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Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant ( rs3115534 ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population., Competing Interests: Competing interests: M.M.B’s, H.L.’s and M.A.N.’s participation in this project was part of a competitive contract awarded to Data Tecnica International by the NIH to support open science research. M.A.N. also currently serves on the scientific advisory board for Character Bio and is a scientific founder at Neuron23. M.R., S.F., C. Beetz and P.B. are employees of Centogene. The remaining authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Parkinson's disease (PD) significantly impacts millions of individuals worldwide. Although our understanding of the genetic foundations of PD has advanced, a substantial portion of the genetic variation contributing to disease risk remains unknown. Current PD genetic studies have primarily focused on one form of genetic variation, single nucleotide variants (SNVs), while other important forms of genetic variation, such as structural variants (SVs), are mostly ignored due to the complexity of detecting these variants with traditional sequencing methods. Yet, these forms of genetic variation play crucial roles in gene expression and regulation in the human brain and are causative of numerous neurological disorders, including forms of PD. This review aims to provide a comprehensive overview of our current understanding of the involvement of coding and noncoding SVs in the genetic architecture of PD.

Background: Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants., Objectives: To identify complex structural variants in PRKN using long-read sequencing., Methods: We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP-PD) and United Kingdom (UK)-Biobank datasets., Results: Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression., Conclusions: This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read sequencing for structural variant analysis in unresolved young-onset PD cases. © 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.)

Parkinson's disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson's disease. To address this gap, we investigated the rare genetic component of Parkinson's disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson's disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson's disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson's disease. To date, this is the largest analysis of rare genetic variants in Parkinson's disease., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

Background: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations., Methods: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity., Findings: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10 -14 ) and age at onset at the GBA1 locus, rs3115534-G (age at onset β=-2·00 [SE=0·57], p=0·0005, for African ancestry; and β=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity., Interpretation: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease., Funding: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research., Competing Interests: Declaration of interests DV, HI, HLL, KSL, CXA, and MAN's participation in this project was part of a competitive contract awarded to Data Tecnica International by the US National Institutes of Health (NIH) to support open science research. MAN also currently serves on the scientific advisory board for Character Biosciences and Neuron 23. KH is employed by 23andMe and holds stock or stock options in 23andMe. AS, MBM, PAJ, CB, KD, MJK, JJK, and PWC are employed by the NIH. AS also declares funding for the present work from the Michael J Fox Foundation (MJFF) and Aligning Science Across Parkinson's (ASAP); royalties for a diagnostic for stroke (unrelated to the current work); honoraria for associate editorial work for the journals Movement Disorders and npj Parkinson's Disease; and travel support from the Chan Zuckerberg Initiative to attend annual investigators’ meeting, MJFF to attend Parkinson's Progression Marker Initiative annual meeting, and Weill Cornell to give grand rounds. The spouse of AS is an employee of GeneDx. OOk, IE, HI, JHK, and DV declare funding from the NIH (1ZIA AG000534-04). HI also declares honoraria from GP2 for a steering committee meeting and from MJFF for a data community meeting. DGS declares support for the present work from ASAP (for the BLAAC-PD study); research support from the NIH (P50 108675), the MJFF, the Parkinson Foundation of the National Capital Area, the American Parkinson Disease Association, AbbVie, and Genentech; book royalties from McGraw Hill; consulting fees from AbbVie, Curium Pharma, F Hoffman-La Roche, Appello Pharma, and Blue Rock Therapeutics; participation on a data safety monitoring board or advisory board for Sanofi-Aventis, Theravance, and Alnylam Pharmaceuticals; being Deputy Editor of the journal Movement Disorders; and being Chair of the Scientific Advisory Board of the American Parkinson Disease Association. DAH declares support for the present work from the NIH, the MJFF, the CHDI Foundation, Parkinson's Foundation, Lundbeck, Uniqure, and Neurocrine. TX declares research funding from the MJFF, the American Parkinson's Disease Association, and the NIH; and consulting fees from Parkinson's Foundation and CVS Caremark. HH and JH declare research funding by the Medical Research Council (UK), the Wellcome Trust, the MSA Trust, NIHR University College London Hospitals Biomedical Research Centre (NIHR-BRC), the MJFF, the Fidelity Trust, the Rosetrees Trust, the Guarantors of Brain, SOLVE-RD, and the Dolby Family Fund. HRM declares support from the MJFF related to this work; grants not related to this work from PSP Association, CBD Solutions, Drake Foundation, and Cure Parkinson's Trust; consulting fees from Roche, Amylyx, and Aprinoia; speaker's honoraria from Kyowa-Kirin, the British Medical Journal, and the Movement Disorders Society; travel support from the MJFF and the Movement Disorders Society; and being on the advisory board for Cure PSP Association, the Association of British Neurologists Movement Disorders special interest group, and the Association of British Neurologists Neurogenetics advisory group. HRM is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). ES declares funding for the present work from the US National Human Genome Research Institute (NHGRI) Intramural Research Program; grants from ASAP and MJFF; and a cooperative research and development agreement with Roche. EAS declares funding for the present work from the MJFF; and travel support from the MJFF. MND declares funding for the present work from MJFF; grant support from ASAP; speaker's honoraria from the Parkinson's Foundation; and is a member of the Parkinson's Foundation Gulf Coast advisory board. Z-HF declares salary support from the MJFF. OOOj declares a study grant from the NIHR; honoraria for educational courses from the International Parkinson and Movement Disorder Society (IPMDS); travel support from P2 for an annual investigators’ meeting and from the IPMDS for congress attendance; and is a member of the executive committee of the IPMDS. NUO declares a study grant from the NIHR; travel support and honoraria for educational courses from the IPMDS; and being Chair of the IPMDS Africa Section. UA declares a study grant from the NIHR. RA declares grant support from the NIH (U01HG010273, U19AG074865), the UK Royal Society and the African Academy of Sciences Future Leaders—African Independent Research (FLR/R1/191813, FCG/R1/201034), and the Global Brain Health Institute, Alzheimer's Association, and Alzheimer's Society UK (GBHI ALZ UK-21- 24204). TF declares speaker's honoraria from Roche; travel support from the Alzheimer's Association; and is a member of the Alzheimer's Disease International medical and scientific advisory panel. CB declares support from ASAP. KD declares a Japan Society for the Promotion of Science Research Fellowship. JJK declares participation in the graduate school programme for Queen Mary University London (London, UK). PAJ declares participation in the graduate school programme for University College London (London, UK). MBM declares participation in a summer internship at Genentech/Roche (unrelated to the current work). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.)

