To investigate whether antidiabetic drugs have a biological basis to be repurposed in PD prevention, we applied a drug target Mendelian randomization framework to assess associations between genetic variation in antidiabetic drug targets and PD risk or age at onset (AAO). Instrumental variables (IVs) were derived from GWAS summary statistics on fasting glucose (FG), glycated hemoglobin (HbA1c), and gene expression data from GTEx. Apart from SGLT2 inhibitors, all other antidiabetic drugs of interest could be instrumented through our methods. Positive and negative control analyses were carried out to validate 20 IVs in the FG arm and 23 IVs in the HbA1c arm. DPP-4 inhibitors failed the positive control. GWAS summary statistics for PD risk and AAO data were sourced from the IPDGC and COURAGE-PD consortia, resulting in 42 083 cases/457 090 controls for risk and 37 103 PD cases for AAO. MR analyses showed no significant associations across consortia or in meta-analysis. These findings do not support a causal role of genetic variation in antidiabetic drug targets in PD risk or AAO.

Introduction Genome-wide association studies (GWAS) have identified over 130 risk loci for Parkinson's disease (PD), yet the majority derive from studies performed in European ancestry populations. African (AFR) and African admixed (AAC) ancestry individuals remain underrepresented in PD genetics research, limiting our understanding of ancestry-specific genetic architecture and the generalizability of known risk factors. Methods We conducted GWAS in AFR and AAC populations by integrating individual-level genotype data from the Global Parkinson's Genetics Program (GP2) with summary statistics from 23andMe Research Institute and the Million Veterans Program. The combined dataset included 3,975 cases and 319,883 controls, representing a 64% increase in total sample size compared with prior analyses. We performed separate GWAS for AFR and AAC cohorts as well as a combined AFR/AAC meta-analysis. Results The intronic GBA1 variant rs3115534 was the most significant association across all analyses, reaching genome-wide significance in AAC individuals for the first time. In the AFR-only analysis, five loci achieved genome-wide significance: GBA1 (rs3115534), the SNCA signal previously reported in European ancestry GWAS (rs356182), a new protein-coding association at LRRK2 (rs72546327, p.T1410M), a non-coding RPL10P13 variant (rs12302417), and a novel signal on chromosome 16 (rs113244182). The combined AFR/AAC meta-analysis identified four genome-wide significant associations at GBA1 (rs3115534), SNCA (rs356182), SCARB2 (rs11547135), and LRRK2 (rs139283662, which is in LD with p.T1410M). Conclusions This study reports the largest GWAS of PD in AFR and AAC populations to date. Our findings confirm trans-ancestry risk loci (GBA1 and SCARB2) and identify an ancestry-enriched coding variant at LRRK2. This convergence of evidence around genes involved in glucocerebrosidase (GCase) trafficking and alpha-synuclein clearance supports current therapeutic strategies targeting this pathway and provides critical targets for developing precision medicine in African ancestry populations. Importantly, the identification of a novel association between a LRRK2 coding variant with disease in the AFR and AAC populations opens up a traditionally underrepresented population for ongoing LRRK2 targeted trials. Furthermore, the identification of novel ancestry-specific loci, including those that are directly relevant to current therapeutic deployment, underlines the importance of understanding the basis of disease in all populations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was supported by the Global Parkinsons Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinsons (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinsons Research (MJFF). For a complete list of GP2 members see https://doi.org/10.5281/zenodo.7904831. This research was supported by the Aligning Science Across Parkinson's Initiative, the Intramural Research Program, National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project ZO1 AG000949, and the Michael J. Fox Foundation for Parkinson's Research. This work utilized the computational resources of the NIH STRIDES Initiative (https://cloud.nih.gov) through the Other Transaction agreement - Azure: OT2OD032100, Google Cloud Platform: OT2OD027060, Amazon Web Services: OT2OD027852. We would like to thank the research participants, Paul Cannon, and employees of 23andMe Research Institute for making this work possible. We would also like to thank Dario Alessi and his team for their valuable contributions in functionally contextualizing this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used in the preparation of this article were obtained from GP2. Specifically we used Tier 2 data from GP2 (release 11: DOI 10.5281/zenodo.17753486). GP2 data can be accessed through AMP PD (https://amp-pd.org). For the MVP dataset, PD summary statistics from the Million Veterans Program (MVP) were downloaded from dbGAP (accession number: phs002453.v1.p1; analysis accession: pha010400.1). Summary statistics from 23andMe were shared under a collaborative agreement submitted at https://research.23andme.com/collaborate/. All code generated for this article, and the identifiers for all software programs and packages used, are available on GitHub (https://github.com/GP2code/GP2-AFR-AAC-metaGWAS) and were given a persistent identifier via Zenodo (DOI: 10.5281/zenodo.7888140)

