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)1, 2, 3, 4, 5. We confirmed associations with SNCA2, 6, 7, 8 and MAPT3, 7, 8, 9, replicated an association with GAK9 (using data from the NGRC and a previous study9, 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-DQ10, 11. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia12, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk4, 13. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.
At a glance
- Increased risk of Parkinson′s disease in parents and siblings of patients. Ann. Neurol. 36, 659–661 (1994). , , &
- Genetic association between alpha-synuclein and idiopathic Parkinson's disease. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 147B, 1222–1230 (2008). et al.
- Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson′s disease. Ann. Neurol. 62, 137–144 (2007). et al.
- Combined effects of smoking, coffee and NSAIDs on Parkinson′s disease risk. Mov. Disord. 23, 88–95 (2008). et al.
- Exploring gene-environment interactions in Parkinson′s disease. Hum. Genet. 123, 257–265 (2008). et al.
- Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. J. Am. Med. Assoc. 296, 661–670 (2006). et al.
- Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308–1312 (2009). et al.
- Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann. Hum. Genet. 74, 97–109 (2010). et al.
- Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum. Genet. 124, 593–605 (2009). et al.
- Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007). et al.
- Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773–777 (2010). et al.
- Glial reactions in Parkinson′s disease. Mov. Disord. 23, 474–483 (2008). &
- Nonsteroidal anti-inflammatory drug use and the risk for Parkinson′s disease. Ann. Neurol. 58, 963–967 (2005). et al.
- Parkinson's disease in 65 pairs of twins and in a set of quadruplets. Neurology 33, 815–824 (1983). et al.
- Parkinson disease in twins: an etiologic study. J. Am. Med. Assoc. 281, 341–346 (1999). et al.
- Familial aggregation of Parkinson′s disease: a meta-analysis. Mov. Disord. 23, 1174–1183 (2008). &
- A SNCA variant associated with Parkinson's disease and plasma α-synuclein level. Arch. Neurol. (in the press). et al.
- A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Ann. Neurol. 52, 276–284 (2002). , , &
- Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat. Genet. 41, 1303–1307 (2009). et al.
- Genome-wide genotyping in Parkinson′s disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 5, 911–916 (2006). et al.
- High-resolution whole-genome association study of Parkinson disease. Am. J. Hum. Genet. 77, 685–693 (2005). et al.
- The heritability of risk and age at onset of Parkinson′s disease after accounting for known genetic risk factors. J. Hum. Genet. 55, 241–243 (2010). &
- The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 51, 745–752 (1988). &
- The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125, 861–870 (2002). , , &
- PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007). et al.
- Parkinson's disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics. Mov. Disord. 21, 519–523 (2006). et al.
- Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001). , &
- Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006). et al.
- Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285–1291 (1988). , , &
- A possible role for humoral immunity in the pathogenesis of Parkinson's disease. Brain 128, 2665–2674 (2005). , , , &
- Parkinson's disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood. Acta Neurol. Scand. 90, 160–166 (1994). , , , &
- Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann. Neurol. 54, 599–604 (2003). , , &
- Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann. Neurol. 46, 598–605 (1999). et al.
- Regulatory T cells attenuate th17 cell-mediated nigrastriatal dopaminergic neurodegeneration in a model of Parkinson' disease. J. Immunol. 184, 2261–2271 (2010). et al.
- Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005). , , &
- Supplementary Text and Figures (536)
Supplementary Tables 1–5 and Supplementary Figures 1–6