In this article, we describe combining both efforts in a merger project resulting in a global monogenic PD cohort with the buildup of a sustainable infrastructure to identify the multi-ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expressivity of monogenic PD.

Aiming to develop recommendations on return of research results (RoR) practice within the Global Parkinson's Genetics Program (GP2), we conducted a global survey to gain insight on GP2 members' perceptions, practice, readiness, and needs surrounding RoR. GP2 members (n = 191), representing 147 institutions and 60 countries across 6 continents, completed the survey. Access to clinical genetic testing services was significantly higher in high-income countries compared with low- and middle-income countries (96.6% vs 58.4%), where funding was predominantly covered by patients themselves. While 92.7% of the respondents agreed that genetic research results should be returned, levels of agreement were higher for clinically relevant results relating to pathogenic or likely pathogenic variants in genes known to cause PD or other neurodegenerative diseases. Less than 10% offered separate clinically accredited genetic testing before returning genetic research results. A total of 48.7% reported having a specific statement on RoR policy in their ethics consent form, while 53.9% collected data on participants' preferences on RoR prospectively. 24.1% had formal genetic counselling training. Notably, the comfort level in returning incidental genetic findings or returning results to unaffected individuals remains low.

Risk prediction models play a crucial role in advancing healthcare by enabling early detection and supporting personalized medicine. Nonetheless, polygenic risk scores (PRS) for Parkinson’s disease (PD) have not been extensively studied across diverse populations, contributing to health disparities. In this study, we constructed 105 PRS using individual-level data from seven ancestries and compared two different models. Model 1 was based on the cumulative effect of 90 known European PD risk variants, weighted by summary statistics from four independent ancestries (European, East Asian, Latino/Admixed American, and African/Admixed). Model 2 leveraged multi-ancestry summary statistics using a p-value thresholding approach to improve prediction across diverse populations. Our findings provide a comprehensive assessment of PRS performance across ancestries and highlight the limitations of a “one-size-fits-all” approach to genetic risk prediction. We observed variability in predictive performance between models, underscoring the need for larger sample sizes and ancestry-specific approaches to enhance accuracy. These results establish a foundation for future research aimed at improving generalizability in genetic risk prediction for PD.

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.

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia.

Africa is the second most populous continent and is expected to host 26% of the global population by 2050.5 Despite exhibiting the highest genetic variation and complex admixture, African populations are significantly underrepresented in PD research, with only a fraction of their extensive genetic diversity being surveyed, primarily focusing on Mendelian genes associated with monogenic PD. Genetic studies have characterized a limited number of Africa's 2000 ethnolinguistic groups, mainly using genotyping arrays with variants common in Europeans, leaving the distribution of novel, rare, and medically relevant variations largely unknown. For instance, although the LRRK2 p.G2019S variant is present in 1% to 2% of Europeans PD patients, 29.7% of familial Ashkenazi Jewish PD patients, and 40% of North African Arabs, it has not been identified in Black Africans to date. Given Africa's ethnic and genetic diversity, including these populations is crucial for understanding novel genetic determinants underlying PD risk, onset, and progression. Research capacity and research infrastructure in Africa remain limited, with PD genetic research facing challenges, including political and economic instability, a predominant focus on infectious diseases, limited medical personnel, and insufficient funds and infrastructure.

Genome-wide association study of Parkinson’s disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinson’s Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p. Met393Thr as an independent genome-wide significant signal. Additionally, a novel independent signal, SCARB2 rs11547135, was detected. The burden analysis linked PD to SCARB2 in African American, Ashkenazi Jewish and East Asian cohorts. Single variants-based tests identified rare missense variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.