Huntington's disease phenocopies are conditions characterized by a phenotype similar to Huntington's disease but without a pathogenic repeat expansion in the HTT gene. The percentage of patients who have a Huntington's disease phenotype but subsequently are shown not to carry a repeat expansion ranges from 2% to 40%, depending on the ethnicity and the geographic location of the population studied, as well as the resources available for investigation of the underlying causes. In descending order of frequency, genetic causes are Huntington disease-like 2/JHP3, spinocerebellar ataxia genes (SCA17/TBP, SCA12/PPP2R2B and SCA3/ATXN3, CACNA1A) and frontotemporal dementia genes (C9orf72 and VCP). In addition, it has been established that a growing list of acquired causes may also mimic Huntington's disease, including autoimmune illnesses such as primary antiphospholipid syndrome, paraneoplastic chorea and anti-IGLON5 (immunoglobulin-like cell adhesion molecule 5). Here, we aim to review the epidemiology, aetiology, clinical and laboratory findings of the wide range of conditions associated with Huntington's disease phenocopies, and proceed to suggest a practical diagnostic approach to the investigation of Huntington's disease phenocopies taking into account the age at onset, ethnicity and geographic location of individuals.

We investigated the role of copy number variations (CNVs) in Parkinson's disease (PD) using genotyping data from 10,815 patients (2731 early-onset PD, EOPD) and 8901 controls from the COURAGE-PD consortium. CNVs were analyzed using a sliding window genome-wide association and burden approach. No genome-wide significant CNVs were detected in the overall cohort, but a robust deletion spanning exons 2-6 of PRKN was identified in EOPD cases, validated by MLPA, and replicated in the GP2 dataset (23,089 cases, 18,824 controls). CNV burden was significantly enriched in PD-related genes, primarily driven by PRKN, with the strongest effect observed in EOPD. PRKN CNV carriers showed earlier age at onset, confirmed by survival analysis. No association was observed for genome-wide or large CNV burden. Our findings reinforce the pivotal role of PRKN deletions in early-onset PD and highlight the need for high-resolution CNV analysis in large cohorts to uncover additional rare contributors to PD risk.

IntroductionAlthough there have been significant advances in the genetic etiology of Parkinson’s disease (PD), most of this research has been conducted in European populations. This study aimed to characterize the genetic landscape of PD in South Africa.MethodsWe recruited 689 PD probands across South Africa. These participants were genotyped using the NeuroBooster array in collaboration with the Global Parkinson’s Genetics Program (GP2). An in-house computational workflow was used to identify pathogenic missense variants, which were validated using Sanger sequencing. The CNV-Finder pipeline was used to screen for copy number variations (CNVs), which were validated using Multiplex Ligation-dependent Probe Amplification (MLPA). Previously identified pathogenic variants were used as positive controls in our analysis.ResultsWe identified 16 unique missense variants, confirming 15 with Sanger sequencing, in 47 individuals across seven well-established PD genes. Variants in GBA1 and PRKN were the most frequent. Additionally, 18 variants of unknown significance were found in known genes. Furthermore, seven new CNVs were identified, five in PRKN and two in SNCA, of which six were validated using MLPA. One of the CNVs was in the 5’ untranslated region of SNCA. When combining this data with previous findings, 3.5% of the probands have a genetic basis for their disease.ConclusionsWe conducted the largest pathogenic variant screening to date in this unique and underrepresented population, and our findings highlight the rare contribution of known pathogenic variants. This study underscores the importance of expanding genetic research in African cohorts to improve global understanding of PD etiology.

