The Present and Future
State-of-the-Art Review
Genome-Wide Significant Loci: How Important Are They?: Systems Genetics to Understand Heritability of Coronary Artery Disease and Other Common Complex Disorders

https://doi.org/10.1016/j.jacc.2014.12.033Get rights and content
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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.

Key Words

atherosclerosis
atherosclerotic plaque
genome-wide association study
myocardial infarction
primary prevention
regulatory gene networks

Abbreviations and Acronyms

CAD
coronary artery disease
eQTL
expression quantitative trait locus
GGES
genetics of gene expression studies
GWA
genome-wide association
GWAS
genome-wide association studies
GWNS
genome-wide network studies
LDL
low-density lipoprotein
SNP
single-nucleotide polymorphism
WES/WGS
whole-exome/whole-genome sequencing

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Drs. Björkegren, Kovacic, and Schadt are supported by the American Heart Association (14SFRN20490315; 14SFRN20840000) and are members of the Consortium “CAD Genomics” (Drs. Björkegren and Schadt) and the Consortium “Cellular and Molecular Targets to Promote Therapeutic Cardiac Regeneration” (Dr. Kovacic), both of which are funded by the Leducq Foundation (Transatlantic Network of Excellence Awards). Dr. Björkegren is also supported by the Swedish Heart-Lung Foundation, the Swedish Research Council, the University of Tartu (SP1GVARENG), the Estonian Research Council, and by a grant from AstraZeneca Translational Science Centre-Karolinska Institutet (joint research program in translational science); and is the founder, a main shareholder, and chairman of the board of Clinical Gene Networks AB (CGN), which has invested interests in the STARNET and STAGE cohorts. Dr. Kovacic is also supported by the National Institutes of Health (K08HL111330) and by a research grant from AstraZeneca. Dr. Dudley is supported in part by funding from the National Institutes of Health (R01 DK098242 and U54 CA189201); and by the PhRMA Foundation. Dr. Schadt is a CGN board member and shareholder. Robert Roberts, MD, served as Guest Editor for this paper.

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