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The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity. The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 × 10-95). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase affecting its activity. Our results nominate GALC as the gene associated with PD in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. Whether altering galactosylceramidase activity could be considered as a therapeutic target should be further studied., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Biallelic pathogenic variants in GBA1 are the cause of Gaucher disease (GD) type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. Heterozygous GBA1 variants are also a common genetic risk factor for Parkinson's disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk for PD., Objective: The objective of this study was to investigate the contribution of PD risk variants to risk for PD in patients with GD1., Methods: We studied 225 patients with GD1, including 199 without PD and 26 with PD. All cases were genotyped, and the genetic data were imputed using common pipelines., Results: On average, patients with GD1 with PD have a significantly higher PD genetic risk score than those without PD (P = 0.021)., Conclusions: Our results indicate that variants included in the PD genetic risk score were more frequent in patients with GD1 who developed PD, suggesting that common risk variants may affect underlying biological pathways. © 2023 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 U.S. Government employees and their work is in the public domain in the USA., (© 2023 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 U.S. Government employees and their work is in the public domain in the USA.)

Objective: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD., Methods: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data., Results: We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4., Interpretation: We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023;93:1012-1022., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD)., Objectives: We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD., Methods: PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment., Results: Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values ( P range 0.003-0.005) and higher LEDD over time ( P range <0.001-0.01) were significantly associated with increased risk for CI., Conclusions: Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course., Trial Registration: Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023)., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Neurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation in the brain. In Parkinson's Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death. The aim of this study was to explore the genetic and genomic connection between NBIA and PD. We screened for known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons' Disease Program and the UKBiobank. We examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. In addition, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1886 PD cases and 1285 controls. Out of 29 previously reported NBIA screened coding variants, four were associated with PD risk at a nominal p value < 0.05. No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested that DCAF17 is differentially expressed in blood from PD cases and controls. Due to low mutation occurrence in the datasets and lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis and growing concerns regarding the neurological impact of the coronavirus pandemic, we examined potential links between viral exposures and neurodegenerative disease risk. Using time series data from FinnGen for discovery and cross-sectional data from the UK Biobank for replication, we identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease and replicated 22 of these associations. The largest effect association was between viral encephalitis exposure and Alzheimer's disease. Influenza with pneumonia was significantly associated with five of the six neurodegenerative diseases studied. We also replicated the Epstein-Barr/multiple sclerosis association. Some of these exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. As vaccines are currently available for some of the associated viruses, vaccination may be a way to reduce some risk of neurodegenerative disease., Competing Interests: Declaration of interests K.S.L., H.L.L., H.I., N.J., F.F., and M.A.N.’s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc., (Published by Elsevier Inc.)

Background: Deep brain stimulation (DBS) is a well-established treatment option for select patients with Parkinson's Disease (PD). However, response to DBS varies, therefore, the ability to predict who will have better outcomes can aid patient selection. Some PD-related monogenic mutations have been reported among factors that influence response to DBS. However, monogenic disease accounts for only a minority of patients with PD. The polygenic risk score (PRS) is an indication of cumulative genetic risk for disease. The PRS in PD has also been correlated with age of onset and symptom progression, but it is unknown whether correlations exist between PRS and DBS response. Here, we performed a pilot study to look for any such correlation., Methods: We performed a retrospective analysis of 33 PD patients from the NIH PD Clinic and 13 patients from the Parkinson's Progression Markers Initiative database who had genetic testing and underwent bilateral subthalamic nucleus DBS surgery and clinical follow-up. A PD-specific PRS was calculated for all 46 patients based on the 90 susceptibility variants identified in the latest PD genome-wide association study. We tested associations between PRS and pre- and post-surgery motor and cognitive measures using multiple regression analysis for up to two years after surgery., Results: Changes in scores on the Beck Depression Inventory (BDI) were not correlated with PRS when derived from all susceptibility variants, however, when removing pathogenic and high-risk carriers from the calculation, higher PRS was significantly associated with greater reduction in BDI score at 3 months and with similar trend 24 months after DBS. PRS was not a significant predictor of Unified Parkinson's Disease Rating Scale, Dementia Rating Scale, or phenomic and semantic fluency outcomes at 3- and 24-months after DBS surgery., Conclusions: This exploratory study suggests that PRS may predict degree of improvement in depressive symptoms after DBS, though was not predictive of motor and other cognitive outcomes after DBS. Additionally, PRS may be most relevant in predicting DBS outcomes in patients lacking pathogenic or high-risk PD variants. However, this was a small preliminary study and response to DBS treatment is multifactorial, therefore, more standardized high-powered studies are needed., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Open science and collaboration are necessary to facilitate the advancement of Parkinson's disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD., (© 2023. The Author(s).)

