A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

Abstract

Common variant genome-wide association studies (GWASs) have, to date, identified >24 risk loci for Parkinson's disease (PD). To discover additional loci, we carried out a GWAS comparing 6,476 PD cases with 302,042 controls, followed by a meta-analysis with a recent study of over 13,000 PD cases and 95,000 controls at 9,830 overlapping variants. We then tested 35 loci (P < 1 × 10^-6) in a replication cohort of 5,851 cases and 5,866 controls. We identified 17 novel risk loci (P < 5 × 10^-8) in a joint analysis of 26,035 cases and 403,190 controls. We used a neurocentric strategy to assign candidate risk genes to the loci. We identified protein-altering or cis-expression quantitative trait locus (cis-eQTL) variants in linkage disequilibrium with the index variant in 29 of the 41 PD loci. These results indicate a key role for autophagy and lysosomal biology in PD risk, and suggest potential new drug targets for PD.

Figure 1

A flow chart of the two-stage meta-analysis design. In stage 1, we carried out a meta-analysis of 9,830 SNPs between the PDWBS and PDGene studies. Thirty-five loci with P < 1 × 10⁻⁶ were carried forward into the replication-phase meta-analysis. In stage 2, we carried out a meta-analysis between the two discovery-phase studies and the NeuroX study for these 35 loci. Of these loci, 16 of the 29 available in NeuroX and 1 locus without replication data were carried forward for downstream analyses (see the main text for further details).

Figure 2

Results of the Parkinson’s disease discovery-phase meta-analysis. The top SNPs in associated regions are indicated by pink symbols. Candidate genes for previously associated loci are labeled in black (P < 5 × 10⁻⁸ in the discovery phase) or gray text (P > 5 × 10⁻⁸ in the discovery phase); candidate genes for newly identified loci are labeled in red. The y-axis shows the two-sided unadjusted −log₁₀(P) values for association with PD. SNPs with P < 1 × 10⁻²⁵ are indicated by triangles.

Figure 3

The candidate genes for regions associated with Parkinson’s disease. The most likely candidate gene is annotated for each region that was significantly associated with PD in the final joint analysis. Black or gray text indicates previously reported loci that had P values less than or greater than 5 × 10⁻⁸ in the discovery phase, respectively. Red text indicates newly identified loci that were significantly associated with PD in the final joint analysis. Gray lines at the outer edge spanning multiple genes indicate candidate genes within a single locus. Chromosome numbers are shown in the gray shaded ring, and support for candidate genes is indicated by color-coding in the inner rings. The innermost ring indicates expression of the gene in brain cell types (in a mouse expression data set) or in human brain regions (in GTEx), or differential expression between PD brains and healthy control brains.