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

• Published in: Nature genetics Vol. 42; no. 9; pp. 781 - 785
• Main Authors: Payami, Haydeh, Hamza, Taye H, Zabetian, Cyrus P, Tenesa, Albert, Laederach, Alain, Montimurro, Jennifer, Yearout, Dora, Kay, Denise M, Doheny, Kimberly F, Paschall, Justin, Pugh, Elizabeth, Kusel, Victoria I, Collura, Randall, Roberts, John, Griffith, Alida, Samii, Ali, Scott, William K, Nutt, John, Factor, Stewart A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2010; Nature Publishing Group
• Subjects: 631/1647/2217/2138; 631/208/727/2000; 692/699/375/365/1718; Adult; Age of Onset; Aged; Aged, 80 and over; Agriculture; Animal Genetics and Genomics; Antiparkinsonian agents; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Case-Control Studies; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Drug therapy; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Genetic aspects; Genetic Linkage; Genetic Predisposition to Disease; Genetic Variation - physiology; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Health aspects; Histocompatibility antigens; HLA Antigens - genetics; HLA histocompatibility antigens; Human Genetics; Humans; letter; Male; Medical sciences; Meta-Analysis as Topic; Middle Aged; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Odds Ratio; Parkinson Disease - epidemiology; Parkinson Disease - genetics; Parkinson's disease; Physiological aspects; Risk factors; Single nucleotide polymorphisms; Young Adult; United States; Nervous system diseases; Late; Genetic variability; Sporadic; Genetic variant; Central nervous system disease; Parkinson disease; Degenerative disease; Cerebral disorder; Extrapyramidal syndrome
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.642

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.