A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response.
Luo Y., Kanai M., Choi W., Li X., Sakaue S., Yamamoto K., Ogawa K., Gutierrez-Arcelus M., Gregersen PK., Stuart PE., Elder JT., Forer L., Schönherr S., Fuchsberger C., Smith AV., Fellay J., Carrington M., Haas DW., Guo X., Palmer ND., Chen Y-DI., Rotter JI., Taylor KD., Rich SS., Correa A., Wilson JG., Kathiresan S., Cho MH., Metspalu A., Esko T., Okada Y., Han B., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium None., McLaren PJ., Raychaudhuri S.
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.