Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study.

BACKGROUND: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. OBJECTIVE: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). METHODS: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). RESULTS: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029). CONCLUSIONS: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.

The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited.

BACKGROUND: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. OBJECTIVE: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. METHODS: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. RESULTS: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, PInteraction  = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. CONCLUSIONS: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Alpha-synuclein repeat variants and survival in Parkinson's disease.

OBJECTIVES: To determine whether α-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. RESULTS: Twenty-one sites contributed data for 6,154 cases. There was no significant association between α-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). CONCLUSIONS: In our large consortium study, α-synuclein REP1 genotypes were not associated with survival in PD. Further studies of α-synuclein's role in disease progression and long-term outcomes are needed.

Fahr's disease linked to a novel SLC20A2 gene mutation manifesting with dynamic aphasia.

BACKGROUND: Idiopathic basal ganglia calcification (IBGC), also known as Fahr's disease, is a rare disorder characterized by widespread cerebral calcifications, an autosomal dominant pattern of inheritance and clinical and genetic heterogeneity. The recently identified IBGC gene, SLC20A2, encodes for type III sodium-dependent phosphate transporter 2 and its loss-of-function mutations may lead to the regional accumulation of inorganic phosphate in the brain, causing calcium phosphate deposition. OBJECTIVE: To describe the clinical, neuroimaging and genetic findings in an Italian family with IBGC. METHODS: The family members underwent clinical and radiological examination in order to diagnose IBGC according to standard criteria and screening for SLC20A2 gene mutations. The affected subjects also underwent neuropsychological longitudinal assessments and functional neuroimaging investigations. RESULTS: The 2 affected family members harbored a novel missense mutation, G1618A, in the SLC20A2 gene, leading to gly540-to-arg (G540R) substitution in a highly conserved residue. This is the first SLC20A2 gene mutation associated with familial IBGC reported in the Italian population and is damaging according to all prediction programs. In the index case we observed a fair correlation between cortical areas with no calcifications but with significant hypometabolism at [18F]FDG-PET (inferior frontal premotor cortex) and the neuropsychological picture dominated by dynamic aphasia and buccofacial apraxia. CONCLUSION: These findings expand the catalog of SLC20A2 mutations identified to date and add dynamic aphasia to the spectrum of neuropsychological deficits reported in IBGC, supporting the use of functional neuroimaging studies for better investigation of genotype-phenotype correlations.

Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. METHODS: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. RESULTS: Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. CONCLUSIONS: Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies.

Hypoglycemic Encephalopathy Manifesting with Cortical Hemichorea-Hemiballismus Syndrome: A Case Report.

Hyper-/hypoglycemic states are rare but well-established causes of hyperkinetic movements, including chorea and ballismus, usually associated with brain lesions in the basal ganglia. We report a case of hemichorea-hemiballismus (HCHB) syndrome that developed after a severe hypoglycemic episode in a 71-year-old man with poorly controlled type 2 diabetes mellitus. Uncommonly, brain MRI showed contralateral cortical-subcortical T2 and T2-FLAIR-hyperintense frontoparietal lesions, with cingulate gyrus involved, while the basal ganglia were unaffected. In patients with hypoglycemic encephalopathy associated with cortical lesions, the long-term prognosis is usually poor. Nevertheless, in our patient, the dyskinesias and the cerebral lesions progressively regressed by achieving good glycemic control. After four and 12 months, the patient's neurological examination was normal. To our knowledge, this is the first evidence of hypoglycemic etiology of cortical HCHB syndrome, supporting recent theories that cortical circuitries may independently contribute to the pathogenesis of chorea and ballismus. This is also the first report of cingulate gyrus involvement in hypoglycemic encephalopathy. Finally, this case may indicate that a subset of patients with cortical lesions due to hypoglycemia could present a good clinical outcome, likely depending on the size of the lesions and the duration and severity of the hypoglycemic episode.

Levodopa Equivalent Dose of Safinamide: A Multicenter, Longitudinal, Case-Control Study.

