Background Genome-wide association studies (GWASs) in Parkinson's disease (PD) have increased the scope of biological knowledge about the disease over the past decade. We sought to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into disease etiology. Methods We performed the largest meta-GWAS of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases (having a first degree relative with PD), and 1.4M controls. We carried out a meta-analysis of this GWAS data to nominate novel loci. We then evaluated heritable risk estimates and predictive models using this data. We also utilized large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type and biological pathway enrichments for the identified risk factors. Additionally we examined shared genetic risk between PD and other phenotypes of interest via genetic correlations followed by Mendelian randomization. Findings We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of PD depending on prevalence. Integrating methylation and expression data within a Mendelian randomization framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested PD loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. Mendelian randomization between cognitive performance and PD risk showed a robust association. Interpretation These data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified. Funding See supplemental materials (Text S2). lead to earlier detection and refined diagnostics, which may help improve clinical trials (4). The generation of copious amounts of public summary statistics created by this effort relating to both the GWAS and subsequent analyses of gene expression and methylation patterns may be of use to investigators planning follow-up functional studies in stem cells or other cellular screens, allowing them to prioritize targets more efficiently using our data as additional evidence. We hope our findings may have some downstream clinical impact in the future such as improved patient stratification for clinical trials and genetically informed drug targets.

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Background Penetrance estimates of the LRRK2 p.G2019S mutation for Parkinson’s disease (PD) vary widely (24%–100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80. Methods The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non-Ashkenazi Jewish LRRK2 p.G2019S carrier probands at eight sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included, when available. Results Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% CI: 26.3 – 65.8%) to age 80 which is not significantly higher than the previously estimated 25% (95% CI: 16.7 – 34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the non-carrier relatives, as seen in Ashkenazi Jewish relatives. Conclusions The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non-Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25–42.5% at age 80 in all populations analyzed.

BackgroundMutations in LRRK2 are a common genetic cause of Parkinson’s disease (PD). LRRK2 interacts with and phosphorylates a subset of Rab proteins including Rab8a, a protein which has been implicated in various centrosome-related events. However, the cellular consequences of such phosphorylation remain elusive.MethodsHuman neuroblastoma SH-SY5Y cells stably expressing wildtype or pathogenic LRRK2 were used to test for polarity defects in the context of centrosomal positioning. Centrosomal cohesion deficits were analyzed from transiently transfected HEK293T cells, as well as from two distinct peripheral cell types derived from LRRK2-PD patients. Kinase assays, coimmunoprecipitation and GTP binding/retention assays were used to address Rab8a phosphorylation by LRRK2 and its effects in vitro. Transient transfections and siRNA experiments were performed to probe for the implication of Rab8a and its phosphorylated form in the centrosomal deficits caused by pathogenic LRRK2.ResultsHere, we show that pathogenic LRRK2 causes deficits in centrosomal positioning with effects on neurite outgrowth, cell polarization and directed migration. Pathogenic LRRK2 also causes deficits in centrosome cohesion which can be detected in peripheral cells derived from LRRK2-PD patients as compared to healthy controls, and which are reversed upon LRRK2 kinase inhibition. The centrosomal cohesion and polarity deficits can be mimicked when co-expressing wildtype LRRK2 with wildtype but not phospho-deficient Rab8a. The centrosomal defects induced by pathogenic LRRK2 are associated with a kinase activity-dependent increase in the centrosomal localization of phosphorylated Rab8a, and are prominently reduced upon RNAi of Rab8a.ConclusionsOur findings reveal a new function of LRRK2 mediated by Rab8a phosphorylation and related to various centrosomal defects.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0235-y) contains supplementary material, which is available to authorized users.

G2385R and G2019S PD appear to have motor differences that may be explained by contrasting local treatment or measurement practices or differences in the biology of the disease. Longitudinal studies should evaluate whether progression is faster in G2385R mutation carriers compared with G2019S PD or idiopathic PD. © 2016 International Parkinson and Movement Disorder Society.