Multi-ancestry MHC-pQTL mapping reveals disease-linked HLA protein networks and shared genetic architecture
- 1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK
Abstract
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.
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BibTeX
@misc{sarguroh2026multiancestry,
title = {{Multi-ancestry MHC-pQTL mapping reveals disease-linked HLA protein networks and shared genetic architecture}},
author = {S. Sarguroh and S. Morris and E. Ng and G. Butler Laporte and R. Nanjala and A. Pozarickij and L. Yang and L. Li and J. Junshi and P. Pei and J. Lv and C. Yu and D. Sun and Z. Chen and I. Millwood and R. Walters and A. J. Mentzer and Y. Luo},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.26362390},
url = {https://www.medrxiv.org/content/10.64898/2026.09.08.26362390v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Multi-ancestry MHC-pQTL mapping reveals disease-linked HLA protein networks and shared genetic architecture
AU - S. Sarguroh
AU - S. Morris
AU - E. Ng
AU - G. Butler Laporte
AU - R. Nanjala
AU - A. Pozarickij
AU - L. Yang
AU - L. Li
AU - J. Junshi
AU - P. Pei
AU - J. Lv
AU - C. Yu
AU - D. Sun
AU - Z. Chen
AU - I. Millwood
AU - R. Walters
AU - A. J. Mentzer
AU - Y. Luo
PY - 2026
DA - 2026/09/08
PB - medRxiv
DO - 10.64898/2026.09.08.26362390
UR - https://www.medrxiv.org/content/10.64898/2026.09.08.26362390v1
AB - 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.
ER -