Abstract 16847: GWAS and Gene Set Enrichment Identifies Expression Based Biological Modules Associated With C-Reactive Protein Plasma Levels
Background: C-reactive Protein level (CRP), a risk factor for coronary artery disease (CAD), is determined in part by genetic factors. Genome-Wide Association Studies (GWAS) provide significant or suggestive SNPs associated with CRP. However these SNP-by-SNP analyses give limited biological insight and explain only a small fraction of the total genetic component. Moreover, many true SNPs will not reach significance when considered individually. A novel application of Gene Set Enrichment Analysis (GSEA) adds evidence from expression studies and prioritizes GWAS results by combining functional and association evidence.
Methods: We performed GWA in a cohort of 607 individuals with angiographically determined CAD using the Affymetrix 6.0 chip. Covariate adjusted single SNP association with CRP was performed using PLINK, SNPs were mapped to their respective gene and GSEA v2.06 software (Broad) was used to test for enrichment. 1,229 general sets plus 32 cardiac expression and drug response sets were tested.
Results: Sets significantly enriched for CRP associations included genes co-expressed during cardiac differentiation (p << 2e-4), WNT targets (p < 0.0018), and genes differentially expressed in response to beta-blockers (p << 2e-4). In total 67 sets were enriched (FDR < 0.25), including 9 of the 32 cardiovascular sets showing significant biological specificity (p < 2.32e-6). Interestingly, genes that would not meet genome-wide significance individually contribute substantially to significant enrichment as groups. For example, as a set, beta blocker responsive genes show multiple biological candidate pathways implicated in CAD. Novel genes enriched for CRP association in this set included GTP cyclohydrolase 1 (GCH1) (SNP-by-SNP p < 2.30e-6) implicated in regulating NOS signaling; histone deacetylase 9 (HDAC9) (p < 0.0005) related to transcriptional regulation; monoamine oxidase A (MAOA) (p < 0.0029) which regulates serotonin signaling and insulin receptor substrate 2 (IRS2) (p < 0.0059) associated with IL 4 and involved in cytokine signaling.
Conclusions: By combining both association and expression data, genes detected as modules by GSEA, provide novel and significant insights into the genetic component of CRP in patients with CAD.
- © 2010 by American Heart Association, Inc.