Background: Effects of dopaminergic medications used to treat Parkinson's disease (PD) may be compared with each other by using conversion factors, calculated as Levodopa equivalent dose (LED). However, current LED proposals on MAO-B inhibitors (iMAO-B) safinamide and rasagiline are still based on empirical approaches. Objectives: To estimate LED of safinamide 50 and 100 mg. Methods: In this multicenter, longitudinal, case-control study, we retrospectively reviewed clinical charts of 500 consecutive PD patients with motor complications and treated with (i) safinamide 100 mg (N = 130), safinamide 50 mg (N = 144), or rasagiline 1 mg (N = 97) for 9 ± 3 months and a control group of patients never treated with any iMAO-B (N = 129). Results: Major baseline features (age, sex, disease duration and stage, severity of motor signs and motor complications) were similar among the groups. Patients on rasagiline had lower UPDRS-II scores and Levodopa dose than control subjects. After a mean follow-up of 8.8-to-10.1 months, patients on Safinamide 50 mg and 100 mg had lower UPDRS-III and OFF-related UPDRS-IV scores than control subjects, who in turn had larger increase in total LED than the three iMAO-B groups. After adjusting for age, disease duration, duration of follow-up, baseline values and taking change in UPDRS-III scores into account (sensitivity analysis), safinamide 100 mg corresponded to 125 mg LED, whereas safinamide 50 mg and rasagiline 1 mg equally corresponded to 100 mg LED. Conclusions: We used a rigorous approach to calculate LED of safinamide 50 and 100 mg. Large prospective pragmatic trials are needed to replicate our findings.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Independent and joint effects of the MAPT and SNCA genes in Parkinson disease.

OBJECTIVE: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. METHODS: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. RESULTS: Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. INTERPRETATION: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects.

Multiple system atrophy and C9orf72 hexanucleotide repeat expansions in a cohort of Italian patients.

Exanucleotide expansions in C9orf72 gene have been described as potential risk factor in some patients with Multiple system atrophy (MSA) and other forms of atypical parkinsonism. The goal of our study was to extend the knowledge on the involvement of C9orf72 in MSA studying a cohort of 100 patients from Italy. We identified 2 heterozygous patients in the pathological range (> 30 repeats) and 4 heterozygous patients for expansions in the premutation range (20 -30 repeats). Our findings strengthen the previously hypothesized role for this gene as a risk factor for MSA and raise the possibility of a more complex and still unknown involvement of this gene in the heterogeneity of MSA.

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease.

BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium.

BACKGROUND AND OBJECTIVES: Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. METHODS: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). RESULTS: The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: ß(SE)COURAGE = 0.477(0.203), p COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: ß(SE)COURAGE+IPDGC = 0.720(0.122), p COURAGE+IPDGC = 3.13 × 10-9) and a novel BST1 locus (rs4698412: ß(SE)COURAGE+IPDGC = -0.526(0.096), p COURAGE+IPDGC = 4.41 × 10-8). DISCUSSION: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.

Vesicular monoamine transporter 2 mRNA levels are reduced in platelets from patients with Parkinson's disease.

Despite advances in neuroimaging, the diagnosis of idiopathic Parkinson's disease (PD) remains clinical. The identification of biological markers for an early diagnosis is of great interest to start a neuroprotective therapy aimed at slowing, blocking or reversing the disease progression. Vesicular monoamine transporter 2 (VMAT2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and release. Thus, VMAT2 impairment can regulate intra- and extracellular dopamine levels, influencing oxidative stress and neuronal death. Because in vivo imaging studies have demonstrated a VMAT2 reduction in PD patients greater than would be explained by neuronal loss alone, as an exploratory study we assessed VMAT2 mRNA and protein levels in platelets from 39 PD patients, 39 healthy subjects and 10 patients with vascular parkinsonism (VP) to identify a possible peripheral biomarker for PD. A significant reduction (p < 0.05) of VMAT2 mRNA levels was demonstrated in PD patients versus healthy controls. Patients with VP showed VMAT2 mRNA levels similar to controls. No difference in VMAT2 mRNA levels was found in untreated versus treated patients. No correlation was observed between mRNA levels and demographic or clinical characteristics. Furthermore, eight SNPs tagging the VMAT2 gene did not show effects on VMAT2 mRNA levels. Western blot analysis did not allow the quantification of VMAT2 protein expression in blood platelets. Although further studies in a greater number of cases are needed to confirm our data, the reduction in VMAT2 mRNA in platelets from PD patients suggests the existence of a systemic impairment of this transporter possibly contributing to PD pathology.

