Contribution of Gene Regulatory Networks to Heritability of Coronary Artery Disease

Abstract

Background: Genetic variants currently known to affect coronary artery disease (CAD) risk explain less than one-quarter of disease heritability. The heritability contribution of gene regulatory networks (GRNs) in CAD, which are modulated by both genetic and environmental factors, is unknown.

Objectives: This study sought to determine the heritability contributions of single nucleotide polymorphisms affecting gene expression (eSNPs) in GRNs causally linked to CAD.

Methods: Seven vascular and metabolic tissues collected in 2 independent genetics-of-gene-expression studies of patients with CAD were used to identify eSNPs and to infer coexpression networks. To construct GRNs with causal relations to CAD, the prior information of eSNPs in the coexpression networks was used in a Bayesian algorithm. Narrow-sense CAD heritability conferred by the GRNs was calculated from individual-level genotype data from 9 European genome-wide association studies (GWAS) (13,612 cases, 13,758 control cases).

Results: The authors identified and replicated 28 independent GRNs active in CAD. The genetic variation in these networks contributed to 10.0% of CAD heritability beyond the 22% attributable to risk loci identified by GWAS. GRNs in the atherosclerotic arterial wall (n = 7) and subcutaneous or visceral abdominal fat (n = 9) were most strongly implicated, jointly explaining 8.2% of CAD heritability. In all, these 28 GRNs (each contributing to >0.2% of CAD heritability) comprised 24 to 841 genes, whereof 1 to 28 genes had strong regulatory effects (key disease drivers) and harbored many relevant functions previously associated with CAD. The gene activity in these 28 GRNs also displayed strong associations with genetic and phenotypic cardiometabolic disease variations both in humans and mice, indicative of their pivotal roles as mediators of gene-environmental interactions in CAD.

Conclusions: GRNs capture a major portion of genetic variance and contribute to heritability beyond that of genetic loci currently known to affect CAD risk. These networks provide a framework to identify novel risk genes/pathways and study molecular interactions within and across disease-relevant tissues leading to CAD.

Keywords: coronary artery disease; gene regulatory networks; heritability; systems genetics.

Figure 1.. Contribution to CAD heritability from expression (e)SNPs of regulatory gene networks identified in STAGE/STARNET.

Bar plots of CAD heritability (H²) contributions from 98 regulatory-gene networks identified in the STAGE study(11) and replicated in STARNET(12) (blue). The yellow bar indicates contribution to H² from the top-28 networks, each contributing >0.2% CAD heritability. The following bars show H² contributions from subsets of these 28 regulatory gene networks according to their tissue of origin (n = number of networks). Non-fat refers to networks found in tissues other than fat; H² error bars are standard error of mean.

Figure 2.. Individual contributions to heritability from top-28 regulatory-gene networks associated with CAD.

Bar plots of CAD heritability (H²) contributions (blue, left y-axis) and network-gene number (red, right y-axis) of the top-28 regulatory-gene networks (>0.2% h²/network, Online Figures 4 and 5).

Figure 3.. Examples of two regulatory gene networks in the arterial wall and whole blood with substantial contributions to CAD heritability.

Shown are two tissue-specific regulatory-gene networks contributing to 0.64% and 0.41% to CAD heritability, respectively. These networks were identified in gene expression data from the internal mammary artery (IMA) (A) and whole blood (B) isolated from CAD patients in the STAGE study(11) and replicated in RNAseq data from corresponding tissues in STARNET.(12) Circles in the network illustrations indicate individual genes. Squares indicate key disease drivers.

Figure 3.. Examples of two regulatory gene networks in the arterial wall and whole blood with substantial contributions to CAD heritability.

Shown are two tissue-specific regulatory-gene networks contributing to 0.64% and 0.41% to CAD heritability, respectively. These networks were identified in gene expression data from the internal mammary artery (IMA) (A) and whole blood (B) isolated from CAD patients in the STAGE study(11) and replicated in RNAseq data from corresponding tissues in STARNET.(12) Circles in the network illustrations indicate individual genes. Squares indicate key disease drivers.

Figure 4.. A regulatory-gene network identified in abdominal fat with major contribution to CAD heritability.

This regulatory-gene network example contributing to 0.57% of CAD heritability was identified in gene expression data from visceral abdominal fat (VAF) from CAD patients in the STAGE study (11) and replicated in RNAseq data from the same tissue in STARNET.(12) Circles in the network illustration indicate individual genes. Squares indicate key disease drivers.