The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population
By onLRRK2-PD represents the most common form of autosomal dominant Parkinson’s disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals. Carriers with available genotyping data shared a common haplotype. The clinical presentation resembles other LRRK2-PD forms. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, we provide evidence that LRRK2 p.L1795F is pathogenic.
Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease
By onThe Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset ≤35 years. We identified pathogenic variants in LRRK2 in 4.2% of families, and biallelic pathogenic variants in PRKN in 3.6% of families. We also identified two families with SNCA duplications and three families with a pathogenic repeat expansion in ATXN2, as well as single families with pathogenic variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk GBA1 variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.
Investigating the Protective Role of the Mitochondrial 2158 T > C Variant in Parkinson’s Disease
By onHudson et al. proposed a protective role of two mitochondrial DNA variants in PD etiology. In an array-based genotyping study, the authors showed that the m.2158 T > C (p.Lys4Arg, rs41349444) variant in SHLP2 is associated with reduced risk for PD (P-value = 2 × 10−2, OR = 0.32). A follow-up functional study by Kim et al. demonstrated that the mutated protein was protective against mitochondrial dysfunction in both in vitro and in vivo models of PD. Nevertheless, the association of this variant with reduced risk of PD has not been confirmed in large-scale sequencing datasets. To further investigate the association between m.2158 T > C and PD, we conducted an extensive genetic characterization utilizing large-scale genome sequencing (GS) datasets, totaling 4358 PD cases and 16,609 controls.
Team Science Approaches to Unravel Monogenic Parkinson’s Disease on a Global Scale
By onIn 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.
Insights into ancestral diversity in Parkinson’s disease risk: a comparative assessment of polygenic risk scores
By onRisk 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.
Global Perspectives on Returning Genetic Research Results in Parkinson Disease
By onAiming 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.
Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)
By onThe 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.
Advancing Parkinson’s Disease Research in Africa: A Strategic Training Framework of the Global Parkinson’s Genetics Program
By onAfrica 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.
Is SH3GL2 p.G276V the Causal Functional Variant Underlying Parkinson’s Disease Risk at this Locus?
By onTo 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.
Long-Read Sequencing Unravels the Complexity of Structural Variants in PRKN in Two Individuals with Early-Onset Parkinson’s Disease
By onAbout 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.
Genome-wide association analyses reveal susceptibility variants linked to Parkinson’s disease in the South African population using inferred global and local ancestry
By onGenome-wide association studies (GWAS) have been successful in identifying over 100 loci associated with Parkinson’s disease (PD) susceptibility. However, the majority of these studies have focused on European cohorts with few including diverse ancestries. Using genotyped and imputed data from 691 South African PD cases and 826 controls, we conducted a conventional GWAS, two local ancestry GWAS (LA-GWAS) approaches (one using local ancestry as a covariate and the other separating the dosage per ancestry), and an association analysis to identify regions of homozygosity associated with PD status. Furthermore, we replicated these findings using another admixed population, a Latin American cohort (LARGE-PD). The ancestry inference suggested that the South African cohort is admixed from five populations, including African (AFR), European (EUR), Malaysian (MAL), Nama (NAMA), and South Asian (SAS), though with varying accuracy levels. The conventional GWAS successfully identified one locus (rs17098735-T) with genome-wide significance (p-value: 1.23×10-8; beta= 2.286; SE= 0.401). Within the local ancestry window of the top GWAS hit, among individuals carrying the variant, 86.7% had AFR ancestry, 11% NAMA ancestry, and 2.2% MAL ancestry, with no EUR or SAS ancestry observed, highlighting a potential ancestry-specific genetic risk factor. Three lead loci were replicated in the LARGE-PD cohort. LA-GWAS using the Cochran-Armitage trend test identified 35 lead SNPs above suggestive significance after multiple test correction. Tractor-based approaches identified three lead loci when analyzing all five ancestry components jointly, as well as three additional lead loci in the AFR-only component, highlighting ancestry-specific loci that may contribute to genetic risk in diverse populations. For the LA-GWAS, one independent locus was replicated in LARGE-PD. Our findings suggest ancestry specificity in PD risk and underscores the importance of including diverse populations in genetics research. The study contributes towards a global understanding of the genetic etiology underlying PD.
