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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. ispartof: BRAIN vol:145 issue:12 pages:4349-4367 ispartof: location:England status: published

Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson’s disease (PD) pathology. Here, we performed snRNA-seq on the prefrontal cortex and anterior cingulate regions from post-mortem control and PD brain tissue. We found a significant association of oligodendrocytes and oligodendrocyte precursor cells with PD-linked risk loci and report several dysregulated genes and pathways, including regulation of tau-protein kinase activity, regulation of inclusion body assembly and protein processing involved in protein targeting to mitochondria.

BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by theMAPTgene. TheMAPTH2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association betweenMAPTH2 and risk of PiD.MethodsWe established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped forMAPTH1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variantMAPTH1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521).FindingsOur primary analysis found that theMAPTH2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotypeMAPTH1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65).InterpretationThe PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, theMAPTH2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.FundingSee funding section

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.

BackgroundThe microtubule-associated protein tau (MAPT) gene is critical because of its putative role in the causal pathway of neurodegenerative diseases including Parkinson’s disease (PD). However, there is a lack of clarity regarding the link between the main H1 haplotype and risk of PD. Inconsistencies in reported association may be driven by genetic variability in the populations studied to date. Data onMAPThaplotype frequencies in the general population and association studies exploring the role ofMAPThaplotypes in conferring PD risk in black Africans are lacking.ObjectivesTo determine the frequencies ofMAPThaplotypes and explore the role of the H1 haplotype as a risk factor for PD risk and age at onset in Nigerian Africans.MethodsThe haplotype and genotype frequencies ofMAPTrs1052553 were analysed using PCR-based KASP™ in 907 individuals with PD and 1,022 age-matched neurologically normal controls from the Nigeria Parkinson’s Disease Research (NPDR) network cohort. Clinical data related to PD included age at study, age at onset, and disease duration.ResultsThe frequency of the mainMAPTH1 haplotype in this cohort was 98.7% in individuals with PD, and 99.1% in healthy controls (p=0.19). The H2 haplotype was present in 41/1929 (2.1%) of the cohort (PD - 1.3%; Controls - 0.9%; p=0.24). The most frequentMAPTgenotype was H1H1 (PD - 97.5%, controls - 98.2%). The H1 haplotype was not associated with PD risk after accounting for gender and age at onset (Odds ratio for H1/H1 vs H1/H2 and H2/H2: 0.68 (95% CI:0.39-1.28); p=0.23).ConclusionsOur findings support previous studies that report a low frequency of theMAPTH2 haplotype in black ancestry Africans, but document its occurrence in the Nigerian population (2.1%). In this cohort of black Africans with PD, theMAPTH1 haplotype was not associated with an increased risk or age at onset of PD.

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.

BackgroundBi-allelic pathogenic variants inGBA1are the cause of Gaucher disease (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. HeterozygousGBA1variants 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 of PD.ObjectiveTo investigate the contribution of PD risk variants to risk of PD in patients with GD1.MethodsWe studied 225 patients with GD1, including 199 without PD and 26 with PD. All cases were genotyped and the genetic data was imputed using common pipelines.ResultsOn average, patients with GD1 with PD have a significantly higher PD genetic risk score than those without PD (P=0.021).ConclusionsOur 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.Supplemental datahere

Overlapping symptoms and copathologies are common in closely related neurodegenerative diseases (NDDs). Investigating genetic risk variants across these NDDs can give further insight into disease manifestations. In this study we have leveraged genome-wide single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) summary statistics to cluster patients based on their genetic status across identified risk variants for five NDDs (Alzheimer’s disease [AD], Parkinson’s disease [PD], amyotrophic lateral sclerosis [ALS], Lewy body dementia [LBD], and frontotemporal dementia [FTD]). The multi-disease and disease-specific clustering results presented here provide evidence that NDDs have more overlapping genetic etiology than previously expected and how neurodegeneration should be viewed as a spectrum of symptomology. These clustering analyses also show potential subsets of patients with these diseases that are significantly depleted for any known common genetic risk factors suggesting environmental or other factors at work. Establishing that NDDs with overlapping pathologies share genetic risk loci, future research into how these variants might have different effects on downstream protein expression, pathology and NDD manifestation in general is important for refining and treating NDDs.

