Proteome-wide Mendelian randomization highlights AIF1 and HLA-DQA2 as targets for primary sclerosing cholangitis.

Abstract

Primary sclerosing cholangitis (PSC) is a kind of cholestatic liver disease without effective therapies and its pathogenesis is largely unknown. We performed the proteome-wide Mendelian randomization (MR) design to estimate the causal associations of protein levels with PSC risk. Therein, genetic associations with 4,907 plasma protein levels were extracted from a proteome-wide genome-wide association study (GWAS) with 35,559 individuals and those with PSC were obtained from the International PSC Study Group (2,871 cases and 12,019 controls) and the FinnGen study (1,491 cases and 301,383 controls). The colocalization analysis was performed to detect causal variants shared by proteins and PSC. The identified proteins were further enriched in pathways and diseases. A phenome-wide association screening was performed and potential drugs were assessed as well. The results indicated that genetically predicted plasma levels of 14 proteins were positively associated with an increased risk of PSC and 8 proteins were inversely associated with PSC risk in both PSC GWAS data sets, and they all survived in sensitivity analyses. The colocalization indicated that AIF1 (allograft inflammatory factor 1) and HLA-DQA2 (major histocompatibility complex, class II, DQ alpha 2) were shared proteins with PSC, and they should be direct targets for PSC. The phenome-wide screening suggested that variants located at AIF1 or HLA-DQA2 region were closely associated with several autoimmune diseases, such as rheumatoid arthritis, implicating the shared pathogenesis among them. Our study highly pinpointed two candidate targets (AIF1 and HLA-DQA2) for PSC.