Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease

By Taye H. Hamza, C. Zabetian, A. Tenesa, Alain Laederach, Jennifer S. Montimurro, Dora Yearout, Denise M. Kay, K. Doheny, J. Paschall, E. Pugh and 9 more. Nature Genetics, 2010

761 citations recorded by the source corpus.

Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 × 10−9) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 × 10−8), which replicated in two datasets (meta-analysis P = 1.9 × 10−10). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 × 10−10) and late-onset (P = 2.4 × 10−8) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.

Subfields: Cognitive Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/4c2cbc57999421a7ac51bd0cfefafe748c12d752

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Citations in the corpus

• T cells of Parkinson’s disease patients recognize α–synuclein peptides (2017, background): “To be considered positive, a response had to match three criteria: (1) elicit at least 100 spot-forming cells (SFC) per 106 PBMC; (2) P ≤ 0.”
• Parkinson’s Disease and PD Medications Have Distinct Signatures of the Gut Microbiome (2017, methodology): “The methods and the clinical and genetic characteristics of the NeuroGenetics Research Consortium dataset have been described in detail.(15) Briefly, PD patients were diagnosed by a movement disorder specialist according to the modified UK Brain Bank criteria.”
• Parkinson Disease Epidemiology, Pathology, Genetics and Pathophysiology (2019, background): “Genetic studies also have linked HLA gene variants with the risk of late-onset PD(51).”
• Parkinson disease: from pathology to molecular disease mechanisms. (2013, background): “This point was brought into focus by recent GWAS that showed HLA to be a risk factor for the occurrence of PD [40].”
• Major Histocompatibility Complex Genomics and Human Disease (2013, neutral): “Some forms of Parkinson’s disease are associated with class II alleles, and studies have demonstrated associations with independent markers in the class II region that are not in strong linkage disequilibrium with one another (42, 47).”
• Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, neutral): “…polymorphisms in the SNCA gene are strongly associated with PD risk (Satake et al , 2009; Simon-Sanchez et al , 2009; Edwards et al , 2010; Hamza et al , 2010; International Parkinson Disease Genomics Consortium et al , 2011). a -Synuclein is a 140 amino-acid protein that is abundantly…”
• Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction (2023, background): “Given the association between inflammation and higher risk for PD [65, 66], these data suggest that α-syn pathology and inflammatory state play a synergistic role in the excessive immune system response contributing to the worsening of the PD state.”
• The Role of Oxidative Stress in Parkinson’s Disease (2013, background): “Although microglia activation and inflammatory changes are generally considered as a consequence of neuronal destruction, the finding of human leukocyte antigen (HLA) as a risk factor for PD in Genome-Wide Association Studies (GWAS) raises the possibility for a more general pro-inflammatory state in”