HLA allele-calling using multi-ancestry whole-exome sequencing from the UK Biobank identifies 129 novel associations in 11 autoimmune diseases

Abstract

The human leukocyte antigen (HLA) region on chromosome 6 is strongly associated with many immune-mediated and infection-related diseases. Due to its highly polymorphic nature and complex linkage disequilibrium patterns, traditional genetic association studies of single nucleotide polymorphisms do not perform well in this region. Instead, the field has adopted the assessment of the association of HLA alleles (i.e., entire HLA gene haplotypes) with disease. Often based on genotyping arrays, these association studies impute HLA alleles, decreasing accuracy and thus statistical power for rare alleles and in non-European ancestries. Here, we use whole-exome sequencing (WES) from 454,824 UK Biobank (UKB) participants to directly call HLA alleles using the HLA-HD algorithm. We show this method is more accurate than imputing HLA alleles and harness the improved statistical power to identify 360 associations for 11 auto-immune phenotypes (at least 129 likely novel), leading to better insights into the specific coding polymorphisms that underlie these diseases. We show that HLA alleles with synonymous variants, often overlooked in HLA studies, can significantly influence these phenotypes. Lastly, we show that HLA sequencing may improve polygenic risk scores accuracy across ancestries. These findings allow better characterization of the role of the HLA region in human disease.

Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults

“…However, WES studies of IMDs in the UKB have been sparse. Some have targeted specific regions, such as the HLA region for 11 autoimmune diseases 29 , or have investigated asthma risk mutations among predetermined variants 30 . Additionally, many of these studies were constrained by their sample sizes; for instance, one identified the TET2 mutation as a risk factor for gout among only 170,000 participants 31 .…”

Haplotype Analysis Reveals Pleiotropic Disease Associations in the HLA Region

“…The major histocompatibility complex (MHC) plays a crucial role in mediating tissue graft compatibility and immune system recognition of pathogens and self [1][2][3]. The human MHC, referred to as the human leukocyte antigen (HLA) region, has been found to be associated with numerous diseases [2][3][4][5][6][7][8]. The tension between being able to recognize a diverse array of pathogens while avoiding autoimmunity suggests that variants within the HLA region may affect multiple distinct phenotypes simultaneously.…”

“…Association studies have implicated particular HLA alleles in many diseases [6,7]. These canonical HLA association studies have provided countless biologically and clinically informative associations, for example, seronegative spondyloarthritis has been associated with the HLA-B27 allele family, Type 1 Diabetes with the HLA-DR3 allele family, and Rheumatoid arthritis with the HLA-DR4 allele family [28,29].…”