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

Shah, Sonia; Henry, Albert; Roselli, Carolina; Lin, Honghuang; Sveinbjörnsson, Garðar; Fatemifar, Ghazaleh; Hedman, Åsa K.; Wilk, Jemma B.; Morley, Michael; Chaffin, Mark; Helgadóttir, Anna; Verweij, Niek; Dehghan, Abbas; Almgren, Peter; Andersson, C; Aragam, Krishna; Ärnlöv, Johan; Backman, Joshua; Biggs, Mary L.; Bloom, Heather; Brandimarto, Jeffrey; Brown, M. R. W.; Buckbinder, Leonard; Carey, David J.; Chasman, Daniel I.; Chen, X; Chung, Jonathan; Chutkow, William A.; Cook, James P.; Delgado, Graciela; Denaxas, Spiros; Doney, Alex S.F.; Dörr, Marcus; Dudley, Samuel C.; Dunn, Michael E.; Engström, Gunnar; Esko, Tõnu; Felix, Stephan B.; Finan, Chris; Ford, Ian; Ghanbari, Mohsen; Ghasemi, Sahar; Giedraitis, Vilmantas; Giulianini, Franco; Gottdiener, John S.; Groß, Stefan; Guðbjartsson, Daníel F.; Gutmann, Rebecca; Haggerty, Christopher M.; Harst, Pim van der; Hyde, Craig; Ingelsson, Erik; Jukema, J. Wouter; Kavousi, Maryam; Khaw, K-T; Kleber, Marcus E.; Køber, Lars; Koekemoer, Andrea; Langenberg, Claudia; Lind, Lars; Lindgren, Cecilia M.; London, Barry; Lotta, Luca A.; Lovering, Ruth C.; Luan, Jian; Magnusson, Patrik K. E.; Mahajan, Anubha; Margulies, Kenneth B.; März, Winfried; Melander, Olle; Mordi, Ify; Morgan, Thomas M.; Morris, Andrew D.; Morrison, Alanna C.; Nagle, Michael W.; Nelson, Christopher P.; Niessner, Alexander; Niiranen, Teemu J.; O’Donoghue, Michelle L.; Owens, Anjali Tiku; Palmer, Colin N.A.; Parry, Helen; Perola, Markus; Portilla‐Fernandez, Eliana; Psaty, Bruce M.; Rice, Ken; Ridker, Paul M.; Spr., Romaine; Rotter, Jerome I.; Salo, Perttu; Salomaa, Veikko; Setten, Jessica van; Shalaby, Alaa; Smelser, Diane T.; Smith, Nicholas L.; Stender, Steen; Stott, David J.; Svensson, Per; M-L., Tammesoo; Taylor, Kent D.; Teder‐Laving, Maris; Teumer, Alexander; Þorgeirsson, Guðmundur; Þorsteinsdóttir, Unnur; Torp‐Pedersen, Christian; Trompet, Stella; Tyl, Benoît; Uitterlinden, André G.; Veluchamy, Abirami; Völker, Uwe; Voors, Adriaan A.; Wang, X; Wareham, Nicholas J.; Waterworth, Dawn; Weeke, Peter; Weiss, Raul; Wiggins, Kerri L.; Xing, Heming; Yerges‐Armstrong, Laura M.; Yu, Bo; Zannad, Faı̈ez; Zhao, Jing Hua; Hemingway, Harry; Samani, Nilesh J.; McMurray, John J.V.; Yang, Jian; Visscher, Peter M.; Newton‐Cheh, Christopher; Mälarstig, Anders; Hólm, Hilma; Lubitz, Steven A.; Sattar, Naveed; Holmes, Michael V.; Cappola, Thomas P.; Asselbergs, Folkert W.; Hingorani, Aroon D.; Kuchenbaecker, Karoline; Ellinor, Patrick T.; Lang, Chim C.; Stefánsson, Kāri; Smith, J. G.; Vasan, Ramachandran S.; Swerdlow, Daniel I.; Lumbers, R. Thomas

doi:10.1038/s41467-019-13690-5

“…Summary-level data for heart failure were extracted from a GWAS of 47,309 individuals with heart failure and 930,014 individuals without heart failure from the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) Consortium [17]. Twelve SNPs were reported to be associated with heart failure at the genome-wide significance level.…”

Section: Methodsmentioning

confidence: 99%

Major depressive disorder and cardiometabolic diseases: a bidirectional Mendelian randomisation study

