Assessment of common genetic variation in Alzheimer’s and Parkinson’s diseases reveals global distinction in population attributable risk
By onEmerging evidence suggests that the genetic architecture of Alzheimer’s (AD) and Parkinson’s diseases (PD) risk varies across ancestries. This study seeks to explore distinct and universal genetic targets across individuals of Latino, African/African Admixed, East Asian, and European populations by implementing Population Attributable Risk (PAR) comparisons on summary statistics from genome-wide association studies (GWAS). PAR was calculated for the most significant disease variants using summary statistics derived from select multi-ancestry GWAS meta-analyses, followed by fine-mapping analysis to validate genetic contribution of disease variants to European, African/African Admixed, East Asian, and Latino individuals. For both AD, APOE4 PAR estimates were universally high across all ancestries, with TSPAN14 and PICALM emerging as other common targets. Attributable risk varied across PD-related major risk loci including variation nearby GBA1 and LRRK2. In contrast, SNCA, MCCC1, VPS13C, and MAPT loci demonstrated comparable attributable risk across ancestries. This cross-ancestry evaluation of PAR reinforces the genetic heterogeneity of AD and PD. In consideration of the complex etiology of these diseases, these findings may inform the strategic prioritization of therapeutic targets and improve global health outcomes.
Parkinson’s Disease Gene Screening in Familial Cases from Central and South America
By onParkinson'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.
Sex-stratified analysis of the potential association between PGLYRP2 rs892145 variant and Parkinson’s disease across diverse ancestral populations
By onVariants in PGLYRP2, particularly rs892145-T, have been suggested as Parkinson’s disease (PD) risk factors. We analyzed data from 31,334 PD patients and 17,772 controls across diverse ancestries. A significant sex-dependent effect of rs892145-T was observed in African (AFR) ancestry males (OR=0.73, 95%CI: 0.57-0.94, p=0.014). Gene-based analyses identified another variant, rs7251871-A, as significantly associated with PD in AFR males (OR=1.34, 95%CI:1.13-1.59, p=6.65E-04, Bonferroni p=0.0432). No associations were observed in other ancestries. Further studies are needed to understand PGLYRP2’s role in PD.
RAB32-Linked Parkinson’s Disease: Deep Phenotyping, MDSGene Literature Review, and Application of SynNeurGe Criteria
By onThe 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).
Rare but Relevant: Assessing Variants in Dystonia-linked Genes in Parkinson’s Disease
By onDystonia and Parkinson’s disease (PD) show clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear. To assess the frequency of dystonia-linked pathogenic variants in PD, we screened sequencing data from 15,738 individuals (7,851 PD, 4,287 atypical parkinsonism, and 3,600 unaffected) from GP2 and AMP-PD for variants in genes linked to isolated dystonia, dystonia-parkinsonism, and myoclonus-dystonia. Pathogenic variants were only identified in PD patients. Forty-five PD individuals (0.57%) carried 26 distinct (likely) pathogenic variants in nine dystonia-linked genes, most frequently in GCH1, followed by VPS16. Though rare, pathogenic variants in dystonia-linked genes are present in clinically and pathologically diagnosed PD. Our results reinforce GCH1 as a PD-relevant gene with clinical implications, while variants identified in other genes are rare and of sometimes uncertain relation to the PD phenotype.