Parkinson's disease (PD) care remains profoundly unequal across and within countries, despite major advances in understanding and treatment. Drawing on PD specialists’ personal stories of real-world experiences from diverse regions across Asia, Africa, and South America, this paper highlights the key barriers to equitable PD care and identifies pragmatic, scalable solutions. Across settings, several major barriers consistently emerge: a critical shortage and uneven distribution of trained specialists; geographic disparities limiting access to care; substantial financial barriers, particularly for comprehensive and advanced therapies; fragmented healthcare systems lacking integration and multidisciplinary support; and low public awareness and persistent stigma, leading to delayed diagnosis and treatment. Strategies to address these challenges include workforce development through training, mentorship, and international collaboration; bringing expertise and services closer to patients via outreach programs and the use of “simple” technologies such as telemedicine and mobile communication platforms; ensuring universal access to essential medications, particularly levodopa; integrating multidisciplinary care models; public awareness campaigns and support groups empowering patients and caregivers and reducing stigma; and embedding research into routine care. The experiences presented here illustrate that meaningful progress is achievable through pragmatic solutions, collaborative networks, and sustained commitment to patient-centered care.

Parkinson's disease (PD) is a complex neurodegenerative disorder with a substantial genetic influence. To better characterize the genetic landscape of PD in South Africa, we conducted the largest genetic screening to date for pathogenic single nucleotide and copy number variations (CNVs) using genotyping array data from 689 PD probands. We identified 16 unique missense variants, confirming 15 with Sanger sequencing, in 47 individuals across seven well-established PD genes, with GBA1 and PRKN being most frequent. Also in known PD genes, 18 variants of unknown significance were found. Additionally, CNV analysis using CNV-Finder revealed seven novel CNVs, five in PRKN and two in SNCA, of which, six were validated with Multiplex Ligation-dependent Probe Amplification. The findings highlight the contribution of both rare variants and structural rearrangements to PD in this underrepresented population. This study underscores the importance of expanding genetic research in African cohorts to improve global understanding of PD etiology.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by motor and non-motor symptoms. Recent evidence suggests a role for gut microbiome composition and diversity in PD aetiology. This study aimed to explore the association between the gut microbiome and PD in a South African population. Gut microbial sequencing data (cases: n = 16; controls: n = 42) was generated using a 16S rRNA gene (V4) primer pair. Alpha- and beta-diversity were calculated using QIIME2, and differential abundance of taxa was evaluated using Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC). Beta-diversity was found to differ significantly between cases and controls, with depletion in the relative abundance of Faecalibacterium, Roseburia, Dorea, and Veillonella, and enrichment of the relative abundance of Akkermansia and Victivallis. Our study found a reduction in butyrate-producing bacteria (e.g. Faecalibacterium and Roseburia) and an increase in mucin-degrading bacteria (Akkermansia) in PD cases compared to controls. These alterations might be associated with heightened gut permeability and inflammation. Longitudinal studies should address the question of whether these microbiome differences are a risk factor for, or are consequent to, the development of PD.

Objective:To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD. Methods:We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings. Results:The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. Interpretation:The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.

