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

Publisher: Nature Publishing Group UK Country of Publication: England NLM ID: 101719179 Publication Model: Electronic Cited Medium: Internet ISSN: 2399-3642 (Electronic) Linking ISSN: 23993642 NLM ISO Abbreviation: Commun Biol Subsets: MEDLINE

Original Publication: London, United Kingdom : Nature Publishing Group UK, [2018]-

Biological Specimen Banks* ; Autoimmune Diseases*/genetics; Humans ; Alleles ; Exome Sequencing ; Genetic Predisposition to Disease ; HLA Antigens/genetics ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class II ; Polymorphism, Single Nucleotide ; United Kingdom

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.
(© 2023. The Author(s).)

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C18281/A29019 United Kingdom CRUK_ Cancer Research UK

0 (HLA Antigens)
0 (Histocompatibility Antigens Class I)
0 (Histocompatibility Antigens Class II)

Date Created: 20231104 Date Completed: 20231106 Latest Revision: 20231106

20250114

PMC10624861

10.1038/s42003-023-05496-5

37923823