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P combined  = 1.47 × 10 -9 ) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P < 5 × 10 -8 ) for PD in Chinese population. Moreover, of the reported genome-wide significant risk variants found mostly in European ancestry populations, the correlation coefficient (r b ) of effect size accounting for sampling errors was 0.91 between datasets and 63.6% attained P < 0.05 in Chinese population. Accordingly, we estimated a heritability of 0.14-0.18 for PD, and a moderate genetic correlation between European ancestry and Chinese populations (r g  = 0.47, se = 0.21). Polygenic risk score (PRS) analysis revealed that individuals with PRS values in the highest quartile had a 3.9-fold higher risk of developing PD than the lowest quartile. In conclusion, the present GWAS identified PD-associated variants in Chinese population, as well as genetic factors shared among distant populations. Our findings shed light on the genetic homogeneity and heterogeneity of PD in different ethnic groups and suggested WGS might continue to improve our understanding of the genetic architecture of PD., (© 2023. The Author(s).)

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.

Parkinson's disease is a complex neurodegenerative disorder with a strong genetic component, for which most known disease-associated variants are single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels). DNA repetitive elements account for >50% of the human genome; however, little is known of their contribution to Parkinson's disease aetiology. While select short tandem repeats (STRs) within candidate genes have been studied in Parkinson's disease, their genome-wide contribution remains unknown. Here we present the first genome-wide association study of STRs in Parkinson's disease. Through a meta-analysis of 16 imputed genome-wide association study cohorts from the International Parkinson's Disease Genomic Consortium (IPDGC), totalling 39 087 individuals (16 642 cases and 22 445 controls of European ancestry), we identified 34 genome-wide significant STR loci (P < 5.34 × 10-6), with the strongest signal located in KANSL1 [chr17:44 205 351:[T]11, P = 3 × 10-39, odds ratio = 1.31 (95% confidence interval = 1.26-1.36)]. Conditional-joint analyses suggested that four significant STRs mapping nearby NDUFAF2, TRIML2, MIRNA-129-1 and NCOR1 were independent from known risk SNPs. Including STRs in heritability estimates increased the variance explained by SNPs alone. Gene expression analysis of STRs (eSTRs) in RNA sequencing data from 13 brain regions identified significant associations of STRs influencing the expression of multiple genes, including known Parkinson's disease genes. Further functional annotation of candidate STRs revealed that significant eSTRs within NUDFAF2 and ZSWIM7 overlap with regulatory features and are associated with change in the expression levels of nearby genes. Here, we show that STRs at known and novel candidate loci contribute to Parkinson's disease risk and have functional effects in disease-relevant tissues and pathways, supporting previously reported disease-associated genes and giving further evidence for their functional prioritization. These data represent a valuable resource for researchers currently dissecting Parkinson's disease risk loci., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Parkinson's disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding of the Parkinson's disease genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial Parkinson's disease, but its relevance to idiopathic Parkinson's disease is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through genome-wide association studies. We identified two new regulators of PINK1-dependent mitophagy initiation, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic Parkinson's disease. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data do not exclude a possible association between the MAPT gene and Parkinson's disease, they provide strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The clinical manifestations of Parkinson's disease (PD) are characterized by heterogeneity in age at onset, disease duration, rate of progression, and the constellation of motor versus non-motor features. There is an unmet need for the characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. We used unsupervised and supervised machine learning methods on comprehensive, longitudinal clinical data from the Parkinson's Disease Progression Marker Initiative (n = 294 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson's Disease Biomarker Program (n = 263 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate, and fast disease progression. We achieved highly accurate projections of disease progression 5 years after initial diagnosis with an average area under the curve (AUC) of 0.92 (95% CI: 0.95 ± 0.01) for the slower progressing group (PDvec1), 0.87 ± 0.03 for moderate progressors, and 0.95 ± 0.02 for the fast-progressing group (PDvec3). We identified serum neurofilament light as a significant indicator of fast disease progression among other key biomarkers of interest. We replicated these findings in an independent cohort, released the analytical code, and developed models in an open science manner. Our data-driven study provides insights to deconstruct PD heterogeneity. This approach could have immediate implications for clinical trials by improving the detection of significant clinical outcomes. We anticipate that machine learning models will improve patient counseling, clinical trial design, and ultimately individualized patient care., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field., Competing Interests: Declaration of interests S.W.S. is on the scientific advisory council of the Lewy Body Dementia Association and the MSA Coalition. S.W.S. is an editorial board member for the Journal of Parkinson Disease and JAMA Neurology. S.W.S. received research support from Cerevel Therapeutics. M.K. serves on the scientific advisory boards of Engine Biosciences, Casma Therapeutics, Cajal Neuroscience, and Alector and is a consultant to Modulo Bio and Recursion Therapeutics. Participation by researchers from Data Tecnica International, LLC in this project was part of a competitive contract awarded to Data Tecnica International, LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc. E.A. is founder, shareholder, and scientific advisor of Cholestenix, Ltd., (Published by Elsevier Inc.)