The age at onset of LRRK2 p.Gly2019Ser Parkinson’s disease across ancestries and countries of origin
By onThe LRRK2 p.Gly2019Ser pathogenic variant has reduced penetrance and presents a wide range of age at onset (AAO) in patients with Parkinson’s disease (PD). We aim to elucidate differences in the cumulative incidence of LRRK2 p.Gly2019Ser-related PD (LRRK2-PD) between ancestries and countries. We included N=922 unrelated LRRK2 p.Gly2019Ser variant carriers (affected: N=762, unaffected: N=160) from the Global Parkinson’s Genetics Program (GP2) in addition to cohorts recruited from the Israeli Ashkenazi Jewish and Tunisian Arab-Berber population. The p.Gly2019Ser variant was present in five ancestries: Ashkenazi Jewish (N=534), North African (N=223), European (N=132), Middle Eastern (N=19) and Latino and Indigenous people of the Americas (N=14). In addition to ancestry derived from the genetic data, we assessed the country of origin in our analysis. The Cox proportional-hazards model and Kaplan-Meier analysis were applied to examine differences in cumulative incidence. All analyses were adjusted for biological sex, and the outcome variable was AAO, including affected and unaffected variant carriers with right censoring for affection status, and all analysis were exploratory. The median AAO of LRRK2-PD was five years younger in the North African (HR=1.48, 95% CI: 1.18-1.86, p=7.0×10−4) compared to the European ancestry group. In contrast, the median AAO was five years older in the Ashkenazi Jewish (HR=0.61, 95% CI: 0.50-0.75, p=4.0×10−6) compared to the European ancestry group. Additionally, patients from Israel (HR=1.59, 95% CI: 1.30-1.39, p=4.0×10−6) and Tunisia (HR=2.57, 95% CI: 2.16-3.06, p<2.0×10−16) had a median 5-year and 10-year younger AAO compared to patients from the USA, respectively. Lastly, when focusing only on individuals with an Ashkenazi Jewish background, patients from Israel still had a younger AAO than those from the USA (HR=1.82, 95% CI: 1.48-2.24, p=1.5×10−8). Analogously, assessing only patients from the USA, the Ashkenazi Jewish ancestry group still had an older AAO than the European ancestry group (HR=0.51, 95% CI: 0.39-0.67, p=1.3×10−6).
Deciphering the Genetic Architecture of Parkinson’s Disease in India
By onThe genomic landscape of the Indian population, particularly for age-related disorders like Parkinson’s disease (PD) remains underrepresented in global research. Genetic variability in PD has been studied predominantly in European populations, offering limited insights into its role within the Indian population. To address this gap, we conducted the first pan-India genomic survey of PD involving 4,806 cases and 6,364 controls, complemented by a meta-analysis integrating summary statistics from a multi-ancestry PD meta-analysis (N=611,485). We further leveraged RNA-sequencing data from lymphoblastoid cell lines of 731 individuals from the 1000 Genomes project to evaluate the expression of key loci across global populations. Our findings reveal a higher genetic burden of PD in the Indian population compared to Europeans, accounting for ∼30% of the previously unexplained heritability. Thirteen genome-wide significant loci were identified, including two novel loci, with an additional three loci uncovered through meta-analysis. Polygenic risk score analysis showed moderate transferability from European populations. Our results highlight the importance of genetic loci in immune function, lipid metabolism and SNCA aggregation in PD pathogenesis, with gene expression variability emphasizing population-specific differences. We also established South Asia’s largest PD biobank, providing a foundation for patient-centric approaches to PD research and treatment in India.
Validation of a Mitochondrial Polygenic Score for Parkinson’s Disease
By onMitochondrial dysfunction is a key player in Parkinson’s disease (PD) pathogenesis. Mitochondrial polygenic scores (MGS) may be associated with PD but require validation across diverse populations. To validate the association between the MGS, PD status and age-at-onset (AAO) in idiopathic and LRRK2-PD across various ancestries. We analyzed data from 17,129 PD patients and 13,872 healthy individuals across 10 ancestries within the Global Parkinson’s Disease Genetic Program. We used regression models to assess the association between MGS, PD status and AAO. The MGS was associated with iPD in Europeans (β=0.19, SE=0.02, p<2.0×10−16) and Ashkenazi Jews (β=0.26, p=3.7×10-4) but not in other populations. Additionally, the MGS was strongly associated with LRRK2-PD status (β=0.82, p=2.0×10−16). No associations with AAO were observed. The MGS is robustly associated with iPD status in Europeans and Ashkenazi Jews and with LRRK2-PD status. Population-specific MGS are needed to improve accuracy in other ancestries.
Novel Parkinson’s Disease Genetic Risk Factors Within and Across European Populations
By onWe conducted a meta-analysis of Parkinson’s disease genome-wide association study summary statistics, stratified by source (clinically-recruited case-control cohorts versus population biobanks) and by general European versus European isolate ancestries. This study included 63,555 cases, 17,700 proxy cases with a family history of Parkinson’s disease, and 1,746,386 controls, making it the largest investigation of Parkinson’s disease genetic risk to date. The final combined cross-European meta-analysis identified 134 risk loci (59 novel), with a total of 157 independent signals, significantly expanding our understanding of Parkinson’s disease risk. Multi-omic data integration revealed that expression of the nominated risk genes are highly enriched in brain tissues, particularly in neuronal and astrocyte cell types. Additionally, we prioritized 33 high-confidence genes across these 134 loci for future follow-up studies.
Does COMT Play a Role in Parkinson’s Disease Susceptibility Across Diverse Ancestral Populations?
