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

Abstract

Parkinson disease (PD) is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study (GWAS) with 2000 PD and 1986 control Caucasian subjects from NeuroGenetics Research Consortium.1–5 We confirmed SNCA2,6–8 and MAPT3,7–9; replicated GAK9 (PPankratz+NGRC=3.2×10−9); and detected a novel association with HLA (PNGRC=2.9×10−8) which replicated in two datasets (PMeta-analysis=1.9×10−10). We designate the new PD genes PARK17 (GAK) and PARK18 (HLA). PD-HLA association was uniform across genetic and environmental risk strata, and strong in sporadic (P=5.5×10−10) and late-onset (P=2.4×10−8) PD. The association peak was at rs3129882, a non-coding variant in HLA-DRA. Two studies suggested rs3129882 influences expression of HLA-DR and HLA-DQ.10,11 PD brains exhibit up-regulation of DR antigens and presence of DR-positive reactive microglia.12 Moreover, non-steroidal anti-inflammatory drugs (NSAID) reduce PD risk.4,13 The genetic association with HLA coalesces the evidence for involvement of the immune system and offers new targets for drug development and pharmacogenetics.

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

“…For AD, Yokoyama et al22 showed that eight variants were associated with both AD and immune‐mediated diseases, and there is further evidence from pathway analysis1, 23, 24 and from animal models 25. For PD, the role of the immune system has been suggested through pathway analyses,26, 27 animal models,28 and variants in the Human Leukocyte Antigen (HLA) region reaching statistical significance in GWASs 3, 29. For ALS, there is evidence of immune abnormalities 30.…”

Genome-wide association study confirms extant PD risk loci among the Dutch

“…In the GWAS carried out by Hamza et al, 10 only one SNP (rs3129882) in this region exceeded genome-wide significance level. After in silico replication and meta-analysis of the most significant SNPs, another six SNPs in this region were associated with PD in their population.…”

“…In a first approach aiming to determine (in the Dutch) the role of previously identified PD genetic risk factors, we decided to look closely at the results for SNCA (chromosome 4q21), [5][6][7] MAPT locus (chromosome 17q21.1), 5,7 LRRK2 (chromosome 12q12), 6,7 PARK16 6,7 (chromosome 1q32), BST1 (chromosome 4p15), 6 the GAK/DGKQ locus (chromosome 4p16), 5 the HLA region (chromosome 6p21.3) 10 and chromosome 12q24 locus. 11 A total of 30 SNPs from these loci were selected for closer scrutiny.…”

“…4 Recently, independent genomewide association studies (GWAS) established an unequivocal role for common genetic variants in the etiology of PD [5][6][7][8][9][10][11] and suggested a population-specific genetic heterogeneity, with SNCA, PARK16, BST1 and LRRK2 as shared risk loci for PD, [6][7][8]10,11 and MAPT as an European-specific risk locus. 6,7 Besides, variation in the GAK/DGKQ, 5 the HLA region 10 and a locus in chromosome 12q24 11 has been proposed to exert a risk for PD in different European populations.…”

Polygenic risk of Parkinson disease is correlated with disease age at onset

“…Recently, our understanding of idiopathic PD has been enhanced by genome‐wide association (GWA) studies6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 that have collectively identified PD risk variants at >18 loci 6, 7. Despite their high levels of significance, these 18 loci are thought to account for only a very small amount (3–5%) of the expected heritability of PD 17.…”