Genotype-phenotype association study conducted on LARGE-PD reveals novel loci associated with Parkinson’s Disease
By onThe Latin American Research Consortium on the Genetics of Parkinson’s Disease (LARGE-PD) is a multicenter collaboration aimed at understanding the genetic architecture of Parkinson’s disease (PD) in this underrepresented population using data from 15 countries across the Americas and the Caribbean. In this study, we conducted the largest genome-wide association studies (GWAS) for PD susceptibility in Latin Americans. We analyzed genotype data from LARGE-PD Phase 1 (n = 1,498) and Phase 2 (n = 4,401) using multiple GWAS approaches: SAIGE, which incorporates a genetic relationship matrix in the model; ATT, which includes global ancestry on the model; TRACTOR, which splits allele dosages by ancestry to detect ancestry-specific risk loci; and admixture mapping. We also assessed linkage disequilibrium (LD) patterns and performed Meta-Regression of Multi-AncEstry Genetic Association (MR-MEGA), integrating data from both LARGE-PD phases and two South Asian GWAS. We identified PD-associated loci on chromosomes 1 and 4. Our results replicated previous findings, including the well-established SNCA variant rs356182-A (OR = 1.517, p = 1.62×10−16). Notably, we identified a locus in ITPKB (rs117185933-A, OR = 1.75, p = 3.8×10−12), which had the highest CADD Phred score (17.92, top ∼3% most deleterious) among all candidate variants, suggesting strong functional relevance. Functional annotation predicted that this variant may create a premature start codon in the 5′ UTR of ITPKB. Although rs117185933-A is in high LD (r2 > 0.8) with a variant previously reported by Kishore et al., our LD analysis and MR-MEGA results indicate that this signal is correlated with ancestry heterogeneity and likely represents an independent PD risk locus and a novel putative causal variant. This variant is most frequent in Peruvians from the 1000 Genomes Project (MAF = 0.20) and more common in admixed American populations in gnomAD (MAF = 0.0835), but nearly absent in non-Finnish Europeans (MAF = 0.0002).
The Global Landscape of Genetic Variation in Parkinson’s disease: Multi-Ancestry Insights into Established Disease Genes and their Translational Relevance
By onThe genetic architecture of Parkinson’s disease (PD) varies considerably across ancestries, yet most genetic studies have focused on individuals of European descent, limiting our insights into the genetic architecture of PD at a global scale. We conducted a large-scale, multi-ancestry investigation of causal and risk variants in PD-related genes. Using genetic datasets from the Global Parkinson’s Genetics Program, we analyzed sequencing and genotyping data from 69,881 individuals, including 41,139 affected and 28,742 unaffected, from eleven different ancestries, including ∼30% of individuals from non-European ancestries. Our findings revealed shared and ancestry-specific patterns in the prevalence and spectrum of PD-associated variants. Overall, ∼2% of affected individuals carried a causative variant, with substantial variations across ancestries ranging from 10% in Middle Eastern and Ashkenazi Jewish ancestries. Including disease-associated GBA1 and LRRK2 risk variants raised the yield to ∼12.5%, largely driven by GBA1, except in East Asians, where LRRK2 risk variants dominated. GBA1 variants were most frequent globally, albeit with substantial differences in frequencies and variant spectra. While GBA1 variants were identified across all ancestries, frequencies ranged from 3·4% in Middle Eastern to 51·7% in African ancestry. Similarly, LRRK2 variants showed ancestry-specific enrichment, with G2019S most frequently seen in Middle Eastern and Ashkenazi Jewish, and risk variants predominating in East Asians. However, clinical trials targeting proteins encoded by these genes are primarily based in Europe and North America.
TMEM175, SCARB2 and CTSB associations with Parkinson’s disease risk across populations
By onGenome-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.
Global Parkinson’s Genetics Program Data Release 7
By onIn December 2025, GP2 announced the 11th data release on the Terra and the Verily® Workbench platforms in collaboration with AMP® PD. This release includes 20,842 additional genotyped participants, 17,153 additional WGS participants, and 4,232 additional clinical exomes. - The genotype array (NBA) data, including locally-restricted samples, now consists of a total of 103,786 genotyped participants (46,327 PD cases, 28,857 Controls, and 28,602 ‘Other’ phenotypes). - The whole genome sequencing (WGS) data now consists of a total of 38,226 sequenced participants (18,219 PD cases, 9,172 Controls, and 10,835 ‘Other’ phenotypes). - The clinical exome data now consists of 14,648 samples with PD. - Of the 122,317 unique samples with genetic data (NBA, WGS, or clinical exome), 32,897 individuals also have additional extended clinical information. Please see the accompanying blog for further description of this release. To obtain data access, please see https://amp-pd.org/researchers/data-use-agreement. For any publications using data from this release, please reference the DOI number and the following statement: "Data (DOI 10.5281/zenodo.17753486, release 11) and/or code used in the preparation of this article were obtained from Global Parkinson’s Genetics Program (GP2). GP2 is funded by the Aligning Science Across 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."
