Trans-ethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals shared but also ethnicity-specific disease associations

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD, and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such a delineation could not be made due to tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a trans-ethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9,272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40,691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analysed the physico-chemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we identified consistent associations across different ethnicities but also identified population-specific signals. We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids such. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

Detailed stratified GWAS analysis for severe COVID-19 in four European populations

“…HLA allele, amino acid, and SNP imputation was performed using the random-forest based HLA genotype imputation with attribute bagging (HIBAG) and applying specially tailored as well as publicly available reference panels. (5,54,55) The resulting data were used as a basis for several subsequent analyses, including: 1) basic association analysis (fine mapping) as described in the section Statistical Analysis and the Supplementary Methods , 2) a peptidome-wide association study(11) (pepWAS), to screen for disease-relevant peptides from SARS-CoV-2, that may present a possible functional link between severe COVID-19 and variation at classical HLA loci, 3) quantitative HLA analyses directed at the number of peptides bound by an HLA allele, as well as 4) an analysis of HLA-presentation of shared peptides (‘molecular mimicry’).…”