Multi-ancestry MHC-pQTL mapping reveals disease-linked HLA protein networks and shared genetic architecture

The major histocompatibility complex (MHC) is one of the most polymorphic and disease-relevant regions of the human genome, yet the downstream effects of MHC variation on circulating protein networks across ancestries remain incompletely defined. Here, we conducted multi-ancestry protein quantitative trait locus (pQTL) mapping in the UK Biobank (n = 43,762) and China Kadoorie Biobank (n = 3,977) to characterise how genetic variation within the MHC region shape plasma protein abundance. Among 2,920 plasma proteins tested, we identified significant MHC associations (13 cis and 606 trans), with most signals showing consistent effects across ancestries, while also identifying an ancestry-enriched association with EDAR in East Asians. Local genetic correlation analyses identified distinct co-regulated protein networks associated with HLA class I and class II regions, consistent with their respective known immune functions. We also conducted HLA-specific colocalisation, and found multiple HLA trans-regulated proteins associations which colocalised with immune-mediated traits at the same classical HLA gene, including colocalisation between B2M and multiple sclerosis at HLA-A (PP = 0.991). Together, these findings describe the principal downstream proteomic consequences of MHC variation and provide a framework for linking disease-associated HLA genes to immune protein networks.