A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response

Journal article

Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.

Authors: Luo, Y; Kanai, M; Choi, W; Li, X; Sakaue, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Genetics
• Volume: 53
• Issue: 10
• Pages: 1504-1516
• Publication date: 2021-10-05
• Acceptance date: 2021-08-02
• DOI: 10.1038/s41588-021-00935-7
• EISSN: 1546-1718
• ISSN: 1061-4036
• Pmid: 34611364
• Language: English
• Keywords: FFR