Abstract Objective: To fine map the association between human leukocyte antigen (HLA) genes and Parkinson's disease (PD) that was discovered using genome-wide association studies (GWASs). Methods: We performed a thorough analysis of the HLA locus in 13,770 PD patients, 20,214 proxy-cases and 490,861 controls of European origin. We used GWAS data to impute HLA types and performed multiple regression models to examine the association of specific HLA types, different haplotypes and specific amino acid changes. We further performed conditional analyzes to identify specific alleles or genetic variants that drive the association with PD. Results: 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 analyzes followed by amino-acid analysis and conditional analyzes 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<8.23x10^-9 for all three variants). No other effects were present after adjustment for these amino acids. Conclusions: Our results suggest that specific variants in the HLA-DRB1 gene 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 identification of new targets for therapeutics development.

中文翻译：

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欧洲人帕金森氏病中HLA基因座的精细定位

摘要目的：精细定位人类白细胞抗原（HLA）基因与帕金森氏病（PD）之间的关联，该关联是通过全基因组关联研究（GWAS）发现的。方法：我们对13770例PD患者，20214例代理病例和490861例欧洲来源的​​对照进行了HLA基因座的全面分析。我们使用GWAS数据估算HLA类型，并执行了多个回归模型以检查特定HLA类型，不同单倍型和特定氨基酸变化的关联。我们进一步进行了条件分析，以确定驱动与PD关联的特定等位基因或遗传变异。结果：四个HLA校正后，多种类型与PD相关联，HLA-DQA1 * 03：01，HLA-DQB1 * 03：02，HLA-DRB1 * 04：01和HLA-DRB1 * 04：04。单倍型分析，然后进行氨基酸分析和条件分析，表明该关联是保护性的，并且主要由大多数HLA-DRB1 * 04亚型中存在的三个特定氨基酸多态性驱动-11V，13H和33H（OR = 0.87 95％CI = 0.83） -0.90，对于所有三个变体，p <8.23x10 ^-9）。调整这些氨基酸后，没有其他作用。结论：我们的结果表明HLA-DRB1中的特定变异该基因与PD的风险降低相关，为免疫系统在PD中的作用提供了额外的证据。尽管效应大小很小并且没有诊断意义，但了解这种关联的机制可能会导致鉴定治疗药物开发的新靶标。