Global Parkinson's Genetics Program (GP2)

Introduction

<div class="infobox infobox-institution">
{| class="infobox-table"
| colspan="2" class="infobox-header" | Global Parkinson's Genetics Program (GP2)
|-
| Established | 2019
|-
| Type | International Genetics Initiative
|-
| Focus | Large-scale PD genetics in diverse populations
|-
| Funding | $25M+ (Michael J. Fox Foundation)
|-
| Sample Size Target | 150,000+ genomes
|}
</div>

The Global Parkinson's Genetics Program (GP2) is an ambitious international initiative to understand the genetic basis of Parkinson's disease through large-scale genomic studies across diverse populations. Launched in 2019 with funding from the [Michael J. Fox Foundation](/institutions/michael-j-fox-foundation), GP2 aims to accelerate precision medicine for PD by identifying genetic risk factors and understanding how they influence disease progression and treatment response.

Background and Rationale

The Diversity Gap in PD Genetics

Prior to GP2, the vast majority of PD genetic studies focused on populations of European ancestry, leaving significant gaps in understanding:

• Genetic risk in populations of African, Asian, and Indigenous ancestry
• Population-specific variants and risk factors
• Gene-environment interactions in diverse populations

Program Launch

GP2 was launched to address these gaps through:

• Massive-scale genomic data collection
• Standardized protocols across global sites
• Open data sharing and collaboration
• Capacity building in understudied regions

Research Objectives

Primary Goals

...

Introduction

<div class="infobox infobox-institution">
{| class="infobox-table"
| colspan="2" class="infobox-header" | Global Parkinson's Genetics Program (GP2)
|-
| Established | 2019
|-
| Type | International Genetics Initiative
|-
| Focus | Large-scale PD genetics in diverse populations
|-
| Funding | $25M+ (Michael J. Fox Foundation)
|-
| Sample Size Target | 150,000+ genomes
|}
</div>

The Global Parkinson's Genetics Program (GP2) is an ambitious international initiative to understand the genetic basis of Parkinson's disease through large-scale genomic studies across diverse populations. Launched in 2019 with funding from the [Michael J. Fox Foundation](/institutions/michael-j-fox-foundation), GP2 aims to accelerate precision medicine for PD by identifying genetic risk factors and understanding how they influence disease progression and treatment response.

Background and Rationale

The Diversity Gap in PD Genetics

Prior to GP2, the vast majority of PD genetic studies focused on populations of European ancestry, leaving significant gaps in understanding:

• Genetic risk in populations of African, Asian, and Indigenous ancestry
• Population-specific variants and risk factors
• Gene-environment interactions in diverse populations

Program Launch

GP2 was launched to address these gaps through:

• Massive-scale genomic data collection
• Standardized protocols across global sites
• Open data sharing and collaboration
• Capacity building in understudied regions

Research Objectives

Primary Goals

Expand Genetic Understanding: Identify novel risk genes in diverse populations

Characterize Rare Variants: Discover low-frequency variants with high impact

Enable Precision Medicine: Support genotype-stratified clinical trials

Build Global Capacity: Train the next generation of PD researchers

Sample Collection Targets

| Population Group | Target Samples | Status |
|------------------|----------------|--------|
| European ancestry | 50,000 | Near target |
| African ancestry | 30,000 | Expanding |
| East Asian | 25,000 | Active |
| South Asian | 25,000 | Active |
| Latin American | 15,000 | Starting |
| Other/Mixed | 15,000 | Developing |

Consortium Structure

Lead Institutions

GP2 is coordinated by a steering committee:

• Data Coordinating Center: University of Washington
• Sequencing Centers: Regeneron Genetics Center, Broad Institute
• Analysis Teams: Multiple academic partners

Regional Networks

| Region | Lead Institution | Countries Represented |
|--------|-----------------|----------------------|
| North America | NIH, Michael J. Fox Foundation | USA, Canada |
| Europe | Wellcome Sanger Institute | UK, Germany, France |
| Latin America | University of São Paulo | Brazil, Argentina |
| Africa | University of Cape Town | South Africa, Nigeria |
| Asia | RIKEN, Seoul National University | Japan, Korea |

Scientific Approach

Study Design

GP2 employs multiple complementary approaches:

1. Genome-Wide Association Studies (GWAS)

• Array genotyping across all cohorts
• Imputation to reference panels
• Meta-analysis across populations

