Haplotype analysis reveals pleiotropic disease associations in the HLA region

Courtney J Smith; Satu Strausz; FinnGen; Jeffrey P Spence; Hanna M Ollila; Jonathan K Pritchard

doi:10.1016/j.ajhg.2025.06.011

Haplotype analysis reveals pleiotropic disease associations in the HLA region

Am J Hum Genet. 2025 Jul 8:S0002-9297(25)00242-3. doi: 10.1016/j.ajhg.2025.06.011. Online ahead of print.

Authors

Courtney J Smith¹, Satu Strausz²; FinnGen; Jeffrey P Spence³, Hanna M Ollila⁴, Jonathan K Pritchard⁵

Affiliations

¹ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland. Electronic address: courtrun@stanford.edu.
² Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Department of Plastic Surgery, Cleft Palate and Craniofacial Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
³ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA. Electronic address: pritch@stanford.edu.

PMID: 40645183
DOI: 10.1016/j.ajhg.2025.06.011

Abstract

The human leukocyte antigen (HLA) region plays an important role in human health through its involvement in immune cell recognition and maturation. While genetic variation in the HLA region is associated with many diseases, the pleiotropic patterns of these associations have not been systematically investigated. Here, we developed a haplotype approach to investigate disease associations phenome wide for 412,181 Finnish individuals and 2,459 diseases. Across the 1,035 diseases with a genome-wide association study association, we found a 17-fold average per-SNP enrichment of hits in the HLA region. Altogether, we identified 7,649 HLA associations across 647 diseases, including 1,750 associations uncovered by haplotype analysis. We found that some haplotypes show both risk-increasing and protective associations across different diseases, while others consistently increase risk across diseases, indicating a complex pleiotropic landscape involving a range of diseases. This study highlights the extensive impact of HLA variation on disease risk and underscores the importance of classical and non-classical genes as well as non-coding variation.

Keywords: FinnGen; GWAS; HLA; UKBB; biobank; genomics; phenome-wide; summary statistics.