We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson’s disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes—11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83–0.90, p < 8.23 × 10⁻⁹ for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.

我们精细绘制了13,770 名帕金森病 (PD) 患者、20,214 名代理病例和 490,861 名欧洲血统对照的白细胞抗原 ( HLA)区域。经多重比较校正后，四种HLA类型与 PD 相关，HLA-DQA1 *03:01、HLA-DQB1 *03:02、HLA-DRB1 *04:01 和HLA-DRB1 *04:04。单倍型分析以及随后的氨基酸分析和条件分析表明，这种关联是保护性的，主要由大多数HLA-DRB1 *04 亚型中存在的三种特定氨基酸多态性驱动——11V、13H 和 33H（OR = 0.87，95% CI： 0.83–0.90，p  < 8.23 × 10 ^-9对于所有三个变体）。调整这些氨基酸后不存在其他影响。我们的结果表明，特定的HLA-DRB1变异体与 PD 风险降低相关，为免疫系统在 PD 中的作用提供了额外的证据。尽管效应量很小且没有诊断意义，但了解这种关联的潜在机制可能会导致确定治疗学开发的新靶点。