Background: Parkinson's disease (PD) affects males more than females. The reasons for the gender differences in PD prevalence remain unclear., Objective: The objective of this systematic review and meta-analysis was to update the overall male/female prevalence ratios (OPR)., Methods: We updated previous work by searching MEDLINE, SCOPUS, and OVID for articles reporting PD prevalence for both genders between 2011 and 2021. We calculated OPRs and investigated heterogeneity in effect estimates., Results: We included 19 new articles and 13 articles from a previously published meta-analysis. The OPR was 1.18, 95% CI, [1.03, 1.36]. The OPR was lowest in Asia and appeared to be decreasing over time. Study design, national wealth, and participant age did not explain OPR heterogeneity., Conclusion: Gender differences in PD prevalence may not be as stark as previously thought. Studies are needed to understand the role of other determinants of gender differences in PD prevalence., (© 2022 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The relationship between APOE polymorphisms and Parkinson's disease (PD) in black Africans has not been previously investigated. We evaluated the association between APOE polymorphic variability and self-declared cognition in 1100 Nigerians with PD and 1097 age-matched healthy controls. Cognition in PD was assessed using the single item cognition question (item 1.1) of the MDS-UPDRS. APOE genotype and allele frequencies did not differ between PD and controls (p > 0.05). No allelic or genotypic association was observed between APOE and age at onset of PD. In PD, APOE ε4/ε4 conferred a two-fold risk of cognitive impairment compared to one or no ε4 (HR: 2.09 (95% CI: 1.13-3.89; p = 0.02)), while APOE ε2 was associated with modest protection against cognitive impairment (HR: 0.41 (95% CI 0.19-0.99, p = 0.02)). Of 773 PD with motor phenotype and APOE characterized, tremor-dominant (TD) phenotype predominated significantly in ε2 carriers (87/135, 64.4%) compared to 22.2% in persons with postural instability/gait difficulty (PIGD) (30/135) and 13.3% in indeterminate (ID) (18/135, 13.3%) (p = 0.037). Although the frequency of the TD phenotype was highest in homozygous ε2 carriers (85.7%), the distribution of motor phenotypes across the six genotypes did not differ significantly (p = 0.18). Altogether, our findings support previous studies in other ethnicities, implying a role for APOE ε4 and ε2 as risk and protective factors, respectively, for cognitive impairment in PD., (© 2022. The Author(s).)

Parkinson's disease (PD) is a complex neurodegenerative condition in which genetic and environmental factors interact to contribute to its etiology. Remarkable progress has been made in deciphering disease etiology through genetic approaches, but there is limited data about how environmental and genetic factors interact to modify penetrance, risk, and disease severity. Here, we provide insights into environmental modifiers of PD, discussing precedents from other neurological and non-neurological conditions. Based on these examples, we outline genetic and environmental factors contributing to PD and review potential environmental modifiers of penetrance and clinical variability in monogenic and idiopathic PD. We also highlight the potential challenges and propose how future studies might tackle these important questions. ANN NEUROL 2022;92:715-724., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Parkinson's disease is a complex neurodegenerative disorder that is about 1.5 times more prevalent in males than females. Extensive work has been done to identify the genetic risk factors behind Parkinson's disease on autosomes and more recently on Chromosome X, but work remains to be done on the male-specific Y chromosome. In an effort to explore the role of the Y chromosome in Parkinson's disease, we analysed whole-genome sequencing data from the Accelerating Medicines Partnership-Parkinson's disease initiative (1466 cases and 1664 controls), genotype data from NeuroX (3491 cases and 3232 controls) and genotype data from UKBiobank (182 517 controls, 1892 cases and 3783 proxy cases), all consisting of male European ancestry samples. We classified sample Y chromosomes by haplogroup using three different tools for comparison (Snappy, Yhaplo and Y-LineageTracker) and meta-analysed this data to identify haplogroups associated with Parkinson's disease. This was followed up with a Y-chromosome association study to identify specific variants associated with disease. We also analysed blood-based RNASeq data obtained from the Accelerating Medicines Partnership-Parkinson's disease initiative (1020 samples) and RNASeq data obtained from the North American Brain Expression Consortium (171 samples) to identify Y-chromosome genes differentially expressed in cases, controls, specific haplogroups and specific tissues. RNASeq analyses suggest Y-chromosome gene expression differs between brain and blood tissues but does not differ significantly in cases, controls or specific haplogroups. Overall, we did not find any strong associations between Y-chromosome genetics and Parkinson's disease, suggesting the explanation for the increased prevalence in males may lie elsewhere., (Published by Oxford University Press on behalf of the Guarantors of Brain 2022.)

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: β(SE) COURAGE = 0.477(0.203), p COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N total = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE) COURAGE+IPDGC = 0.720(0.122), p COURAGE+IPDGC = 3.13 × 10 -9 ) and a novel BST1 locus (rs4698412: β(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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available., Methods: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses., Results: A higher polygenic resilience score was associated with a lower risk for PD (β = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h 2  = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci., Interpretation: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Studies of multiple neurodegenerative disorders have identified many genetic variants that are associated with risk of disease throughout a lifetime. For example, Parkinson's disease (PD) risk is attributed in part to both coding mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene and to a common noncoding variation in the 5' region of the LRRK2 locus, as identified by genome-wide association studies (GWAS). However, the mechanisms linking GWAS variants to pathogenicity are largely unknown. Here, we found that the influence of PD-associated noncoding variation on LRRK2 expression is specifically propagated through microglia and not by other cell types that express LRRK2 in the human brain. We find microglia-specific regulatory chromatin regions that modulate the LRRK2 expression in human frontal cortex and substantia nigra and confirm these results in a human-induced pluripotent stem cell-derived microglia model. We showed, using a large-scale clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen, that a regulatory DNA element containing the single-nucleotide variant rs6581593 influences the LRRK2 expression in microglia. Our study demonstrates that cell type should be considered when evaluating the role of noncoding variation in disease pathogenesis and sheds light on the mechanism underlying the association of the 5' region of LRRK2 with PD risk.

