In-depth genetic analysis of 6p21.3 reveals insights into associations between HLA types and complex traits and disease

Abstract The highly polymorphic major histocompatibility (MHC) region encodes the human leucocyte antigen (HLA) gene complex and is associated with many autoimmune and infectious diseases. Despite the importance of this interval, comprehensive genetic studies interrogating associations between HLA types, expression of non-HLA genes and disease, have not yet been conducted. To address this issue, we collected high-coverage whole genome sequence from 419 individuals and performed HLA typing at the highest resolution. Using RNA-seq from matched iPSC lines, we conducted an in-depth eQTL analysis using “personalized” transcripts, which significantly improved estimated expression levels of HLA genes, and showed HLA types have genetic associations independent from SNPs. We leveraged the eQTL results to examine associations between expression levels of non-HLA genes and disease. As a proof-of-principle, we investigated RNF5, whose protein product is a novel drug target in cystic fibrosis. We observed that decreased expression of RNF5 was associated with the 8.1 ancestral haplotype, which was previously found associated with protection against infection in cystic fibrosis. Overall, our study shows that genetically dissecting the MHC region provides novel insights into mechanisms underlying associations of this interval with disease.