title: Genome-wide significant loci: how important are they? Systems genetics to understand heritability of coronary artery disease and other common complex disorders.
abstract: Genome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD), revealing 153 suggestive CAD loci, of which at least 46 have been validated as having genome-wide significance. However, these loci collectively explain <10% of the genetic variance in CAD. Thus, we must address the key question of what factors constitute the remaining 90% of CAD heritability. We review possible limitations of GWAS, and contextually consider some candidate CAD loci identified by this method. Looking ahead, we propose systems genetics as a complementary approach to unlocking the CAD heritability and etiology. Systems genetics builds network models of relevant molecular processes by combining genetic and genomic datasets to ultimately identify key "drivers" of disease. By leveraging systems-based genetic approaches, we can help reveal the full genetic basis of common complex disorders, enabling novel diagnostic and therapeutic opportunities.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York; Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Pathological Anatomy and Forensic Medicine, University of Tartu, Tartu, Estonia. Electronic address: johan.bjorkegren@mssm.edu.
authors.forename: Johan L M
authors.initials: JLM
authors.lastname: Björkegren
authors.affiliation: Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kovacic
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
mesh_terms: D003324:Coronary Artery Disease / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
keywords: atherosclerosis; atherosclerotic plaque; genome-wide association study; myocardial infarction; primary prevention; regulatory gene networks