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.

Abstract Body

Pathogenic mutations in several genes (such as SNCA, LRRK2, PRKN, PINK1, DJ-1 and GBA) have been identified in familial Parkinson’s disease (PD) and more than 90 gene loci have been associated with sporadic PD risk. These discoveries have made important contributions in diagnosis and disease association, and provided some clues underlying the pathophysiology of the disease.

The clinical translational potential of these genetic discoveries have been debated. Will these genetic discoveries lead to a cure or therapies that will prevent or slow down the disease?

Currently, research on the proteins encoded by disease causing genes such as SNCA, LRRK2 and GBA, among others, have provide promising evidence that these targets could lead to neuroprotective therapies.

This lecture will summarise genetic discoveries in PD, highlight it role in clinical diagnosis, its potential in risk prediction, and stratifying patients for neuroprotective trials and for precision medicine. In addition, experimental evidence of the therapeutic potential and clinical trials of genetic targets will be discussed.

Abstract Body

Pathogenic mutations in several genes (such as SNCA, LRRK2, PRKN, PINK1, DJ-1 and GBA) have been identified in familial Parkinson’s disease (PD) and more than 90 gene loci have been associated with sporadic PD risk. These discoveries have made important contributions in diagnosis and disease association, and provided some clues underlying the pathophysiology of the disease.

The clinical translational potential of these genetic discoveries have been debated. Will these genetic discoveries lead to a cure or therapies that will prevent or slow down the disease?

Currently, research on the proteins encoded by disease causing genes such as SNCA, LRRK2 and GBA, among others, have provide promising evidence that these targets could lead to neuroprotective therapies.

This lecture will summarise genetic discoveries in PD, highlight it role in clinical diagnosis, its potential in risk prediction, and stratifying patients for neuroprotective trials and for precision medicine. In addition, experimental evidence of the therapeutic potential and clinical trials of genetic targets will be discussed.