Disproportionate Contributions of Select Genomic Compartments and Cell Types to Genetic Risk for Coronary Artery Disease.
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.
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
Hong-Hee
HH
Won
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
Pradeep
P
Natarajan
Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Amanda
A
Dobbyn
Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Charles Bronfman Institute for Personalized Medicine, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Daniel M
DM
Jordan
Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Panos
P
Roussos
Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Kasper
K
Lage
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
Soumya
S
Raychaudhuri
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Center for Statistical Genetics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Eli
E
Stahl
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Charles Bronfman Institute for Personalized Medicine, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Center for Statistical Genetics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Ron
R
Do
D003324:Coronary Artery Disease / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D012307:Risk Factors