Tang

¹

,

Yuan

²

,

Xiong

³

et al. 2020

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Aims/hypothesis Observational studies have shown a bidirectional association between major depressive disorder (MDD) and cardiometabolic diseases. We conducted a two-sample bidirectional Mendelian randomisation (MR) study to assess the causal associations of MDD with type 2 diabetes, coronary artery disease (CAD) and heart failure and vice versa. Methods We extracted summary-level data for MDD, type 2 diabetes, CAD and heart failure from corresponding published large genome-wide association studies of individuals mainly of European-descent. In total, 96 SNPs for MDD, 202 SNPs for type 2 diabetes, 44 SNPs for CAD and 12 SNPs for heart failure were proposed as instrumental variables at the genome-wide significance level (p < 5 × 10 −8). The random-effects inverse-variance weighted method was used for the main analyses. Results Genetic liability to MDD was significantly associated with type 2 diabetes and CAD at the Bonferroni-corrected significance level. The ORs of type 2 diabetes and CAD were respectively 1.26 (95% CI 1.10, 1.43; p = 6 × 10 −4) and 1.16 (95% CI 1.05, 1.29; p = 0.0047) per one-unit increase in log e odds of MDD. There was a suggestive association between MDD and heart failure (OR 1.11 [95% CI 1.01, 1.21]; p = 0.033). We found limited evidence supporting causal effects of cardiometabolic diseases on MDD risk in the reverse MR analyses. Conclusions/interpretation The present study strengthened the evidence that MDD is a potential risk factor for type 2 diabetes and CAD. Whether MDD is causally related to heart failure needs further study. Data availability All data included in this study were uploaded as supplements and are also publicly available through published GWASs and open GWAS datasets (UK Biobank, 23andMe and Psychiatric Genomics: https://datashare.is.ed.ac.uk/handle/

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“…TBX5 acts as a key transcription factor during embryonic development, and its mutations have been linked to several cardiac defects and diseases, including atrial fibrillation and cardiac septal defect 12,13 . PITX2 gene encodes a regulator of TBX5 14 and has also been implicated in the pathogenesis of atrial fibrillation and cardiomyopathy 15 . Interestingly, PITX2 has multiple CAGE peaks with left atrial specificity ( Supplementary Fig.…”

Section: Cage Library Identified Cardiac-specific Alternative Promotersmentioning

confidence: 99%

Human library of cardiac promoters and enhancers

Deviatiiarov

¹

,

Gams

²

,

Syunyaev

³

et al. 2020

Preprint

0

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Genome regulatory elements play a critical role during cardiac development and maintenance of normal physiological homeostasis, and genome-wide association studies identified a large number of SNPs associated with cardiovascular diseases localized in intergenic zones. We used cap analysis of gene expression (CAGE) to identify transcription start sites (TSS) with one nucleotide resolution that effectively maps genome regulatory elements in a representative collection of human heart tissues. Here we present a comprehensive and fully annotated CAGE atlas of human promoters and enhancers from four chambers of the non-diseased human donor hearts, including both atria and ventricles. We have identified 10,528 novel regulatory elements, where 2,750 are classified as TSS and 4,258 novel enhancers, which were validated with ChIP-seq libraries and motif enrichment analysis. We found that heart-region specific expression patterns are primarily based on the alternative promoter and specific enhancer activity. Our study significantly increased evidence of the association of regulatory elements-located variants with heart morphology and pathologies. The precise location of cardiac disease-related SNPs within the regulatory regions and their correlation with a specific cell type offers a new understanding of genetic heart diseases.

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“…gene encodes a regulator of TBX5 14 and has also been implicated in the pathogenesis of atrial brillation and cardiomyopathy 15 . Interestingly, PITX2 has multiple CAGE peaks with left atrial speci city ( Supplementary Fig.…”

Section: Cage Library Identi Ed Cardiac-speci C Alternative Promotersmentioning

confidence: 99%

Human atlas of cardiac promoters and enhancers reveals important role of regulatory elements in heritable diseases

Deviatiiarov

¹

,

Gams

²

,

Syunyaev

³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

Genome regulatory elements play a critical role during cardiac development and maintenance of normal physiological homeostasis, and genome-wide association studies identified a large number of SNPs associated with cardiovascular diseases localized in intergenic zones. We used cap analysis of gene expression (CAGE) to identify transcription start sites (TSS) with one nucleotide resolution that effectively maps genome regulatory elements in a representative collection of human heart tissues. Here we present a comprehensive and fully annotated CAGE atlas of human promoters and enhancers from four chambers of the non-diseased human donor hearts, including both atria and ventricles. We have identified 10,528 novel regulatory elements, where 2,750 are classified as TSS and 4,258 novel enhancers, which were validated with ChIP-seq libraries and motif enrichment analysis. We found that heart-region specific expression patterns are primarily based on the alternative promoter and specific enhancer activity. Our study significantly increased evidence of the association of regulatory elements-located variants with heart morphology and pathologies. The precise location of cardiac disease-related SNPs within the regulatory regions and their correlation with a specific cell type offers a new understanding of genetic heart diseases.

show abstract

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

Cited by 517 publications

References 96 publications

Major depressive disorder and cardiometabolic diseases: a bidirectional Mendelian randomisation study

Major depressive disorder and cardiometabolic diseases: a bidirectional Mendelian randomisation study

Human library of cardiac promoters and enhancers

Human atlas of cardiac promoters and enhancers reveals important role of regulatory elements in heritable diseases

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