Background Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. Objectives To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. Methods We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross‐sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease‐risk variants, were also investigated post hoc for candidate associations with these phenotypes. Results Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58–2.62]; P value = 3.46E‐8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α‐2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52–0.75]; P value = 4.74E‐8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. Conclusions We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society

Background Parkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome‐wide association studies. The most recent large‐scale PD genome‐wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome‐wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus. Methods We included all significant genome‐wide signals from multiple recent PD genome‐wide association studies including themost recent PD risk genome‐wide association study, age‐at‐onset genome‐wide association study, progression genome‐wide association study, and Asian population PD risk genome‐wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self‐ranked criteria. Multiple databases were queried for each gene to collect additional causal data. Results We created a PD genome‐wide association study browser tool ( https://pdgenetics.shinyapps.io/GWASBrowser/ ) to assist the PD research community with the prioritization of genes for follow‐up functional studies to identify potential therapeutic targets. Conclusions Our PD genome‐wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large‐scale PD genome‐wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

Background Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. Objectives We examined sex associations to PD phenotypes cross‐sectionally and longitudinally in large‐scale data. Methods We tested 40 clinical phenotypes, using longitudinal, clinic‐based patient cohorts, consisting of 5946 patients, with a median follow‐up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex‐associated differences in presentation, and linear mixed‐effects models to test sex‐associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non‐PD participants from an online‐only, self‐assessment PD cohort were cross‐sectionally evaluated to determine whether the sex‐associated differences identified in the primary analyses were consistent and unique to PD. Results Female PD patients had a higher risk of developing dyskinesia early during the follow‐up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic‐based cohorts were mostly consistent with the results of the online‐only cohort. Conclusions We observed sex‐associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society

Objective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average $ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner.

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic cortical interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated five differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

Objectives: Identifying the contribution of biological sex to the heterogeneity in presentation and progression of Parkinson's disease (PD).Background: The different prevalence of Parkinson's disease (PD) in men and women suggests that sex-associated

Background Parkinson's disease (PD) is a genetically complex neurodegenerative disease with ~20 genes known to contain mutations that cause PD or atypical parkinsonism. Large‐scale next‐generation sequencing projects have revolutionized genomics research. Applying these data to PD, many genes have been reported to contain putative disease‐causing mutations. In most instances, however, the results remain quite limited and rather preliminary. Our aim was to assist researchers on their search for PD‐risk genes and variant candidates with an easily accessible and open summary‐level genomic data browser for the PD research community. Methods Sequencing and imputed genotype data were obtained from multiple sources and harmonized and aggregated. Results In total we included a total of 102,127 participants, including 28,453 PD cases, 1650 proxy cases, and 72,024 controls. Conclusions We present here the Parkinson's Disease Sequencing Browser: a Shiny‐based web application that presents comprehensive summary‐level frequency data from multiple large‐scale genotyping and sequencing projects https://pdgenetics.shinyapps.io/VariantBrowser/. Published © 2021 This article is a U.S. Government work and is in the public domain in the USA. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.