PRKN mutations are the most common recessive cause of Parkinson's disease and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients at the population scale, however, remains a challenge, as roughly half are copy number variants and many single nucleotide polymorphisms are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN mutations has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in two cohorts with near complete genotyping of both single nucleotide polymorphisms and copy number variants: the NIH-PD + AMP-PD cohort, the largest Parkinson's disease case-control cohort with whole genome sequencing data from 4094 participants, and the UK Biobank, the largest cohort study with whole exome sequencing and genotyping array data from 200 606 participants. Using the NIH-PD participants, who were genotyped using whole genome sequencing, genotyping array, and multi-plex ligation-dependent probe amplification, we validated genotyping array for the detection of copy number variants. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and suggested that cryptic loss of function variants in monoallelic carriers are not a substantial confounder for association studies. In the UK Biobank, we identified 2692 PRKN copy number variants from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exon 2 accounted for roughly half of all copy number variants and the vast majority (88%) involved exons 2, 3, or 4. In the UK Biobank, we found a pathogenic PRKN mutation in 1.8% of participants and two mutations in ∼1/7800 participants. Those with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 0.91 (0.58-1.38), P-value 0.76] or a parent with Parkinson's disease [odds ratio = 1.12 (0.94-1.31), P-value = 0.19]. Similarly, those in the NIH-PD + AMP + PD cohort with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 1.29 (0.74-2.38), P-value = 0.43]. Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of Parkinson's disease., (Published by Oxford University Press on behalf of the Guarantors of Brain 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Endocannabinoid (eCB), 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase β (DAGLB) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, the SN 2-AG levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb in nigral DANs substantially reduced SN 2-AG levels and impaired locomotor skill learning, particularly the across-session learning. Conversely, pharmacological inhibition of 2-AG degradation increased nigral 2-AG levels, DAN activity and dopamine release and rescued the locomotor skill learning deficits. Together, we demonstrate that DAGLB-deficiency contributes to the pathogenesis of Parkinsonism, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neuronal activity and dopamine release, and suggest potential benefits of 2-AG augmentation in alleviating Parkinsonism., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: To date, variants in the GBA gene represent the most frequent large-effect genetic factor associated with Parkinson's disease (PD). However, the reason why individuals with the same GBA variant may or may not develop neurodegeneration and PD is still unclear., Objectives: Therefore, we evaluated the contribution of rare variants in genes responsible for lysosomal storage disorders (LSDs) to GBA-PD risk, comparing the burden of deleterious variants in LSD genes in PD patients versus asymptomatic subjects, all carriers of deleterious variants in GBA., Methods: We used a custom next-generation sequencing panel, including 50 LSD genes, to screen 305 patients and 207 controls (discovery cohort). Replication and meta-analysis were performed in two replication cohorts of GBA-variant carriers, of 250 patients and 287 controls, for whom exome or genome data were available., Results: Statistical analysis in the discovery cohort revealed a significantly increased burden of deleterious variants in LSD genes in patients (P = 0.0029). Moreover, our analyses evidenced that the two strongest modifiers of GBA penetrance are a second variation in GBA (5.6% vs. 1.4%, P = 0.023) and variants in genes causing mucopolysaccharidoses (6.9% vs. 1%, P = 0.0020). These results were confirmed in the meta-analysis, where we observed pooled odds ratios of 1.42 (95% confidence interval [CI] = 1.10-1.83, P = 0.0063), 4.36 (95% CI = 2.02-9.45, P = 0.00019), and 1.83 (95% CI = 1.04-3.22, P = 0.038) for variants in LSD genes, GBA, and mucopolysaccharidosis genes, respectively., Conclusion: The identification of genetic lesions in lysosomal genes increasing PD risk may have important implications in terms of patient stratification for future therapeutic trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.)

