Background-Recent studies indicate an increased frequency of mutations in the gene for Gaucher disease, glucocerebrosidase (GBA), among patients with Parkinson disease. An international collaborative study was conducted to ascertain the frequency of GBA mutations in ethnically diverse patients with Parkinson disease.

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.

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Objective-An inversion polymorphism of approximately 900kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case-control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson's disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings.Methods-We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the H1 and H2 clades. We also analyzed four SNPs that define subhaplotypes within H1 previously reported to associate with PD or other neurodegenerative disorders.Results-After adjusting for age, sex, and site, we observed a robust association between the H1/ H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25-1.69; p = 8 × 10 −7 ). The effect was evident in both familial and sporadic subgroups, men and women, and early-and late-onset disease. Within H1/H1 individuals, there was no significant NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes.Interpretation-Our data provide strong evidence that the H1 clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD.The microtubule-associated protein tau, encoded by the MAPT gene, is primarily expressed in neurons and plays a key role in the organization and integrity of the cytoskeleton.1 ,2 Filamentous neuronal tau inclusions define a set of neurodegenerative diseases collectively known as the tauopathies, which include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia with parkinsonism linked to chromosome 17. 1, 2 MAPT sequence variation was first linked to the etiopathogenesis of tauopathies by the discovery of mutations resulting in frontotemporal dementia with parkinsonism linked to chromosome 17, and subsequently an extended common haplotype (H1) across the gene was shown to associate with disease risk in PSP and CBD. 3-7Though Parkinson's disease (PD) shares some clinical features with the tauopathies, it has been assigned to a distinct subset of neurodegenerative diseases (the α-synucleinopathies) by histopathology because it is characterized by intraneuronal accumulation of α-synuclein, rather than tau. 8 Thus, initial reports that the MAPT H1 haplotype was also associated with PD were intriguing but met with some skepticism. Since then the association between MAPT variants and PD has remained tenuous with a number of small case-control studies report...

Referral-based studies indicate that a mutation (G2019S) in exon 41 of the LRRK2 gene might be a common cause of Parkinson disease (PD). The authors sequenced leucine-rich repeat kinase 2 (LRRK2) exons 31, 35, and 41 in 371 consecutively recruited patients with PD and found mutations in six (1.6%) subjects, including two heterozygous for new putative pathogenic variants (R1441H, IVS31 + 3A-->G). These data confirm the important contribution of LRRK2 to PD susceptibility in a clinic-based population.