The Global Landscape of Genetic Variation in Parkinson's disease: Multi-Ancestry Insights into Established Disease Genes and their Translational Relevance

Abstract

Background: The 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.

Methods: 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.

Findings: 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 <0·5% in African, African-admixed, and Central Asian to >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.

Interpretation: This large-scale, multi-ancestry assessment offers crucial insights into the population-specific genetic architecture of PD. It underscores the critical need for increased diversity in PD genetic research to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure the equitable development and application of emerging precision therapies.

Keywords: GBA1; Genetics; LRRK2; Multi-ancestry; PD; PRKN; SNCA; causal variants; precision medicine; risk variants.

Figure 1.. Study workflow.

We used short-read sequencing and genome-wide genotyping data and investigated variants in 18 genes linked to PD and parkinsonism. Pathogenic/likely pathogenic variants according to ClinVar and/or ACMG criteria are referred to as causative variants, and selected variants with an established PD-risk association are referred to as risk variants. Figure created with BioRender. * For the purpose of this study and in the context of PD, all variants in GBA1 (including variants causal for Gaucher’s disease) are considered PD risk variants (regardless of their Gaucher’s severity). ** Select LRRK2 variants with established PD-risk associations included rs33949390 (chr12:40320043:G:C, R1628P) and rs34778348 (chr12:40363526:G:A, G2385R). AAC = African Admixed, ACMG = American College of Medical Genetics and Genomics, AFR = African, AJ = Ashkenazi Jewish, AMR = Latinos and Indigenous people of the Americas, CAH = Complex Admixture, CES = clinical exome sequencing, CAS = Central Asian, EAS = East Asian, EUR = European, FIN = Finnish, GP2 = Global Parkinson’s Genetics Program, MDE = Middle Eastern, OR = Odds ratio, PD = Parkinson’s disease, SAS = South Asian, WGS = whole-genome sequencing

Figure 2.. Mutational and severity spectrum of GBA1 variants across ancestries.

Donut charts illustrate the spectrum of GBA1 variants identified across ancestries, stratified by variant severity. Severity was assessed using the GBA1-PD browser (https://pdgenetics.shinyapps.io/GBA1Browser/); notably, the newly identified c.1225–34C>A variant (rs3115534-G) is not yet included and was therefore grouped as unknown. Each segment size reflects the percentage of variant carriers within each ancestry. The inner colors represent variant severity categories: Severe (purple), Mild (blue), Risk (green), and Unknown (gray). The outer segments show individual variants, with color shades corresponding to the inner severity group. Due to the high number of different variants, for EAS, all severe variants with <3 carriers were grouped as “Other”, and for EUR, all variants with <10 carriers were grouped as “Other”. Similarly, due to the very small percentage of GBA1 variants other than c.1225–34C>A in AFR, all severe and mild variants were each grouped as “Other”. AAC = African Admixed, AFR = African, AJ = Ashkenazi Jewish, AMR = Latinos and Indigenous people of the Americas, CAH = Complex Admixture, CAS = Central Asian, EAS = East Asian, EUR = European, FIN = Finnish, MDE = Middle Eastern, SAS = South Asian.

Figure 3.. Distribution of variants in genes linked to Parkinson’s disease (PD) and parkinsonism across ancestries.

Horizontal stacked bar charts displaying the percentage of identified variant carriers per gene amongst all carriers per ancestry: (A) only variants considered causal (excluding genetically enriched cohorts), (B) causal and risk variants excluding genetically enriched cohorts, and (C) causal and risk variants including genetically enriched cohorts. Numbers in bars indicate the absolute number of carriers. Dual carriers harbor variants in two different genes (e.g., LRRK2 and GBA1). Atypical includes carriers of variants in ATP13A2, RAB39B, SLC20A2, and WDR45. LRRK2 risk variants are R1628P and G2385R. AAC = African Admixed, AFR = African, AJ = Ashkenazi Jewish, AMR = Latinos and Indigenous people of the Americas, CAH = Complex Admixture, CAS = Central Asian, EAS = East Asian, EUR = European, FIN = Finnish, MDE = Middle Eastern, SAS = South Asian.

Figure 4.. Global genetic spectrum of PD and locations of clinical trials targeting gene variant carriers.

(A) Donut charts displaying the percentage of identified carriers per gene amongst all carriers per ancestry. Dual carriers harbor variants in two different genes (e.g., LRRK2 and GBA1). Atypical includes carriers of variants in ATP13A2, RAB39B, SLC20A2, and WDR45. LRRK2 risk variants are R1628P and G2385R. (B) Global map of clinical trial locations recruiting gene variant carriers (GBA1, LRRK2, PINK1, and PRKN), obtained from the clinical trial registry https://clinicaltrials.gov/. Only one pin per gene and country is shown, regardless of the number of study sites within that country. AAC = African Admixed, AFR = African, AJ = Ashkenazi Jewish, AMR = Latinos and Indigenous people of the Americas, CAH = Complex Admixture, CAS = Central Asian, EAS = East Asian, EUR = European, FIN = Finnish, MDE = Middle Eastern, SAS = South Asian.

Figure 5.. Ancestry-Stratified Age at Onset in Idiopathic, GBA1-, and LRRK2-associated Parkinson’s Disease.

(A) Boxplots of ages at onset (AAO) for individuals with idiopathic Parkinson’s disease (IPD; gray), GBA1-associated PD (green), and LRRK2-linked PD (blue) grouped by ancestry. Boxes indicate interquartile ranges, horizontal lines represent median, and whiskers show the range. Outliers are plotted as individual points. Statistically significant group differences within ancestry based on linear regression are indicated by asterisks. (B) and (C) Violin plots of AAO for GBA1-associated PD (Panel B; green) and LRRK2-linked PD (Panel C; blue) across ancestries. Each violin reflects the distribution and median AAO within each ancestry group. AAC = African Admixed, AFR = African, AJ = Ashkenazi Jewish, AMR = Latinos and Indigenous people of the Americas, CAH = Complex Admixture, CAS = Central Asian, EAS = East Asian, EUR = European, FIN = Finnish, MDE = Middle Eastern, SAS = South Asian.