Global Parkinson’s Genetics Program Data Release 8
By onIn September 2024, GP2 announced the eighth data release on the Terra and the Verily® Workbench platforms in collaboration with AMP® PD. This release includes 5,481 additional whole genome sequences and 10,454 clinical exome sequences. Additional genotyping will be provided in the following release. - The whole genome sequencing (WGS) data now consists of a total of 7,734 sequenced participants (6,113 PD cases, 617 Controls, and 1,004 ‘Other’ phenotypes). - Additionally, included in this WGS release is a partial release of whole genome sequences from two AMP® PD cohorts (BioFind and PPMI) that have been joint-called with GP2 WGS. Released samples can be linked back to the original AMP® PD IDs through an ID crosswalk file included with the release. - This release also includes 10,454 joint-called clinical exome sequencing participants from the Parkinson’s Foundation. - This release includes a total of 62,087 individuals who have core clinical data available. Among these, 16,800 individuals have deep clinical phenotyping and genetic data available. Please see the accompanying blog for further description of this release. To obtain data access, please see https://amp-pd.org/researchers/data-use-agreement. For any publications using data from this release, please reference the DOI number and the following statement: "Data (DOI 10.5281/zenodo.10962119, release 8) used in the preparation of this article were obtained from the Global Parkinson’s Genetics Program (GP2)."
Global Parkinson’s Genetics Program Data Release 9
By onIn December 2024, GP2 announced the 9th data release on the Terra and the Verily® Workbench platforms in collaboration with AMP® PD. This release includes 17,690 additional genotyped participants. The genotype array data, including locally-restricted samples, now consists of a total of 71,835 genotyped participants (31,985 PD cases, 18,249 Controls, and 21,601 ‘Other’ phenotypes) When removing the locally-restricted samples, these now consist of 55,305 samples (23,709 PD cases, 13,404 Controls, and 18,192 ‘Other’ phenotypes) Of those 71,835 samples with genotyped data: 16,800 individuals also have deep clinical phenotyping information (Release 8) 10,454 total individuals also have clinical exomes information (Release 8) 7,732 total individuals also have WGS data (Release 8) Please see the accompanying blog for further description of this release. To obtain data access, please see https://amp-pd.org/researchers/data-use-agreement. For any publications using data from this release, please reference the DOI number and the following statement: "Data (DOI 10.5281/zenodo.14510099, release 9) and/or code used in the preparation of this article were obtained from Global Parkinson’s Genetics Program (GP2). GP2 is funded by the Aligning Science Across 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."
Global Parkinson’s Genetics Program Data Release 10
By onIn July 2025, GP2 announced the 10th data release on the Terra and the Verily® Workbench platforms in collaboration with AMP® PD. This release includes 11,109 additional genotyped participants and 13,339 additional WGS participants. The genotype array (NBA) data, including locally-restricted samples, now consists of a total of 82,944 genotyped participants (36,939 PD cases, 19,821 Controls, and 26,184 ‘Other’ phenotypes). When removing the locally-restricted samples, these now consist of 65,303 samples (28,586 PD cases, 15,258 Controls, and 21,459 ‘Other’ phenotypes). The whole genome sequencing (WGS) data now consists of a total of 21,073 sequenced participants (8,134 PD cases, 3,531 Controls, and 9,408 ‘Other’ phenotypes). When removing the locally-restricted samples, these now consist of 16,608 participants (6,801 PD cases, 3,244 Controls, and 6,563 ‘Other’ phenotypes). Of note, cases recruited via the Monogenic network are coded as ‘Other’. The clinical exome data now consists of 10,454 samples with PD (Release 8). Of the 92,021 unique samples with genetic data (NBA, WGS, or clinical exome), 26,982 individuals also have additional extended clinical information. Please see the accompanying blog for further description of this release. To obtain data access, please see https://amp-pd.org/researchers/data-use-agreement. For any publications using data from this release, please reference the DOI number and the following statement: "Data (DOI 10.5281/zenodo.15748014, release 10) and/or code used in the preparation of this article were obtained from Global Parkinson’s Genetics Program (GP2). GP2 is funded by the Aligning Science Across 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."
