Fine mapping of the HLA locus in Parkinson’s disease in Europeans
Eric Yu, Aditya Ambati, Maren Stolp Andersen, Lynne Krohn, Mehrdad A. Estiar, Prabhjyot Saini, Konstantin Senkevich, Yuri L. Sosero, Ashwin Ashok Kumar Sreelatha, Jennifer A. Ruskey, Farnaz Asayesh, Dan Spiegelman, Mathias Toft, Marte K. Viken, Manu Sharma, Cornelis Blauwendraat, Lasse Pihlstrøm, Emmanuel Mignot, Ziv Gan‐Or
Abstract
Abstract 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.