Personalized medicine promises individualized disease prediction and treatment. The convergence of machine learning (ML) and available multimodal data is key moving forward. We build upon previous work to deliver multimodal predictions of Parkinson's disease (PD) risk and systematically develop a model using GenoML, an automated ML package, to make improved multi-omic predictions of PD, validated in an external cohort. We investigated top features, constructed hypothesis-free disease-relevant networks, and investigated drug-gene interactions. We performed automated ML on multimodal data from the Parkinson's progression marker initiative (PPMI). After selecting the best performing algorithm, all PPMI data was used to tune the selected model. The model was validated in the Parkinson's Disease Biomarker Program (PDBP) dataset. Our initial model showed an area under the curve (AUC) of 89.72% for the diagnosis of PD. The tuned model was then tested for validation on external data (PDBP, AUC 85.03%). Optimizing thresholds for classification increased the diagnosis prediction accuracy and other metrics. Finally, networks were built to identify gene communities specific to PD. Combining data modalities outperforms the single biomarker paradigm. UPSIT and PRS contributed most to the predictive power of the model, but the accuracy of these are supplemented by many smaller effect transcripts and risk SNPs. Our model is best suited to identifying large groups of individuals to monitor within a health registry or biobank to prioritize for further testing. This approach allows complex predictive models to be reproducible and accessible to the community, with the package, code, and results publicly available., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit ( CHRNA1 ) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit ( CHRNB1 ) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22 , HLA-DQA1/HLA-B , and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis., Competing Interests: Competing interest statement: R.J.B. served as a consultant for NuFactor and Momenta Pharmaceutical and receives research support from PTC Therapeutics, Ra Pharma, Orphazyme, Sanofi Genzyme, FDA OOPD, NIH, and Patient-Centered Outcomes Research Institute (PCORI). M.B. reports grant support from Muscular Dystrophy Association, ALS Association, ALS Recovery Fund, Kimmelman Estate, Target ALS, Eli Lilly and Company, and NIH during the conduct of the study. He also reports grant support from FDA, Centers for Disease Control and Prevention (CDC), and DOD; research support from Alexion Pharmaceuticals, UCB, Cytokinetics, Neuraltus, Biogen, and Orphazyme A/S; and personal fees from NMD Pharma, Ra Pharmaceuticals, Mitsubishi Tanabe, Avexis, UCB, and Denali outside the submitted work. V.C. served as a consultant for review and expert testimony for the Department of Health and Human Services and the Department of Justice under the Vaccine Injury and Compensation Program. Dr. Chaudhry has received a royalty for total neuropathy score (TNS) patented (through Johns Hopkins University) for the license of TNS use from AstraZeneca, Genentech, Seattle Genetics, Calithera Biosciences, Merrimack Pharmaceuticals, Levicept, and Acetylon Pharmaceuticals. M.M.D. serves or recently served as a consultant for Argenx Pharmaceuticals, Catalyst, CSL Behring, Kezar, Momenta, NuFactor, RMS Medical, Sanofi Genzyme, Shire Takeda, and Spark Therapeutics. Dr. Dimachkie received grants from Alexion Pharmaceuticals, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, CSL Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Mitsubishi Tanabe Pharma, Muscular Dystrophy Association (MDA), NIH, Novartis, Sanofi Genzyme, Octapharma, Orphazyme, Sarepta Therapeutics, Shire Takeda, Spark, UCB Biopharma, Viromed, and TMA. A.E. was a member of the advisory board for Alexion Pharmaceuticals, a scientific award jury member for Grifols, and safety data monitor for UCB. M.F. has received honoraria for serving on advisory boards for Argenx Pharmaceuticals and Alexion Pharmaceuticals. M.F. also has research support from Catalyst, Ra pharma, Amicus, Orphazyme, Alexion Pharmaceuticals, Momenta, and Alnylam. J.F.H. reports research support and grants from Alexion Pharmaceuticals and Argenx Pharmaceuticals, Centers for Disease Control and Prevention, MDA, NIH (including the National Institute of Neurologic Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Disease), PCORI, and Ra Pharmaceuticals (now UCB Biosciences); honoraria from Alexion Pharmaceuticals, Argenx Pharmaceuticals, Immunovant, Ra Pharmaceuticals (now UCB Biosciences), Regeneron Pharmaceuticals, and Viela Bio; and nonfinancial support from Alexion Pharmaceuticals, Argenx Pharmaceuticals, Ra Pharmaceuticals (now UCB Biosciences), and Toleranzia. P.J.T. holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72 and has received grant funding from the Helsinki University Hospital, Finnish Academy, Sigrid Juselius Foundation, EU Marie Curie action, Biogen Finland, Roche Finland, Merck Finland, Sanofi Genzyme Finland, and Novartis Finland and has made consultations to Alexion Pharmaceuticals, Biogen, Novartis, Orion, Roche, Sanofi Genzyme, Santen, and Teva. H.J.K. is funded by the MDA (508240) and NIH grant U54NS115054; is a consultant for Alnylam Pharmaceuticals, Ra Pharmaceuticals, and UCB Pharmaceuticals; and is CEO of ARC Biotechnology, LLC, which receives support from the NIH (R41NS110331). He serves on the Editorial Board of Experimental Neurology. M.M.M. has received honoraria as a speaker and/or moderator from Alnylam, Akcea, Pfizer, and CSL Behring. She has served on Advisory Boards for Pfizer, Alnylam, and Akcea. She serves as an investigator for clinical trials with Alnylam and Biogen. S.M. has served on advisory board meetings for Alexion Pharmaceuticals and Argenx Pharmaceuticals. M.P. served on the advisory boards for CSL Behring, Alexion Pharmaceuticals, and Argenx Pharmaceuticals and has been a consultant for Momenta Pharmaceuticals. D.P.R. receives research funding from a Sponsored Research Agreement from Cabaletta Bioscience. B.J.T. holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72 and has received research grants from the Myasthenia Gravis Foundation, the Robert Packard Center for ALS Research, the ALS Association, the Italian Football Federation, the CDC, the MDA, Merck, and Microsoft Research. B.J.T. receives funding through the Intramural Research Program at NIH., (Copyright © 2022 the Author(s). Published by PNAS.)