The human genome contains numerous duplicated regions, such as parent-pseudogene pairs, causing sequencing reads to align equally well to either gene. The extent to which this ambiguity complicates transcriptomic analyses is currently unknown. This is concerning as many parent genes have been linked to disease, includingGBA1,causally linked to both Parkinson’s and Gaucher disease. We find that most of the short sequencing reads that map toGBA1, also map to its pseudogene,GBAP1. Using long-read RNA-sequencing in human brain, where all reads mapped uniquely, we demonstrate significant differences in expression compared to short-read data. We identify novel transcripts from bothGBA1andGBAP1, including protein-coding transcripts that are translatedin vitroand detected in proteomic data, but that lack GCase activity. By combining long-read with single-nuclear RNA-sequencing to analyse brain-relevant cell types we demonstrate that transcript expression varies by brain region with cell-type-selectivity. Taken together, these results suggest a non-lysosomal function for both GBA1 and GBAP1 in brain. Finally, we demonstrate that inaccuracies in annotation are widespread among parent genes, with implications for many human diseases.

BackgroundGBA1 variants are among the most common genetic risk factors for Parkinson’s Disease (PD). GBA1 variants can be classified into three categories based on their role in Gaucher’s Disease (GD) or PD: severe, mild, and risk variant (for PD).ObjectivesThis paper aims to generate and share a comprehensive database for GBA1 variants reported in PD to support future research and clinical trials.MethodsWe performed a literature search for all GBA1 variants that have been reported in PD. The data has been standardized and complimented with variant classification, Odds Ratio (OR) if available and other data.ResultsWe found 371 GBA1 variants reported in PD: 22 mild, 84 severe, 3 risk variants, and 262 of unknown status. We created a browser, containing up-to-date information on these variants (https://pdgenetics.shinyapps.io/GBA1Browser/).ConclusionsThe classification and browser presented in this work should inform and support basic, translational, and clinical research on GBA1-PD.

Genome-wide association studies (GWAS) of Alzheimer’s disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer’s disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer’s disease and related dementias.

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 theLRRK2locus, 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 onLRRK2expression is specifically propagated through microglia and not by other cell types that expressLRRK2in the human brain. We find microglia-specific regulatory chromatin regions that modulate theLRRK2expression 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 theLRRK2expression 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.

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., This work was supported in part by the Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Against Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (https://gp2.org). For a complete list of GP2 members see https://gp2.org. This research was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute on Aging, Z01-AG000949-02). The Preventive Neurology Unit is funded by the Barts Charity.

BackgroundThere are 90 genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments.MethodsWe studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to motor progression, defined by reaching Hoehn and Yahr stage 3 or greater, cognitive impairment as defined by serial cognitive examination, and death (mortality).FindingsThere was a robust effect of the APOE ε4 allele on mortality and cognitive impairment in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity or expression quantitative trait loci data. One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10-10). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31×10-8). A genomic variant associated with the expression of ADORA2A, encoding the A2A adenosine receptor, was associated with motor progression (HR=4.83 [95% CI 2.89 to 8.08], p-value=1.94×10-9). Only the non-Gaucher disease causing GBA PD risk variant E326K, of the known PD risk variants, was associated with progression in PD.InterpretationWe report three novel loci associated with PD progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release and the A2A adenosine receptor may represent new candidates for disease modification in PD.RESEARCH IN CONTEXTEvidence before this studyWe searched PubMed for articles on Parkinson’s disease (PD) with no language restrictions from database inception up to February 9, 2022. We used the search terms “Parkinson disease AND genetics” and “disease progression OR survival OR mortality OR prognosis OR longitudinal studies”. We also conducted this search with the addition of “genome-wide association study” (GWAS) to focus on these genome-wide analyses. There are now three published large-scale GWASs investigating PD progression, and many candidate variant studies. However, no genome-wide studies have reported on survival/mortality in PD.Added value of this studyTo our knowledge, this is the first GWAS of survival in PD. Our study highlights new loci influencing survival in PD, including TBXAS1 and SYT10. We also conducted GWASs of progression to other clinical milestones, Hoehn and Yahr stage 3 or greater, and cognitive impairment. We show that APOE influences both mortality and cognitive progression in PD, and report an additional locus influencing expression of ADORA2A which affects the rate of motor progression.Implications of all the available evidenceWith the exception of APOE, we report new loci which have not been previously associated with PD progression or for mortality and ageing in the general population. These loci could be investigated in functional studies as potential drug targets to stop or slow progression of PD. In addition, new genetic loci can help to improve our understanding of the biology of PD progression and prediction of progression. Further replication of these loci is also needed in independent, longitudinal PD cohorts.

