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

Area of Science:

• Genetics
• Immunogenetics
• Population Genetics

Background:

• Fine-mapping causal genetic variants is crucial for understanding disease mechanisms.
• The Major Histocompatibility Complex (MHC) region exhibits significant population-specific structure, complicating imputation in multi-ancestry cohorts.
• Accurate imputation in diverse populations is essential for robust genome-wide association studies (GWAS).

Purpose of the Study:

• To construct a large, multi-ancestry Human Leukocyte Antigen (HLA) reference panel for improved genetic fine-mapping.
• To apply this panel to identify causal variants associated with HIV-1 viral load.
• To pinpoint specific amino acid positions within HLA-B influencing HIV-1 viral load.

Main Methods:

• Construction of a large HLA reference panel (n=21,546) from whole-genome sequences across five global populations.
• Imputation of HLA alleles at G-group resolution across admixed African (AA), East Asian (EAS), European (EUR), and Latino (LAT) populations.
• Application of HLA imputation to GWAS data for HIV-1 viral load in EUR, AA, and LAT populations.

Main Results:

• Demonstrated accurate HLA imputation across diverse populations, achieving high G-group resolution.
• Obviated population-specific associations and discovered a novel association at position 156 in HLA-B for HIV-1 viral load.
• Pinpointed the MHC association to three amino acid positions (97, 67, 156) in HLA-B, explaining 12.9% of trait variance.

Conclusions:

• A multi-ancestry HLA reference panel enables effective fine-mapping of complex genetic regions like the MHC.
• This approach successfully identified novel causal variants for HIV-1 viral load, highlighting specific amino acid residues in HLA-B.
• The findings provide a deeper understanding of the genetic architecture of HIV-1 viral load and its population-specific influences.