Background: The leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (eg, p.G2019S) and common noncoding variants (eg, rs76904798) with lower effect sizes that are associated with Parkinson's disease (PD) risk., Objectives: This study aimed to investigate in a large meta-analysis whether the LRRK2 Genome-Wide Association Study (GWAS) signal represented by rs76904798 is independently associated with PD risk from LRRK2 coding variation and whether complex linkage disequilibrium structures with p.G2019S and the 5' noncoding haplotype account for the association of LRRK2 coding variants., Methods: We performed a meta-analysis using imputed genotypes from 17,838 patients, 13,404 proxy patients, and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798, and p.N2081D., Results: LRRK2 rs76904798 remained significantly associated with PD after excluding the carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798, and the allele distribution of p.S1647T significantly changed among patients after removing rs76904798 carriers., Conclusions: These data suggest that the LRRK2 coding variants previously related to PD (p.N551K, p.R1398H, p.M1646T, and p.N2081D) do not drive the 5' noncoding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background: Parkinson's disease (PD) is a highly age-related disorder, where common genetic risk variants affect both disease risk and age at onset. A statistical approach that integrates these effects across all common variants may be clinically useful for individual risk stratification. A polygenic hazard score methodology, leveraging a time-to-event framework, has recently been successfully applied in other age-related disorders., Objectives: We aimed to develop and validate a polygenic hazard score model in sporadic PD., Methods: Using a Cox regression framework, we modeled the polygenic hazard score in a training data set of 11,693 PD patients and 9841 controls. The score was then validated in an independent test data set of 5112 PD patients and 5372 controls and a small single-study sample of 360 patients and 160 controls., Results: A polygenic hazard score predicts the onset of PD with a hazard ratio of 3.78 (95% confidence interval 3.49-4.10) when comparing the highest to the lowest risk decile. Combined with epidemiological data on incidence rate, we apply the score to estimate genetically stratified instantaneous PD risk across age groups., Conclusions: We demonstrate the feasibility of a polygenic hazard approach in PD, integrating the genetic effects on disease risk and age at onset in a single model. In combination with other predictive biomarkers, the approach may hold promise for risk stratification in future clinical trials of disease-modifying therapies, which aim at postponing the onset of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Risk factors for Parkinson's disease (PD) can be more or less relevant to a population due to population-specific genetic architecture, local lifestyle habits, and environmental exposures. Therefore, it is essential to study PD at a local, regional, and continental scale in order to increase the knowledge on disease etiology., Objective: We aimed to investigate the contribution of genetic and environmental factors to PD in a new Swedish case-control cohort., Methods: PD patients (n = 929) and matched population-based controls (n = 935) from the southernmost county in Sweden were included in the cohort. Information on environmental exposures was obtained using questionnaires at inclusion. Genetic analyses included a genome-wide association study (GWAS), haplotype assessment, and a risk profile analysis using cumulative genetic risk scores., Results: The cohort is a representative PD case-control cohort (64% men, mean age at diagnosis = 67 years, median Hoehn and Yahr score 2.0), in which previously reported associations between PD and environmental factors, such as tobacco, could be confirmed. We describe the first GWAS of PD solely composed of PD patients from Sweden, and confirm associations to well-established risk alleles in SNCA. In addition, we nominate an unconfirmed and potentially population-specific genome-wide significant association in the PLPP4 locus (rs12771445)., Conclusion: This work provides an in-depth description of a new PD case-control cohort from southern Sweden, giving insights into environmental and genetic risk factors for PD in the Swedish population.

Parkinson's disease (PD) is a complex neurodegenerative disorder in which both rare and common genetic variants contribute to disease risk. Multiple genes have been reported to be linked to monogenic PD but these only explain a fraction of the observed familial aggregation. Rare variants in RIC3 have been suggested to be associated with PD in the Indian population. However, replication studies yielded inconsistent results. We further investigate the role of RIC3 variants in PD in European cohorts using individual-level genotyping data from 14,671 PD patients and 17,667 controls, as well as whole-genome sequencing data from 1,615 patients and 961 controls. We also investigated RIC3 using summary statistics from a Latin American cohort of 1,481 individuals, and from a cohort of 31,575 individuals of East Asian ancestry. We did not identify any association between RIC3 and PD in any of the cohorts. However, more studies of rare variants in non-European ancestry populations, in particular South Asian populations, are necessary to further evaluate the world-wide role of RIC3 in PD etiology., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cytoplasmic inclusions of α-synuclein (α-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α-syn have not been reported., Objective: This cross-sectional observational study compared magnitudes of intraneuronal deposition of α-syn in common and rare genetic forms of PD., Methods: α-Syn deposition was quantified by the α-syn-tyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (n = 3), PRKN [biallelic (n = 7) and monoallelic (n = 3)], LRRK2 (n = 7), GBA (n = 7), or PARK7/DJ1 [biallelic (n = 1) and monoallelic (n = 2)]. Twenty-five of the mutation carriers had PD and five did not. Data were also analyzed from 19 patients with idiopathic PD and 16 control participants., Results: α-Syn deposition varied as a function of genotype (F = 16.7, P < 0.0001). It was above the control range in 100% of subjects with SNCA mutations, 100% with LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. α-Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher α-syn deposition than their unaffected siblings., Conclusions: Individuals with SNCA, DJ-1, LRRK2, or GBA mutations have substantial intraneuronal α-syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased α-syn deposition compared with control subjects. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson's disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes-11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83-0.90, p < 8.23 × 10 -9 for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development., (© 2021. The Author(s).)