BACKGROUNDWith recent findings connecting Epstein-Barr virus to increased risk of multiple sclerosis and growing concerns regarding the potential neurological impact of the coronavirus pandemic, we surveyed biobank scale real-world data to identify potential links between viral exposures and neurodegenerative disease risks.METHODSTo assess the potential increased risk of neurodegenerative diseases due to viral exposures, we mined time series data from FinnGen as a discovery dataset and cross-sectional data from the UK Biobank as a replication dataset for 73 pairs of common viral exposures and neurodegenerative disease outcomes. We investigated the impact of time span between viral exposure and disease risk using time series data from FinnGen at 1, 5, and 15 year intervals between exposure and disease onset. This analysis helped us to avoid the potential confounding of concurrent diagnosis due to hospitalization with viral infection. Further, to address the possible bias of reverse causality we examined risk for severe viral infections after NDD diagnosis.RESULTSWe identified 45 viral exposures significantly associated with increased risk of post-exposure neurodegenerative disease onset after multiple test correction in the discovery phase using longitudinal data. 22 of these associations were replicated in cross sectional data from the UK Biobank. The largest effect association we saw replicated was between viral encephalitis exposure and Alzheimer’s disease, with discovery hazard estimates of ∼30 and a replication odds ratio of ∼22. We also replicated the association between Epstein-Barr virus exposure and multiple sclerosis 5-15 years before diagnosis of multiple sclerosis. In total, 17 virus/neurodegeneration pairs were significant with 5-15 years between viral exposure and NDD diagnosis. In an investigation of potential confounding and reverse causality, we generally see larger hazard ratios associated with viruses preceding NDD diagnosis than viruses post NDD diagnosis.CONCLUSIONSViral exposures contribute to later in life risk of neurodegenerative disease with increased risk of neurodegeneration still significant at up to 15 years between some events in this report.

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 cognition in 1100 Nigerians with PD and 1097 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)). Altogether, our findings support previous studies in other ancestries, implying a role for APOE ε4 and ε2 as risk and protective factors respectively for cognitive decline in PD.

Introduction: Recent pan-cancer whole-genome sequencing studies revealed the rich landscape of structural variants (SV), from simpler indels to complex events involving multiple breakpoints and sequence gain/loss. SVs may contribute to tumorigenesis through direct modification of coding sequence or deregulation from copy number alterations, enhancer hijacking, or topological domain modification. A substantial part of the variation in the human genome is not accessible to short reads due to mapping ambiguities. Recent benchmarking studies reported that the best short-read methods only have 30-70% SV sensitivity. Long-read sequencing (such as PacBio or Oxford Nanopore) can overcome the limitations of short reads, however the current methods were not designed for the analysis of rearranged cancer genomes with complex copy number profiles. Methods: We developed BGA (Breakpoint Graph Assembler), a method that combines the ideas from long-read assembly and breakpoint graph frameworks. BGA detects abnormally mapped reads and builds a breakpoint graph that characterizes the structure of derived cancer karyotypes. Complex events with multiple breakpoints form connectivity clusters and are classified based on the subgraph properties. BGA also takes advantage of phased haplotypes and can incorporate multiple related datasets (such as in tumor-normal comparison or multi-site tumor sampling). BGA is freely available at: https://github.com/KolmogorovLab/BGA. Results: We first analyzed three cancer cell lines and corresponding matching normal DNAs (HCC1954, H2009, and COLO829). In each cell line, we identified 8-56 somatic rearrangement clusters involving more than two breakpoints and at least 1kb of sequence. In H2009, we identified a chromoplexy event involving chr13 and chr1, consistent with previous FISH experiments. COLO829 showed the lowest number of somatic rearrangement clusters (n=8), including translocation and inversion events between chr3, chr10, and chr12 within the RARB, BICC1, and TRHDE genes. Homologous recombination deficient HCC1954 has the highest number of complex events including the chr17q arm which hosts ERBB2, chromoplexy between chr8, chr5, and chromothripsis in chr21. In addition, we analyzed three other HPV-infected cell lines (CaSki, SCC152, SNU1000). In each of them, we observed complex clusters of HPV-HPV and HPV-human breakpoints that formed cycles, suggesting extrachromosomal amplification. The HPV fragments had many interactions with chromosomal DNA in CaSki and SC152, but not in mostly episomal SNU1000 cells. We also observed karyotype-scale changes that did not involve HPV sequences, such as the simultaneous exchange of six chromosome arms of chr2, chr7, and chr17 in CaSki. Citation Format: Ayse Keskus, Tanveer Ahmad, Ataberk Donmez, Yi Xie, Isabel Rodriguez, Rose Milano, Nicole Rossi, Hong Lou, Laksh Malik, Kimberley Billingsley, Cornelis Blauwendraat, Michael Dean, Mikhail Kolmogorov. Long-read, assembly-based characterization of rearranged cancer karyotypes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4289.

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.