Jun Hirata (Japan)
Osaka University Statistical GeneticsAuthor Of 1 Presentation
TRANS-ETHNIC FINE-MAPPING OF THE MHC REGION ON PARKINSON’S DISEASE IDENTIFIED SHARED GENETIC FEATURES ASSOCIATED WITH THE RISK
- Tatsuhiko Naito (Japan)
Abstract
Background and Aims:
Although different studies reported the genetic predisposition of human leukocyte antigen (HLA) to the risk of Parkinson’s disease (PD), the complex haplotype structure and highly polymorphic feature of the major histocompatibility complex (MHC) region has hampered a unified insight. In addition, the evidence for non-European populations was scarce. We conducted trans-ethnic fine-mapping for large cohorts to elucidate shared genetic features of the MHC region associated with the PD risk.
Methods:
We targeted European populations (14,650 cases and 1,288,625 controls) and East Asian populations (7,712 cases and 27,372 controls). We adopted a hybrid fine-mapping approach including: (1) HLA genotype imputation of GWAS genotype data using our novel imputation method, DEEP*HLA; and (2) direct imputation of HLA variant risk from the GWAS summary statistics.
Results:
The strongest association was observed at the protective effect of His13 in HLA-DRβ1 (P = 6.0 × 10−15), and this position explained the majority of the risk in HLA-DRB1. In silico prediction revealed that HLA-DRB1 alleles with His13 (protective) and Arg13 (risk) had significantly weaker and stronger binding-affinity to an α-synuclein epitope than other alleles (P = 9.6 × 10−4 and 1.0 × 10−3, respectively). Stepwise conditional analysis revealed additional independent associations at Ala69 in HLA-B (P = 1.0 × 10−7). We experimentally fine-mapped Alzheimer's disease risk, but the lead variants were not consistent.
Conclusions:
The current study highlights the genetic features of the MHC region associated with the risk of PD across ethnicities, enhancing our understanding of the immunologic pathophysiology of PD.