Background: Whole-genome sequencing data are available from several large studies across a variety of diseases and traits. However, massive storage and computation resources are required to use these data, and to achieve sufficient power for discoveries, harmonization of multiple cohorts is critical., Objectives: The Accelerating Medicines Partnership Parkinson's Disease program has developed a research platform for Parkinson's disease (PD) that integrates the storage and analysis of whole-genome sequencing data, RNA expression data, and clinical data, harmonized across multiple cohort studies., Methods: The version 1 release contains whole-genome sequencing data derived from 3941 participants from 4 cohorts. Samples underwent joint genotyping by the TOPMed Freeze 9 Variant Calling Pipeline. We performed descriptive analyses of these whole-genome sequencing data using the Accelerating Medicines Partnership Parkinson's Disease platform., Results: The clinical diagnosis of participants in version 1 release includes 2005 idiopathic PD patients, 963 healthy controls, 64 prodromal subjects, 62 clinically diagnosed PD subjects without evidence of dopamine deficit, and 705 participants of genetically enriched cohorts carrying PD risk-associated GBA variants or LRRK2 variants, of whom 304 were affected. We did not observe significant enrichment of pathogenic variants in the idiopathic PD group, but the polygenic risk score was higher in PD both in nongenetically enriched cohorts and genetically enriched cohorts. The population analysis showed a correlation between genetically enriched cohorts and Ashkenazi Jewish ancestry., Conclusions: We describe the genetic component of the Accelerating Medicines Partnership Parkinson's Disease platform, a solution to democratize data access and analysis for the PD research community. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article is a U.S. Government work and is in the public domain in the USA., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article is a U.S. Government work and is in the public domain in the USA.)

Genetic risk factors are occasionally shared between different neurodegenerative diseases. Previous studies have linked ANG, a gene encoding angiogenin, to both Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Functional studies suggest ANG plays a neuroprotective role in both PD and amyotrophic lateral sclerosis by reducing cell death. We further explored the genetic association between ANG and PD by analyzing genotype data from the International Parkinson's Disease Genomics Consortium (14,671 cases and 17,667 controls) and whole genome sequencing data from the Accelerating Medicines Partnership - Parkinson's disease initiative (AMP-PD, https://amp-pd.org/) (1,647 cases and 1,050 controls). Our analysis did not replicate the findings of previous studies and identified no significant association between ANG variants and PD risk., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Published by Elsevier Inc.)

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., Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases., Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%)., Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41-48., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Neuropathological and experimental evidence suggests that the cell-to-cell transfer of α-synuclein has an important role in the pathogenesis of Parkinson's disease (PD). However, the mechanism underlying this phenomenon is not fully understood. We undertook a small interfering RNA (siRNA), genome-wide screen to identify genes regulating the cell-to-cell transfer of α-synuclein. A genetically encoded reporter, GFP-2A-αSynuclein-RFP, suitable for separating donor and recipient cells, was transiently transfected into HEK cells stably overexpressing α-synuclein. We find that 38 genes regulate the transfer of α-synuclein-RFP, one of which is ITGA8, a candidate gene identified through a recent PD genome-wide association study (GWAS). Weighted gene co-expression network analysis (WGCNA) and weighted protein-protein network interaction analysis (WPPNIA) show that those hits cluster in networks that include known PD genes more frequently than expected by random chance. The findings expand our understanding of the mechanism of α-synuclein spread., Competing Interests: Declaration of interests B.T.H. has a family member who works at Novartis, and owns stock in Novartis; he serves on the scientific advisory board (SAB) of Dewpoint and owns stock; he serves on an SAB or is a consultant for Avrobio, AZTherapies, Biogen, Novartis, Cell Signaling, the U.S. Department of Justice, Takeda, Vigil, W20 Group, and Seer; and his laboratory is supported by sponsored research agreements with Abbvie and F-Prime and has research grants from the National Institutes of Health, Cure Alzheimer’s Fund, Tau Consortium, and the JPB Foundation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (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.)

