Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2017 Oct;49(10):1511-1516.
doi: 10.1038/ng.3955. Epub 2017 Sep 11.

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

Diana Chang  1 , Mike A Nalls  2   3 , Ingileif B Hallgrímsdóttir  4 , Julie Hunkapiller  1 , Marcel van der Brug  1 , Fang Cai  1 ; International Parkinson's Disease Genomics Consortium; 23andMe Research Team; Geoffrey A Kerchner  1 , Gai Ayalon  1 , Baris Bingol  1 , Morgan Sheng  1 , David Hinds  4 , Timothy W Behrens  1 , Andrew B Singleton  2 , Tushar R Bhangale  1 , Robert R Graham  1
Affiliations
Meta-Analysis

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

Diana Chang et al. Nat Genet. 2017 Oct.

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.

PubMed Disclaimer

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare competing financial interests: details are available in the online version of the paper.

Figures

Figure 1
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
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
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.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol. Rev. 2011;91:1161–1218. - PubMed
    1. Verstraeten A, Theuns J, Van Broeckhoven C. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet. 2015;31:140–149. - PubMed
    1. Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N. Engl. J. Med. 2003;348:1356–1364. - PubMed
    1. Shulman JM, De Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu. Rev. Pathol. 2011;6:193–222. - PubMed
    1. Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2012;2:a008888. - PMC - PubMed

Publication types