A high-resolution HLA reference panel capturing global population diversity enables multi-ethnic fine-mapping in HIV host response
Peter K Gregersen,
Philip E Stuart,
James T Elder,
David W. Haas,
Nicholette D Palmer,
Yii-Der Ida Chen,
Jerome I. Rotter,
Kent D. Taylor,
James G Wilson,
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,
Paul J Mclaren,
Posted 18 Jul 2020
medRxiv DOI: 10.1101/2020.07.16.20155606
Posted 18 Jul 2020
Defining causal variation by fine-mapping can be more effective in multi-ethnic genetic studies, particularly in regions such as the MHC with highly population-specific structure. To enable such studies, we constructed a large (N=21,546) high resolution HLA reference panel spanning five global populations based on whole-genome sequencing data. Expectedly, we observed unique long-range HLA haplotypes within each population group. Despite this, we demonstrated consistently 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)). We jointly analyzed genome-wide association studies (GWAS) of HIV-1 viral load from EUR, AA and LAT populations. Our analysis 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, and obviating effects of previously reported associations from population-specific HIV studies.
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