Multi-ancestry genome-wide association meta-analysis of Parkinson's disease

Abstract

Although over 90 independent risk variants have been identified for Parkinson's disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson's disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.

Fig. 1. MAMA study design.

Top panel: four ancestry groups used in the meta-analysis. Middle panel: MAMA and the two methods used. Random-effect (top) is better suited for risk variants with homogeneous effect direction across different ancestries, whereas MR-MEGA (bottom) can identify risk variants with heterogeneous effects due to population stratification introduced by ancestry differences. The densely dashed lines indicate Bonferroni adjusted suggestive threshold of two-sided P < 1 × 10⁻⁶, and the loosely dashed lines indicate Bonferroni adjusted significant threshold of two-sided P < 5 × 10⁻⁹. Bottom panel: downstream analyses and their examples. Created with Biorender.com.

Fig. 2. Manhattan plots of the meta-analysis results across 2,525,730 participants.

a, Random-effects model test. b, MR-MEGA meta-regression test (chi-squared test with df = 4). The x axis shows chromosome and base pair positions of each variant tested in the meta-analyses. The y axis shows the two-sided P value with no multiple-test correction in the −log₁₀ scale. Orange horizontal dashed line indicates the Bonferroni-adjusted significant threshold of P < 5 × 10⁻⁹. Gray horizontal dashed line indicates the truncation line, where all −log₁₀ P values greater than 40 were truncated to 40 for visual clarity. Novel loci are highlighted in red and annotated with the nearest protein coding gene.

Fig. 3. Heterogeneity upset plots.

a, Top variants per novel loci. b, Top variants per MR-MEGA identified locus with moderate to high heterogeneity (I² > 30). The top bar plot illustrates heterogeneity with dark blue indicating ancestry heterogeneity proportion and light blue indicating other residual heterogeneity proportion. The bottom plot shows the subcohort level beta values with blue indicating positive and red indicating negative effect directions. Three variants with greater than 30% I² total heterogeneity were only identified in the MR-MEGA meta-analysis method, whereas little to no heterogeneity is observed in loci identified in random effect.