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Meta-Analysis

Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2

Nathan Pankratz et al. Ann Neurol. 2012 Mar.

Abstract

Objective: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility.

Methods: A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls).

Results: Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3×10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5×10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2×10(-9)/rs11248060; T: OR=1.35; p=2.0×10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2×10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5×10(-8) Combined Sample) (N370; OR=3.08; p=7×10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5×10(-5) Discovery Sample; p=1.52×10(-7) Replication sample; p=2×10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes.

Interpretation: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.

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Figures

Figure 1
Figure 1
Genome-wide association results for PD susceptibility.
Figure 2
Figure 2. Manhattan plot of Results
(A) Replication Sample results alone (B) Meta-analyzed with the Discovery Sample; the blue line indicates the study-wide significance level (p<9.4 × 10−5 for the replication stage alone, p<5 × 10−8 for the meta-analysis)
Figure 3
Figure 3. Forest plot of the novel RIT2 SNP (rs12456492)
Rsq values are a measure of imputation quality generated by MACH that range from 0 to 1, with 1 being highly accurate
Figure 4
Figure 4
Ingenuity Analysis
See this image and copyright information in PMC

References

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    1. Fung HC, et al. Genome-wide genotyping in Parkinson’s disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 2006;5:911–6. - PubMed
    1. Pankratz N, et al. Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet. 2009;124:593–605. - PMC - PubMed

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