Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

Abstract

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10⁻¹⁶ and P = 4.1 × 10⁻⁸, respectively).

Figure 1

Association results at the MST1 and BCL2L11 loci. (a,c) The association results from the genotyped and imputed markers at the MST1 and BCL2L11 loci are shown as the −log₁₀ of the P values plotted against the genomic position (NCBI build 36). The MST1 and BCL2L11 SNPs with robust evidence for replication are highlighted with green circles. (b,d) The recombination rates (gray lines) derived from the HapMap project, along with the association results based on an imputed dataset using reference data from the 1000 Genomes Project. None of the imputed 1000 Genomes Project SNPs in the region from 111,745,000 bp to 111,929,500 bp on chromosome 2 passed imputation quality thresholds (Supplementary Methods). The MST1 and BCL2L11 associations (represented by the SNPs given in Table 1) were independent of the HLA association in a logistic regression analysis with inclusion of rs3134792 (the most strongly associated HLA SNP) as a covariate and in a stratified analysis according to rs3134792 risk allele carriership (Supplementary Table 2). Association results at the MST1 and BCL2L11 loci in ulcerative colitis compared to PSC are shown in Supplementary Figure 3.