Global Parkinson’s Genetics Program Data Release 11
By onIn December 2025, GP2 announced the 11th data release on the Terra and the Verily® Workbench platforms in collaboration with AMP® PD. This release includes 20,842 additional genotyped participants, 17,153 additional WGS participants, and 4,232 additional clinical exomes. - The genotype array (NBA) data, including locally-restricted samples, now consists of a total of 103,786 genotyped participants (46,327 PD cases, 28,857 Controls, and 28,602 ‘Other’ phenotypes). - The whole genome sequencing (WGS) data now consists of a total of 38,226 sequenced participants (18,219 PD cases, 9,172 Controls, and 10,835 ‘Other’ phenotypes). - The clinical exome data now consists of 14,648 samples with PD. - Of the 122,317 unique samples with genetic data (NBA, WGS, or clinical exome), 32,897 individuals also have additional extended clinical information. Please see the accompanying blog for further description of this release. To obtain data access, please see https://amp-pd.org/researchers/data-use-agreement. For any publications using data from this release, please reference the DOI number and the following statement: "Data (DOI 10.5281/zenodo.17753486, release 11) and/or code used in the preparation of this article were obtained from Global Parkinson’s Genetics Program (GP2). GP2 is funded by the Aligning Science Across 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."
2025: A Year in Review
We are proud to share how we impacted the Parkinson’s disease research field in 2025. Read our report to see how the infrastructure and processes we established are changing the way science is done and are generating significant momentum.
100,000 Participants and Counting – Massive Global Genetic Dataset Powers Discoveries in Parkinson’s Disease
Researchers have reached a major milestone in the effort to understand and treat Parkinson’s disease: more than 100,000 DNA samples from study participants around the world have now been genotyped and sequenced through the Global Parkinson’s Genetics Program (GP2).
GP2’s 11th Data Release
GP2 announced its 11th data release at the end of 2025, bringing the total to over 100,000 samples from individuals worldwide, making it one of the most comprehensive and globally representative PD datasets to date.
ASAP Research Round-Up | Q3 2025
In this second edition of the ASAP Research Round-Up, ASAP shares advancements in Q2 2025 across the ASAP portfolio that fill critical knowledge gaps, promote rapid dissemination of scientific insights, expand resource accessibility, and support the next generation of Parkinson’s researchers.
Decoding Parkinson’s Genetics on a Global Scale with Andy Singleton and Sonya Dumanis
ASAP’s Sonya Dumanis, PhD, and Andrew Singleton, PhD, joined The Genetics Podcast to discuss their recent publication in the American Journal of Human Genetics. In the episode, they emphasize the importance of increasing genetic diversity in Parkinson’s disease research and highlight GP2’s role in creating a scalable roadmap for building global research collaborations that can be adapted to other diseases and regions.
ASAP Research Round-Up | Q2 2025
In this second edition of the ASAP Research Round-Up, ASAP shares advancements in Q2 2025 across the ASAP portfolio that fill critical knowledge gaps, promote rapid dissemination of scientific insights, expand resource accessibility, and support the next generation of Parkinson’s researchers.
ASAP Research Round-Up | Q1 2025
In this first edition of the ASAP Research Round-Up, ASAP shares advancements in Q1 2025 across the ASAP portfolio that fill critical knowledge gaps, promote rapid dissemination of scientific insights, expand resource accessibility, and support the next generation of Parkinson’s researchers.
