An in silico Post-GWAS Analysis of C-Reactive Protein Loci Reveals an Important Role for Interferons.

Genome-wide association studies (GWASs) have successfully identified a number of Single Nucleotide Polymorphisms (SNPs) associated with serum levels of C-reactive protein (CRP). An important limitation of GWASs is that the identified variants merely flag the nearby genomic region and do not necessarily provide a direct link to the biological mechanisms or pathways underlying their corresponding phenotype. To this end we assembled an integrated pipeline of sequentialbioinformatics-based approaches for post-GWAS analysis of human traits or diseases. In the first phase of ‘in silico’sequencing it explores the nearby genomic region to identify all linked variants, with a focus on non-synonymous SNPs. Inthe second phase of eQTL analysis, it attempts to identify all nearby genes whose expression levels are associated with the corresponding GWAS SNPs. These two phases generate a number of relevant genes that serve as input to the next phase of functional network analysis. We applied this pipeline to the 18 SNPs that had previously been associated with CRP at a genome-wide significant level. Our in silico sequencing analysis using 1000 Genomes Project data identified 3,801 linkedvariants, including 25 non-synonymous SNPs. Our eQTL analysis, based on one of the largest single datasets of genomewideexpression probes (n>5000) assessed in participants from the Netherlands twin Register (NTR) and the Netherlandsstudy of Depression and Anxiety (NESDA) identified 23 significantly associated expression probes (FDR<0.01). The final phase of functional network analysis revealed 93 significantly enriched biological processes (FDR<0.01). This post-GWAS study confirmed the previously known overlap between CRP and lipids biology. Additionally, it revealed an important role for interferons in the metabolism of CRP.

Keywords:

Genome-wide association study (GWAS) , Post-GWAS , eQTL analysis , Network analysis , Genomics of inflammatory markers