The RAB32 p.Ser71Arg variant is a novel cause of monogenic Parkinson's disease (PD), for which detailed phenotypic information is currently scarce. Our aim was to clinically and biologically characterize individuals with PARK-RAB32 to gain insights into genotype–phenotype relationships, disease severity, and underlying pathology. We conducted a literature review following the MDSGene protocol, alongside detailed phenotyping of 11 PARK-RAB32 patients and one prodromal individual from the Rostock International PD (ROPAD) study. In addition to comprehensive scale-based assessments, including olfactory testing, we obtained neuroimaging data and various biomaterials, and performed α-synuclein seeding assays (SAA) in cerebrospinal fluid in a subset. 83 patients (72 from the literature) were included in the analysis. The median age at onset was 54 (IQR: 46–61) years. Typical parkinsonism with a favorable dopaminergic response was observed in all patients. In our cohort, after a median disease duration of 11 years (IQR: 7–19.5), the mean Movement Disorders Society Modified Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III score was 38.5 ± 21.8 points. Targeted testing revealed autonomic symptoms were present in all individuals, and 10 of 11 patients had hyposmia. Misfolded α-synuclein was identified in 2 of 2 patients, but not in the prodromal individual. 123I-FP-CIT imaging was available for eight patients, revealing neurodegeneration in all of them. While PARK-RAB32 is clinically and likely pathologically similar to idiopathic PD, our study underscores the importance of carefully assessing non-motor symptoms in this newly described form of PD. According to SynNeurGe criteria, PARK-RAB32 is classified as S+ (evidence of synucleinopathy), N+ (neurodegeneration supported by imaging data), and GP+ (presence of a genetic variant).

Parkinson's disease (PD) is the second most common neurodegenerative disease following Alzheimer's disease. Nearly 30 causative genes have been identified for PD and related disorders. However, most of these genes were identified in European-derived families, and little is known about their role in Latin American populations. Our goal was to assess the spectrum and frequency of pathogenic variants in known PD genes in familial PD patients from Latin America. We selected 335 PD patients with a family history of PD from the Latin American Research Consortium on the Genetics of PD. We capture-sequenced the coding regions of 26 genes related to neurodegenerative parkinsonism. Of the 335 PD patients, 324 had sufficient sequencing coverage to be analyzed. We identified pathogenic variants in 41 individuals (12.7%) in FBXO7, GCH1, LRRK2, PARK7, PINK1, PLA2G6, PRKN, SNCA, and TARDBP, GBA1 risk variants in 25 individuals (7.7%), and variants of uncertain significance in another 24 individuals (7.4%) in ATP13A2, ATP1A3, DNAJC13, DNAJC6, GBA1, LRKK2, PINK1, VPS13C, and VPS35. Of the 70 unique variants identified, 19 were more frequent in Latin Americans than in any other population. This is the first screening of known PD genes in a large cohort of patients with familial PD from Latin America. There were substantial differences in the spectrum of variants observed in comparison to previous findings from PD families of European origin. Our data provide further evidence that differences exist between the genetic architecture of PD in Latinos and European-derived populations.

To clarify the association between SH3GL2 and PD, we leveraged whole-genome sequencing (WGS) data from the Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD; https://amp-pd.org/) release 3.0, consisting of 3,105 cases and 3,670 controls from European descent, and large-scale genotyping imputed data from the Global Parkinson's Genetics Program (GP2; https://gp2.org/) release 5.0, consisting of 12,728 cases and 10,533 controls from 10 different ancestries.

About 5% to 10% of Parkinson's disease (PD) cases are monogenic; otherwise PD is generally known to be idiopathic. Although more than a dozen genes that contain disease-causing mutations have been identified to date, PRKN is the most frequently mutated gene in autosomal recessive early-onset PD (EOPD). However, the genetic cause of patients with a typical PRKN phenotype is sometimes elusive because of the limitations of traditional genetic methods to detect complex structural mutations that are frequent in PRKN. The phenotype is usually specific, consisting of a slowly progressive EOPD with a good and long-standing response to levodopa. Dystonia, dyskinesia, and motor fluctuations are typical, whereas autonomic dysfunction, psychotic symptoms, and cognitive decline are usually absent. We report 2 siblings of European ancestries exhibiting PRKN phenotype left undiagnosed for years after multiple genetic investigations.

Elucidating the genetic contributions to Parkinson’s disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among PD patients, with a frequency of 4% in our case cohort. Out of the 18 GBA1 variants identified, ten were previously classified as pathogenic or likely pathogenic, four were novel, and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met, and p.Glu365Lys, were not identified among the screened PD cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in PD etiology among West African-ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance overrepresented in cases, two of which — p.Glu268Ala and p.Arg1538Cys — had a higher prevalence in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile PD in these populations. Novel genetic variation overrepresented in cases versus controls among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalog of both known and novel coding and splicing variants potentially linked to PD etiology in an underserved population. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future PD treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.