International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

Abstract

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

“…We then created a ranked distribution of the maximum test statistics over all SNV-phenotype combinations in each of the 50,000 permutations. [22][23][24][25][26][27][28][29][30] We supplemented the full GWAS summary statistics lookups with the GRASP database 31 to include other immunologically relevant clinical phenotypes and quantitative traits. Similarly, to assess whether the WBC variants were associated with other blood cell traits, we obtained effect sizes and p values for these variants from RBC-and platelet-related traits exome array analyses within the BCX consortium.…”

The epigenetics of PBC: The link between genetic susceptibility and environment

“…Thanks to genome-wide association studies (GWAS) numerous genetic loci underlying PBC have already been identified (mainly intronic and intergenic). Besides that, some mechanisms remain largely unknown, such as causal nucleotide changes, rare genetic variants or the missing heritability sequencing [19][20][21]. Indeed, the use of GWAS have been very disappointing, i.e., it is likely that there are loci that have not been identified due to a lack of statistical significance; this is true not only of PBC, but also for a variety of other AIDs, many of which have been recently reviewed [22][23][24][25][26][27][28][29][30][31][32][33].…”

Genetics and epigenetics in the pathogenesis of primary biliary cholangitis

“…Among the SNPs previously reported to be associated with susceptibility to PBC, only HLA has been consistently linked to the disease in distinct patient cohorts across ethnicities as depicted by many significant dots on genome-wide Manhattan plots of GWASs [34][35][36][37][38][39][40][41][42][43].…”

“…There have been extensive GWASs aiming to clarify genetic susceptibility in patients with PBC. To date, seven GWASs [34-38, 42, 43], two Illumina immunochip studies [39,40], and one genome-wide meta-analysis (GWMA) [41] on PBC have been documented in well-characterized cohorts in North American, European, Japanese, and recently Chinese populations ( Table 2). All studies confirmed that the HLA class II domain showed the strongest association with PBC susceptibility, particularly at the HLA-DRB1, -DQA1, and -DQB1 loci, and indicated the involvement of HLA class II polymorphisms in the pathogenesis of PBC across ethnicities.…”