2. Whole Exome Sequencing (WES)

• Focus on rare, protein-altering variants
• Family-based studies for Mendelian forms
• Case-control analysis

3. Whole Genome Sequencing (WGS)

• Deep sequencing of selected cohorts
• Detection of structural variants
• Non-coding regulatory variant analysis

Data Analysis Pipeline

Sample Collection → Genotyping/ Sequencing →
QC and Harmonization → Population-specific Analysis →
Cross-population Meta-analysis → Functional Validation →
Drug Target Identification

Key Findings to Date

Risk Loci Discovery

GP2 has contributed to identifying novel PD risk genes:

| Gene | Population | Discovery Method | Impact |
|------|------------|------------------|--------|
| GBA1 | Multiple | WES | Major risk factor |
| LRRK2 | Multiple | GWAS | Common risk |
| New loci | Diverse | GWAS meta-analysis | Novel discoveries |

Population-Specific Findings

| Population | Key Finding | Clinical Implication |
|------------|-------------|---------------------|
| East Asian | Novel risk alleles | Population-specific testing |
| African | LRRK2 variants | Genetic counseling |
| South Asian | GBA1Founder effects | Carrier screening |

Collaboration with Drug Development

Accelerating Medicines Partnership (AMP-PD)

GP2 is closely integrated with the NIH's [AMP-PD](/institutions/amp-pd) program:

• Shared data resources
• Coordinated analysis efforts
• Joint publication initiatives

Support for Clinical Trials

Genetic data from GP2 enables:

| Application | Example |
|-------------|---------|
| Patient stratification | GBA carrier trials |
| Target validation | LRRK2 inhibitor trials |
| Biomarker development | Genetic progression markers |
| Precision recruitment | Genotype-specific enrollment |

Data Resources and Tools

GP2 Data Portal

GP2 provides open-access data resources:

• Variant Browser: Search genetic variants by gene or region
• Summary Statistics: GWAS results for download
• Cohort Descriptions: Metadata for all contributing studies

Analysis Tools

| Tool | Purpose |
|------|---------|
| GP2 Browser | Variant lookups |
| MAGMA | Gene set enrichment |
| PRSice | Polygenic risk scores |
| LDpred | PRS calculation |

Impact on Drug Development

Target Discovery

GP2 findings have informed drug development programs:

| Target | Approach | Development Stage |
|--------|----------|-------------------|
| LRRK2 | Kinase inhibitors | Phase II/III |
| GBA1 | Chaperone therapy | Phase I/II |
| ATP13A9 | Lysosomal function | Preclinical |

Repurposing Opportunities

Genetic findings enable drug repurposing:

• GBA modulators: Originally developed for Gaucher disease
• LRRK2 inhibitors: Originally developed for cancer
• [Autophagy](/entities/autophagy) enhancers: Various existing compounds

Training and Capacity Building

Fellowship Program

GP2 supports early-career researchers:

• Postdoctoral fellowships
• Visiting scientist awards
• Computational training workshops

Global Network Development

The program builds research capacity:

• Sample collection training
• Data analysis workshops
• Scientific exchange programs

Future Directions

Phase III Expansion (2024-2028)

Complete 150,000 genomes: Achieve full target sample size

Functional genomics: Integrate iPSC and model organism studies

Clinical translation: Implement genetic testing pathways

Longitudinal studies: Link genetics to progression

Precision Medicine Implementation

GP2 aims to enable:

• Genetic testing for PD diagnosis
• Risk stratification for prevention trials
• Genotype-guided treatment selection

See Also

• [International Parkinson's Disease Genomics Consortium](/institutions/ipdgc)](/institutions)
• [Parkinson's Disease Drug Repurposing Consortia](/institutions/parkinsons-disease-repurposing-consortia)](/institutions)
• [Michael J. Fox Foundation](/institutions/michael-j-fox-foundation)](/institutions)
• [Parkinson's Disease](/diseases/parkinsons-disease)](/proteins/parkin)
• [GBA1](/genes/gba1)](/genes)
• [LRRK2](/genes/lrrk2)

References

Unknown, Global Parkinson's Genetics Program (n.d.)

Unknown, GP2 Data Portal (n.d.)

Unknown, Michael J. Fox Foundation GP2 (n.d.)

Unknown, GP2 Publications (n.d.)

Unknown, Accelerating Medicines Partnership for Parkinson's Disease (n.d.)