Non-replication of association for six polymorphisms from meta-analysis of genome-wide association studies of Parkinson's disease: large-scale collaborative study.

Early genome-wide association (GWA) studies on Parkinson's disease (PD) have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the meta-analysis of the first two GWA investigations might be replicable in different populations. We examined six single-nucleotide polymorphisms (SNPs) (rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626) that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the "Genetic Epidemiology of Parkinson's Disease" (GEOPD) consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs (599 PD cases, 592 controls and 443 sibling pairs) were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets (excluding the original GWA data) were very close to 1.00 (range 0.98-1.09) and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques.

DCTN1 mutation analysis in Italian patients with PSP, MSA, and DLB.

DCTN1 encodes the largest subunit of dynactin complex essential in the retrograde axonal transport and cytoplasmic transport of vesicles; mutations in DCTN1 have been reported predominantly in individuals with Perry syndrome and, recently, in patients with progressive supranuclear palsy. Our genetic screening of DCTN1 in 79 patients with progressive supranuclear palsy, 100 patients with multiple system atrophy, and 28 patients with dementia with Lewy bodies from Italy revealed only synonymous and intronic variants, suggesting that DCTN1 mutations do not have a key role in the development of atypical parkinsonism in the Italian population.

Genetic mutation analysis of the COQ2 gene in Italian patients with multiple system atrophy.

COQ2 encodes para-hydroxybenzoate-polyprenyl transferase and, recently, mutations in this gene have been associated with the increase of the risk of multiple system atrophy (MSA) in Japanese cases. Subsequently, studies in Asian patients confirmed the role of COQ2 in the development of MSA, while other analysis failed to replicate these results in Caucasian population. We performed genetics screening of COQ2 in 100 MSA Italian patients. We did not find any pathogenic mutations; our results suggest that COQ2 is not a genetic risk factor for MSA in Italian population.

Beta-synuclein gene variants and Parkinson's disease: a preliminary case-control study.

Aggregation and fibrillization of the alpha-synuclein protein, which is the main component of Lewy bodies, may represent important processes in the pathogenesis of Parkinson's disease (PD). Several in vivo and in vitro studies suggest that beta-synuclein may be a natural negative regulator of alpha-synuclein aggregation and fibrillization. The goal of the present study was to investigate the association of two polymorphisms (rs35035889 and rs1352303) in the beta-synuclein (SNCB) gene with PD. Our case-control study included a total of 370 case-unaffected sibling pairs and 168 case-unrelated control pairs (538 pairs total). The subjects were recruited from an ongoing study of the molecular epidemiology of PD in the Upper Midwest (USA). We employed a liberalization of the sibling transmission disequilibrium test to study the main effects of the gene variants for subjects overall and for strata defined by age at study, gender, ethnicity, clinical diagnostic certainty, dementia, and family history of PD (adjusted for age at study and gender as appropriate). The analyses were conducted for each SNCB variant separately, and also for two-locus haplotypes using score tests. Neither of the SNCB SNPs examined were associated with PD overall or in strata, and haplotype analyses were negative as well. However, one of the two SNPs (rs1352303) was associated with a delayed age at onset of PD in women. The results of this preliminary study suggest that the SNCB locus, though not a susceptibility gene for PD, might modify the age at onset of PD.