By onThe catechol-O-methyltransferase (COMT) gene is involved in brain catecholamine metabolism, but its association with Parkinson’s disease (PD) risk remains unclear. To investigate the relationship between COMT genetic variants and PD risk across diverse ancestries. We analyzed COMT variants in 2,251 PD patients and 2,835 controls of European descent using whole-genome sequencing from the Accelerating Medicines Partnership-Parkinson Disease (AMP-PD), along with 20,427 PD patients and 11,837 controls from 10 ancestries using genotyping data from the Global Parkinson’s Genetics Program (GP2). Utilizing the largest case-control datasets to date, no significant enrichment of COMT risk alleles in PD patients was observed across any ancestry group after correcting for multiple testing. Among Europeans, no correlations with cognitive decline, motor function, motor complications, or time to LID onset were observed. These findings emphasize the need for larger, diverse cohorts to confirm the role of COMT in PD development and progression.
Large-scale genetic characterization of Parkinson’s disease in the African and African admixed populations
By onElucidating 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.
Parkinson’s Disease Pathogenic Variants: Cross-Ancestry Analysis and Microarray Data Validation
By onThis study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of pathogenic variants across ancestries. We analyzed the presence and allele frequency of 34 pathogenic variants in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinson’s Genetics Program dataset. Of these, 25 were genotyped on NBA and cluster plots were used to assess their quality. Genes previously predicted to have high or very high confidence of causing PD tend to have more pathogenic variants and are present across ancestry groups. Twenty-five of the 34 pathogenic variants were typed by the NBA array and classified “good” (n=12), “medium” (n=4), and “bad” (n=9) variants. Our results confirm the likelihood that established PD genes are pathogenic and highlight the importance of ancestrally diverse research in PD. We also show the usefulness of the NBA as a reliable tool for genotyping of rare variants for PD.
CNV-Finder: Streamlining Copy Number Variation Discovery
By onCopy Number Variations (CNVs) play pivotal roles in the etiology of complex diseases and are variable across diverse populations. Understanding the association between CNVs and disease susceptibility is significant in disease genetics research and often requires analysis of large sample sizes. One of the most cost-effective and scalable methods for detecting CNVs is based on normalized signal intensity values, such as Log R Ratio (LRR) and B Allele Frequency (BAF), from Illumina genotyping arrays. In this study, we present CNV-Finder, a novel pipeline integrating deep learning techniques on array data, specifically a Long Short-Term Memory (LSTM) network, to expedite the large-scale identification of CNVs within predefined genomic regions. This facilitates efficient prioritization of samples for time-consuming or costly subsequent analyses such as Multiplex Ligation-dependent Probe Amplification (MLPA), short-read, and long-read whole genome sequencing. We incorporate four genes to establish our methods—Parkin (PRKN), Leucine Rich Repeat And Ig Domain Containing 2 (LINGO2), Microtubule Associated Protein Tau (MAPT), and alpha-Synuclein (SNCA)—which may be relevant to neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Progressive Supranuclear Palsy (PSP), or related disorders such as essential tremor (ET). By training our models on expert-annotated samples and validating them across diverse cohorts, including those from the Global Parkinson’s Genetics Program (GP2) and additional dementia-specific databases, we demonstrate the efficacy of CNV-Finder in accurately detecting deletions and duplications. Our pipeline outputs app-compatible files for visualization within CNV-Finder’s interactive web application. This interface enables researchers to review predictions and filter displayed samples by model prediction values, LRR range, and variant count in order to explore or confirm results. Our pipeline integrates this human feedback to enhance model performance and reduce false positive rates. Through a series of comprehensive analyses and validations using visual inspection, MLPA, short-read, and long-read sequencing data, we demonstrate the robustness and adaptability of CNV-Finder in identifying CNVs with regions of varied size, probe density, and noise. Our findings highlight the significance of contextual understanding and human expertise in enhancing the precision of CNV identification, particularly in complex genomic regions like 17q21.31. The CNV-Finder pipeline is a scalable, publicly available resource for the scientific community, available on GitHub (https://github.com/GP2code/CNV-Finder; DOI 10.5281/zenodo.14182563). CNV-Finder not only expedites accurate candidate identification but also significantly reduces the manual workload for researchers, enabling future targeted validation and downstream analyses in regions or phenotypes of interest.
Genome-wide assessment identifies novel runs of homozygosity linked to Parkinson’s disease etiology across diverse ancestral populations
By onWe conducted the first large-scale, multi-ancestral investigation of Parkinson’s disease (PD) to examine the impact of genome-wide homozygosity on disease risk and age at onset. Using genotyping, imputed, and whole-genome sequencing (WGS) data from 16,599 PD cases and 13,585 controls across nine ancestral populations from the Global Parkinson’s Genetics Program, we aimed to identify novel regions of homozygosity contributing to PD heritability. Our findings suggest that ROH regions contribute to PD heritability in a global context, with a portion attributed to recessive allelic architecture. We developed an open-science framework for unbiased homozygosity mapping. Future studies should use larger, diverse cohorts and WGS data to uncover rare recessive variants linked to PD susceptibility.
