Disproportionate Contributions of Select Genomic Compartments and Cell Types to Genetic Risk for Coronary Artery Disease.

PLoS Genet
Authors
Keywords
Abstract

Large genome-wide association studies (GWAS) have identified many genetic loci associated with risk for myocardial infarction (MI) and coronary artery disease (CAD). Concurrently, efforts such as the National Institutes of Health (NIH) Roadmap Epigenomics Project and the Encyclopedia of DNA Elements (ENCODE) Consortium have provided unprecedented data on functional elements of the human genome. In the present study, we systematically investigate the biological link between genetic variants associated with this complex disease and their impacts on gene function. First, we examined the heritability of MI/CAD according to genomic compartments. We observed that single nucleotide polymorphisms (SNPs) residing within nearby regulatory regions show significant polygenicity and contribute between 59-71% of the heritability for MI/CAD. Second, we showed that the polygenicity and heritability explained by these SNPs are enriched in histone modification marks in specific cell types. Third, we found that a statistically higher number of 45 MI/CAD-associated SNPs that have been identified from large-scale GWAS studies reside within certain functional elements of the genome, particularly in active enhancer and promoter regions. Finally, we observed significant heterogeneity of this signal across cell types, with strong signals observed within adipose nuclei, as well as brain and spleen cell types. These results suggest that the genetic etiology of MI/CAD is largely explained by tissue-specific regulatory perturbation within the human genome.

Year of Publication
2015
Journal
PLoS Genet
Volume
11
Issue
10
Pages
e1005622
Date Published
2015 Oct
ISSN
1553-7404
URL
DOI
10.1371/journal.pgen.1005622
PubMed ID
26509271
PubMed Central ID
PMC4625039
Links
Grant list
R01 AG050986 / AG / NIA NIH HHS / United States
1U01HG0070033 / HG / NHGRI NIH HHS / United States
Canadian Institutes of Health Research / Canada
5U01GM092691-04 / GM / NIGMS NIH HHS / United States
I01 BX002395 / BX / BLRD VA / United States