Characterizing the HLA region's genetic architecture through local heritability and correlation analyses across complex traits in diverse ancestries.

The human leukocyte antigen (HLA) region is a critical genetic locus associated with diverse complex traits, yet its intricate genetic architecture poses significant challenges to elucidation. Leveraging recent advances in regional heritability estimation and extensive datasets from the Million Veteran Program (MVP), we conducted a comprehensive investigation of the HLA region's genetic architecture. This involved heritability estimation and genetic correlation analyses within the HLA region across European Americans (EAs) and African Americans (AAs). Our analyses demonstrated that in EAs, the HLA region exhibited significantly greater local heritability than other genomic regions of comparable length for lipid metabolic traits (triglycerides [TG], total cholesterol [TC], high-density lipoprotein [HDL], low-density lipoprotein [LDL]), anthropometric measures (body mass index [BMI]), and suicide-related traits (suicidal ideation without suicide attempts [IDE] and suicidal thoughts and behaviors [SITB]) (false discovery rate [FDR]-adjusted empirical p-values < 0.05). Notably, this enrichment was not observed in AAs. Genetic correlation analyses revealed disparities between local HLA and genome-wide findings. EAs exhibited 16 significant local HLA correlations and 32 genome-wide correlations. Conversely, AAs displayed more significant local genetic correlations within the HLA region (14 pairs) than genome-wide (3 pairs), with two pairs (IDE-SITB, LDL-TC) concordantly significant. These findings underscore the HLA region's substantial contribution to the variance of these lipid metabolic traits, BMI, and suicide-related traits. Further investigation into the genetic mechanisms by which HLA-mediated pathways influence these phenotypes is crucial for elucidating the complex role of this region, particularly concerning lipid metabolism and suicidal behaviors.