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Comparative Study
, 5 (11), 917-23

Lack of Replication of Thirteen Single-Nucleotide Polymorphisms Implicated in Parkinson's Disease: A Large-Scale International Study

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Comparative Study

Lack of Replication of Thirteen Single-Nucleotide Polymorphisms Implicated in Parkinson's Disease: A Large-Scale International Study

Alexis Elbaz et al. Lancet Neurol.

Abstract

Background: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain.

Methods: Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies.

Findings: In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966.

Interpretation: Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.

Figures

Figure 1
Figure 1. Subgroup analyses for (A) age at study entry, (B) sex, and (C) history of Parkinson’s disease
In each plot the two subgroups are shown for each of the 13 SNPs with point estimates of summary OR and 95% CIs according to random-effects calculations. Fixed-effects estimates are very similar (not shown).
Figure 2
Figure 2. Tier 2 results from the whole genome-association versus meta-analysis of all replication data
Point estimates and 95% CIs are shown (random-effects calculations for the meta-analysis). Results are shown for each of the 13 SNPs.

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