Use of ENCODE and eQTL data to identify potential functional genetic variants at the 5q31 psoriatic arthritis susceptibility locus

Abstract

BackgroundPsoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. Results from family studies have shown a strong genetic component to risk for developing PsA with heritability estimates of 80–100%. There is evidence from subgroup analysis of a genome-wide association study (GWAS) that a locus on chromosome 5q31 is specifically associated with PsA and not psoriasis. This result has been replicated in two independent studies involving UK and Canadian individuals. A recent GWAS done in a UK population (unpublished data) has refined and strengthened this association to a region approximately 500 kb upstream of the original GWAS. However, substantial linkage disequilibrium within this region means that functional data are needed to determine the causal variant. MethodsGenotype data for a total of 179 602 single-nucleotide polymorphisms (SNPs) including the 5q31 region were available for 929 individuals with PsA and 4537 controls (www.wtccc.org.uk). Genotyping was performed with Illumina Immunochip, a custom genotype chip designed for fine mapping of established GWAS loci in autoimmune diseases. The lead SNP from the 5q31 region was selected, and SNPs highly correlated (r2>0·8) to the lead SNP were identified by interrogating 1000 genomes project (May, 2011, release). Data from ENCODE (Encyclopedia of DNA elements) and eQTL (expression quantitative trait loci) were searched with the Regulome database and other publicly available databases to explore evidence for transcription factor binding, DNase hypersensitivity sites, and eQTL. FindingsThe lead SNP rs715285 (p=8·92 × 10−5, odds ratio 1·22) lies within an intergenic region and does not overlie a known transcription factor binding site or DNAse1 hypersensitivity site but was associated with a significant change in gene expression of SLC22A5 (p=8·58 × 10−51) in monocytes. rs27437 is highly correlated with the lead SNP (r2=0·88) and lies within a region that has been identified as a transcription factor binding site, DNase peak and is associated with a significant change in gene expression of SLC22A5 (p=8·58 × 10−44) in monocytes. InterpretationIn conclusion, there is a wealth of experimental evidence demonstrating the functional impact of genetic variation in this region associated with PsA. FundingUniversity of Manchester.