No abstract present., Competing Interests: The authors declare that they have no conflict of interest., (© 2020 Hall et al. Published by IMR Press.)

Parkinson's disease (PD) is a complex disorder underpinned by both environmental and genetic factors. The latter only began to be understood around two decades ago, but since then great inroads have rapidly been made into deconvoluting the genetic component of PD. In particular, recent large-scale projects such as genome-wide association (GWA) studies have provided insight into the genetic risk factors associated with genetically ''complex'' PD (PD that cannot readily be attributed to single deleterious mutations). Here, we discuss the plethora of genetic information provided by PD GWA studies and how this may be utilized to generate polygenic risk scores (PRS), which may be used in the prediction of risk and trajectory of PD. We also comment on how pathway-specific genetic profiling can be used to gain insight into PD-related biological pathways, and how this may be further utilized to nominate causal PD genes and potentially druggable therapeutic targets. Finally, we outline the current limits of our understanding of PD genetics and the potential contribution of variation currently uncaptured in genetic studies, focusing here on uncatalogued structural variants.

Repetitive elements (RE) constitute the majority of the human genome and have a range of functions both structural and regulatory on genomic function and gene expression. RE overexpression has been observed in several neurodegenerative diseases, consistent with the observation of aberrant expression of RE posing a mutagenic threat. Despite reports that associate RE expression with PD no study has comprehensively analysed the role of these elements in the disease. This study presents the first genome-wide analysis of RE expression in PD to date. Analysis of RNA-sequencing data of 12 PD patients and 12 healthy controls identified tissue-specific expression differences and more significantly, differential expression of four satellite elements; two simple satellite III (repName = CATTC&#95;n and &#95;GAATG&#95;n) a high-copy satellite II (HSATII) and a centromeric satellite (ALR&#95;Alpha) in the blood of PD patients. In support of the growing body of recent evidence associating REs with neurodegenerative disease, this study highlights the potential importance of characterization of RE expression in such diseases.

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.