Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis

Abstract

We genotyped individuals with primary biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 x 10(-4)) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 x 10(-13)), 17q12-21 (combined P = 3.50 x 10(-13)) and MMEL1 (combined P = 3.15 x 10(-8)) as new primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases.

figure 1

Association plots for the IRF5-TNPO3, 17q12-21 and MMEL1 loci. (a–c) Strength of the associations and recombination rates estimated from HapMap data for genotyped SNPs are shown for the (a) IRF5-TNPO3, (b) 17q12-21 and (c) MMEL1 loci. Both genome-wide association (circles) and combined fine-mapping (diamonds) data are shown where available. The extent of linkage disequilibrium with the most significant polymorphisms are indicated by the size of each data point; larger data points indicate stronger linkage disequilibrium. Gene positions for each gene region are indicated by the arrows, with the arrow direction representing the orientation of translation. Linkage disequilibrium was calculated using observed data in PLINK.