Javier Gutierrez-Achury

TL;DR: This work identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease and identified 3 associated variants that are correlated with expression changes in response to immune stimulus at two of these genes.

TL;DR: The genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis is modeled and a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs is developed.

TL;DR: This analysis compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip to identify 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16.

Abstract: Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

TL;DR: This study undertook the largest genome-wide association study of PSC and identified four new genome- wide significant loci, with the most associated SNP at one locus predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A.