Smith Courtney J, Strausz Satu, Spence Jeffrey P, Ollila Hanna M, Pritchard Jonathan K
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 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.
Am J Hum Genet. 2025 Jul 8. doi: 10.1016/j.ajhg.2025.06.011.
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.
人类白细胞抗原（HLA）区域通过参与免疫细胞识别和成熟，在人类健康中发挥着重要作用。虽然HLA区域的基因变异与许多疾病相关，但这些关联的多效性模式尚未得到系统研究。在此，我们开发了一种单倍型方法，对412,181名芬兰个体和2,459种疾病进行全表型组疾病关联研究。在1,035种具有全基因组关联研究关联的疾病中，我们发现HLA区域中每个单核苷酸多态性（SNP）的命中富集平均为17倍。我们总共鉴定出647种疾病中的7,649个HLA关联，其中包括通过单倍型分析发现的1,750个关联。我们发现，一些单倍型在不同疾病中既显示增加风险的关联又显示保护性关联，而另一些单倍型则在各种疾病中持续增加风险，这表明涉及一系列疾病的多效性景观十分复杂。这项研究突出了HLA变异对疾病风险的广泛影响，并强调了经典和非经典基因以及非编码变异的重要性。