Rotenone down-regulates HSPA8/hsc70 chaperone protein in vitro: A new possible toxic mechanism contributing to Parkinson's disease.

HSPA8/hsc70 (70-kDa heat shock cognate) chaperone protein exerts multiple protective roles. Beside its ability to confer to the cells a generic resistance against several metabolic stresses, it is also involved in at least two critical processes whose activity is essential in preventing Parkinson's disease (PD) pathology. Actually, hsc70 protein acts as the main carrier of chaperone-mediated autophagy (CMA), a selective catabolic pathway for alpha-synuclein, the main pathogenic protein that accumulates in degenerating dopaminergic neurons in PD. Furthermore, hsc70 efficiently fragments alpha-synuclein fibrils in vitro and promotes depolymerization into non-toxic alpha-synuclein monomers. Considering that the mitochondrial complex I inhibitor rotenone, used to generate PD animal models, induces alpha-synuclein aggregation, this study was designed in order to verify whether rotenone exposure leads to hsc70 alteration possibly contributing to alpha-synuclein aggregation. To this aim, human SH-SY5Y neuroblastoma cells were treated with rotenone and hsc70 mRNA and protein expression were assessed; the effect of rotenone on hsc70 was compared with that exerted by hydrogen peroxide, a generic oxidative stress donor with no inhibitory activity on mitochondrial complex I. Furthermore, the effect of rotenone on hsc70 was verified in primary mouse cortical neurons. The possible contribution of macroautophagy to rotenone-induced hsc70 modulation was explored and the influence of hsc70 gene silencing on neurotoxicity was assessed. We demonstrated that rotenone, but not hydrogen peroxide, induced a significant reduction of hsc70 mRNA and protein expression. We also observed that the toxic effect of rotenone on alpha-synuclein levels was amplified when macroautophagy was inhibited, although rotenone-induced hsc70 reduction was independent from macroautophagy. Finally, we demonstrated that hsc70 gene silencing up-regulated alpha-synuclein mRNA and protein levels without affecting cell viability and without altering rotenone- and hydrogen peroxide-induced cytotoxicity. These findings demonstrate the existence of a novel mechanism of rotenone toxicity mediated by hsc70 and indicate that dysfunction of both CMA and macroautophagy can synergistically exacerbate alpha-synuclein toxicity, suggesting that hsc70 up-regulation may represent a valuable therapeutic strategy for PD.

Genome-wide gene-environment interaction analysis of pesticide exposure and risk of Parkinson's disease.

INTRODUCTION: Genetic factors and environmental exposures, including pesticides, contribute to the risk of Parkinson's disease (PD). There have been few studies of gene and pesticide exposure interactions in PD, and all of the prior studies used a candidate gene approach. METHODS: We performed the first genome-wide gene-environment interaction analysis of pesticide exposure and risk of Parkinson's disease. Analyses were performed using data on >700,000 single nucleotide polymorphisms (SNPs) in 364 discordant sibling pairs. In addition to testing for SNP-pesticide interaction effects, we also performed exploratory analyses of gene-pesticide interactions at the gene level. RESULTS: None of the gene-environment interaction results were significant after genome-wide correction for multiple testing (α = 1.5E-07 for SNP-level tests; α = 2.1E-06 for gene-level tests). Top results in the SNP-level tests provided suggestive evidence (P < 5.0E-06) that the effect of pesticide exposure on PD risk may be modified by SNPs in the ERCC6L2 gene (P = 2.4E-06), which was also supported by suggestive evidence in the gene-level analysis (P = 4.7E-05). None of the candidate genes assessed in prior studies of gene-pesticide interactions reached statistical support in this genome-wide screen. CONCLUSION: Although no significant interactions were identified, several of the genes with suggestive evidence of gene-environment interaction effects have biological plausibility for PD risk. Further investigation of the role of those genes in PD risk, particularly in the context of pesticide exposure, in large and carefully recruited samples is warranted.