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

Shah, Sonia ; Almgren, Peter LU ; Engström, Gunnar LU ; Melander, Olle LU ; Smith, Gustav LU and Lumbers, R. Thomas (2020) In Nature Communications 11(1).
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... (More)
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. © 2020, The Author(s). (Less)
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published
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Nature Communications
volume
11
issue
1
article number
163
publisher
Nature Publishing Group
external identifiers
  • scopus:85077697294
  • pmid:31919418
ISSN
2041-1723
DOI
10.1038/s41467-019-13690-5
language
English
LU publication?
yes
id
53a12482-9dd1-4daa-aa64-79a288cf3ce3
date added to LUP
2020-01-22 12:33:39
date last changed
2020-01-30 03:59:03
@article{53a12482-9dd1-4daa-aa64-79a288cf3ce3,
  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. © 2020, The Author(s).},
  author       = {Shah, Sonia and Almgren, Peter and Engström, Gunnar and Melander, Olle and Smith, Gustav and Lumbers, R. Thomas },
  issn         = {2041-1723},
  language     = {eng},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure},
  url          = {http://dx.doi.org/10.1038/s41467-019-13690-5},
  doi          = {10.1038/s41467-019-13690-5},
  volume       = {11},
  year         = {2020},
}