Previous research using genome-wide association studies has identified variants that may contribute to lifetime risk of multiple neurodegenerative diseases. However, whether there are common mechanisms that link neurodegenerative diseases is uncertain. Here, we focus on one gene, GRN , encoding progranulin, and the potential mechanistic interplay between genetic risk, gene expression in the brain and inflammation across multiple common neurodegenerative diseases. We utilized genome-wide association studies, expression quantitative trait locus mapping and Bayesian colocalization analyses to evaluate potential causal and mechanistic inferences. We integrate various molecular data types from public resources to infer disease connectivity and shared mechanisms using a data-driven process. Expression quantitative trait locus analyses combined with genome-wide association studies identified significant functional associations between increasing genetic risk in the GRN region and decreased expression of the gene in Parkinson's, Alzheimer's and amyotrophic lateral sclerosis. Additionally, colocalization analyses show a connection between blood-based inflammatory biomarkers relating to platelets and GRN expression in the frontal cortex. GRN expression mediates neuroinflammation function related to multiple neurodegenerative diseases. This analysis suggests shared mechanisms for Parkinson's, Alzheimer's and amyotrophic lateral sclerosis., (Published by Oxford University Press on behalf of the Guarantors of Brain 2021. This work is written by US Government employees and is in the public domain in the US.)

Pathogenic missense variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified through linkage analysis in familial Parkinson disease (PD). Subsequently, other missense variants with lower effect sizes on PD risk have emerged, as well as non-coding polymorphisms (e.g. rs76904798) enriched in PD cases in genome-wide association studies. Here we leverage recent whole-genome sequences from the Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) and the Genome Aggregation (gnomAD) databases to characterize novel missense variants in LRRK2 and explore their relationships with known pathogenic and PD-linked missense variants. Using a computational prediction tool that successfully classifies known pathogenic LRRK2 missense variants, we describe an online web-based resource that catalogs characteristics of over 1200 LRRK2 missense variants of unknown significance. Novel high-pathogenicity scoring variants, some identified exclusively in PD cases, tightly cluster within the ROC-COR-Kinase domains. Structure-function predictions support that some of these variants exert gain-of-function effects with respect to LRRK2 kinase activity. In AMP-PD participants, all p.R1441G carriers (N = 89) are also carriers of the more common PD-linked variant p.M1646T. In addition, nearly all carriers of the PD-linked p.N2081D missense variant are also carriers of the LRRK2 PD-risk variant rs76904798. These results provide a compendium of LRRK2 missense variants and how they associate with one another. While the pathogenic p.G2019S variant is by far the most frequent high-pathogenicity scoring variant, our results suggest that ultra-rare missense variants may have an important cumulative impact in increasing the number of individuals with LRRK2-linked PD., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Parkinson's disease (PD) is a complex neurodegenerative disease with a strong genetic component. To date, several genes have been associated with monogenic forms of the disease, but these only explain a small fraction of the observed familial aggregation in PD. Recently, a heterozygous loss-of-function variant in LIN28A was associated with PD pathogenesis in the Asian population. Here, we comprehensively investigate the role of LIN28A variants in PD patients of European ancestry and assess susceptibility using individual-level genotyping data from 14,671 PD cases and 17,667 controls, as well as whole-genome sequencing data from 1647 patients with PD and 1050 controls. In addition, we further assess the summary statistics from the most recent genome-wide association studies meta-analyses to date for PD risk and age at onset. After evaluating these data, we did not find evidence to support a role for LIN28A as a major causal gene for PD. However, additional large-scale familial and case-control studies in non-European ancestry populations are necessary to further evaluate the role of LIN28A in PD etiology., (Published by Elsevier Inc.)

Objectives: Patients with established Parkinson's disease (PD) display differences in peripheral blood markers of immune function, including leukocyte differential counts, compared with controls. These differences may be useful biomarkers to predict PD and may shed light on pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with increased risk of subsequent PD diagnosis., Methods: We examined the relationship between incident PD, baseline differential leukocyte count and other blood markers of acute inflammation in UK Biobank (UKB), a longitudinal cohort with ~500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations., Results: After excluding individuals with comorbidities which could influence biomarkers of inflammation, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of subsequent PD diagnosis (per 1-SD decrease in lymphocyte count odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.07-1.32, p adjusted = 0.01). There was some evidence that reductions in eosinophil counts, monocyte counts and C-reactive protein (CRP) were associated with increased PD risk, and that higher neutrophil count was also associated. Only the association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1-SD decrease in lymphocyte count; OR MR = 1.09, 95% CI = 1.01-1.18, p = 0.02)., Interpretation: We provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD. ANN NEUROL 2021;89:803-812., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Biallelic Parkin (PRKN) mutations cause autosomal recessive Parkinson's disease (PD); however, the role of monoallelic PRKN mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PRKN mutations in three large independent case-control cohorts totalling 10 858 PD cases and 8328 controls. Overall, after exclusion of biallelic carriers, single PRKN mutations were more common in PD than controls conferring a >1.5-fold increase in the risk of PD [P-value (P) = 0.035], with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk [Odds ratio (OR) = 1.65, P = 3.69E-07]. Carriers were shown to have significantly younger ages at the onset compared with non-carriers (NeuroX: 56.4 vs. 61.4 years; exome: 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PRKN copy number variant (CNV) carriers compared with single nucleotide variant carriers. Studies that did not assess biallelic PRKN mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR = 1.23, P = 0.614; n = 4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PRKN mutations, we found that 44% had biallelic mutations, suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PRKN mutations with PD, it highlights confounding effects; therefore, caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PRKN mutations., (© The Author(s) 2021. Published by Oxford University Press.)

Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.