Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

Abstract

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P<5×10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r2>0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2>0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

Figure 1. Manhattan plot and list of genome-wide significant PBC risk loci across Immunochip

Novel risk loci are highlighted in blue. Loci with more than one independent signal are highlighted in red. The vertical red line indicates the genome-wide significance threshold of P=5×10⁻⁸. The peak on chromosome 6 is the HLA region.

Figure 2. Enrichment of DNase-seq peaks among PBC risk loci in Gm12878 compared to other ENCODE cell lines

The relative enrichment (E) of SNPs within DNase-seq peaks was calculated across the 35 most associated loci. There is suggestive, though non-significant, evidence that genome-wide significant loci (P<5×10⁻⁸ - vertical blue line) are more likely to lie within DNase-seq peaks in B-lymphoblastoid cell lines (solid red line) than they are to lie within the union of all other annotated cell lines (solid black line) (P=0.068). Dotted grey lines denote E for other annotated cell lines. The shaded grey area represents the 95% confidence interval of E for Gm12878 from 1000 permutations. Cell types: Gm12878: B-lymphoblastoid, H1hesc: embryonic stem cells, H9es: embryonic stem cells, Helas3: cervical carcinoma, Hepg2: liver carcinoma, Hsmm: skeletal muscle myoblasts, Huvec: umbilical vein endothelial cells, K562: leukemia, Lhsr: prostate epithelial cells, Mcf7: mammary gland adenocarcinoma, Medullo: medulloblastoma, Melano: epidermal melanocytes, Myometr: Myometrial cells, Nhbe: bronchial epithelial cells, Nhek: epidermal keratinocytes, Panislets: pancreatic islets, Progfib: fibroblasts.