Next generation sequencing (NGS) based tests have become first-line investigative modalities in adult neurogenetic clinics. Studies in high-income countries (HICs) show that NGS is cost-effective and reliable in diagnosing adult neurogenetic disorders (NGDs). African populations harbour vast genomic diversity, but there is limited knowledge on the molecular basis of NGDs affecting these populations due to lack of access to the necessary technology. The primary objective of this retrospective study was to describe the clinical utility of NGS panels in an African low-middle income country (LMIC). It included data of 74 adult participants seen at the multidisciplinary neurogenetic clinic at Tygerberg Hospital, South Africa, over a 4 – year period. Forty-three symptomatic index cases underwent NGS panel testing, while 31 relatives received targeted familial variant testing based on specific indications relevant to each case. Twenty-two different disease group-specific NGS panels were requested, spanning the NGD phenotypic spectrum. The diagnostic yield (DY) in index cases was 39.5% (17/43). Four relatives were clinically affected, and all tested positive for the familial-specific variant. This study demonstrated the DY achieved with NGS testing in an LMIC adult neurogenetic cohort, was comparable to DYs previously reported in HICs. These results argue for the use of NGS panels as first-tier testing in resource constrained LMICs, to limit lengthy diagnostic odysseys and unnecessary investigations. A definitive molecular diagnosis enables evidence-based management, surveillance, genetic counselling, and familial variant screening for relatives. Lastly, it assists with enrolment into clinical trials focussed on the development of precision medicine.

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)–derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration–approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

Background and Objectives The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. Methods We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m(2) [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. Results Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (<= 67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (<= 7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. Discussion Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.

The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR.

BACKGROUND:Huntington disease-like 2 (HDL2) is a neurodegenerative disorder, affecting only individuals of African ancestry. Full penetrance occurs in individuals with 40 repeats or more. OBJECTIVE:To describe the phenotypic variability of HDL2 in a group of mixed ancestry individuals from South Africa. METHODS:Eight patients were assessed with analysis of repeat size and magnetic resonance brain imaging. We applied the Unified Huntington's Disease Rating Scale (UHDRS), but in deceased patients (4), this was estimated from video material. RESULTS:Cognitive domains were more severely affected than motor; UHDRS motor scores were notable for bradykinesia, and to a slightly lesser extent, for rigidity and dystonia; a single patient had marked chorea. Repeat lengths ranged from 45 to 63 (median, 52). CONCLUSION:This South African group of mixed ancestry HDL2 individuals presented with severe cognitive and behavioral impairments, with lesser degrees or absence of chorea. This presentation is possibly related to large repeat sizes.

BackgroundRapid eye movement sleep behavior disorder (RBD) is an established prodrome and symptom of synucleinopathies. The pathophysiology of this disorder has been well studied but there is a lack of functional imaging data to illustrate the dysfunction in vivo. ObjectivesWe aimed to investigate the functional changes of RBD, by performing ictal REM sleep SPECT, comparing subjects with Parkinson's Disease (PD) and evidence of RBD to subjects with PD and no RBD. MethodsParticipants underwent a targeted clinical assessment, followed by video polysomnography (vPSG). Ictal 99mTc-HMPAO SPECT was performed by injecting the tracer during vPSG confirmed REM sleep in seven cases (PD with RBD) and five controls (PD without RBD). Voxel-wise, whole brain regional relative perfusion changes between both groups were assessed using statistical parametric mapping. ResultsNo difference in relative regional brain perfusion was demonstrated at a family wise error corrected p-value of 0.05 between the case and control groups. At an uncorrected P-value of <0.01, combined with a cluster extent threshold of 300 voxels, four clusters of increased perfusion were identified in the case group compared to the control group. The clusters were seen in the motor, somatosensory association, and prefrontal cortices. The reverse contrast did not show any significant clusters. ConclusionsIncreased perfusion of the motor cortex is in keeping with previous publications and motor phenomena seen in RBD. However, clusters included additional cortical regions. These findings demonstrate RBD as a wider sleep network dysfunction, rather than a manifestation of simple pontomedullary interruption.