Graciela E GE Denaxas Spiros S Doney Alexander S AS Dörr Marcus M Dudley Samuel C SC Dunn Michael E ME Engström Gunnar G Esko Tõnu T Felix Stephan B SB Finan Chris C Ford Ian I Ghanbari Mohsen M Ghasemi Sahar S Giedraitis Vilmantas V Giulianini Franco F Gottdiener John S JS Gross Stefan S Guðbjartsson Daníel F DF Gutmann Rebecca R Haggerty Christopher M CM van der Harst Pim P Hyde Craig L CL Ingelsson Erik E Jukema J Wouter JW Kavousi Maryam M Khaw Kay-Tee KT Kleber Marcus E ME Køber Lars L Koekemoer Andrea A Langenberg Claudia C Lind Lars L Lindgren Cecilia M CM London Barry B Lotta Luca A LA Lovering Ruth C RC Luan Jian'an J Magnusson Patrik P Mahajan Anubha A Margulies Kenneth B KB März Winfried W Melander Olle O Mordi Ify R IR Morgan Thomas T Morris Andrew D AD Morris Andrew P AP Morrison Alanna C AC Nagle Michael W MW Nelson Christopher P CP Niessner Alexander A Niiranen Teemu T O'Donoghue Michelle L ML Owens Anjali T AT Palmer Colin N A CNA Parry Helen M HM Perola Markus M Portilla-Fernandez Eliana E Psaty Bruce M BM Rice Kenneth M KM Ridker Paul M PM Romaine Simon P R SPR Rotter Jerome I JI Salo Perttu P Salomaa Veikko V van Setten Jessica J Shalaby Alaa A AA Smelser Diane T DT Smith Nicholas L NL Stender Steen S Stott David J DJ Svensson Per P Tammesoo Mari-Liis ML Taylor Kent D KD Teder-Laving Maris M Teumer Alexander A Thorgeirsson Guðmundur G Thorsteinsdottir Unnur U Torp-Pedersen Christian C Trompet Stella S Tyl Benoit B Uitterlinden Andre G AG Veluchamy Abirami A Völker Uwe U Voors Adriaan A AA Wang Xiaosong X Wareham Nicholas J NJ Waterworth Dawn D Weeke Peter E PE Weiss Raul R Wiggins Kerri L KL Xing Heming H Yerges-Armstrong Laura M LM Yu Bing B Zannad Faiez F Zhao Jing Hua JH Hemingway Harry H Samani Nilesh J NJ McMurray John J V JJV Yang Jian J Visscher Peter M PM Newton-Cheh Christopher C Malarstig Anders A Holm Hilma H Lubitz Steven A SA Sattar Naveed N Holmes Michael V MV Cappola Thomas P TP Asselbergs Folkert W FW Hingorani Aroon D AD Kuchenbaecker Karoline K Ellinor Patrick T PT Lang Chim C CC Stefansson Kari K Smith J Gustav JG Vasan Ramachandran S RS Swerdlow Daniel I DI Lumbers R Thomas RT

Nature communications 20200109 1

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one o ...[more]

PMID: 31919418

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Dataset Information

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Publications

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

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