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

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.

SUBMITTER: Pankratz N

PROVIDER: S-EPMC3354734 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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

Pankratz Nathan N Beecham Gary W GW DeStefano Anita L AL Dawson Ted M TM Doheny Kimberly F KF Factor Stewart A SA Hamza Taye H TH Hung Albert Y AY Hyman Bradley T BT Ivinson Adrian J AJ Krainc Dmitri D Latourelle Jeanne C JC Clark Lorraine N LN Marder Karen K Martin Eden R ER Mayeux Richard R Ross Owen A OA Scherzer Clemens R CR Simon David K DK Tanner Caroline C Vance Jeffery M JM Wszolek Zbigniew K ZK Zabetian Cyrus P CP Myers Richard H RH Payami Haydeh H Scott William K WK Foroud Tatiana T

Annals of neurology 20120301 3

<h4>Objective</h4>Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility.<h4>Methods</h4>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 res ...[more]

PMID: 22451204

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Project description:BackgroundParkinson's disease (PD) is complex and heterogeneous. The numerous susceptibility loci that have been identified reaffirm the complexity of PD but do not fully explain it; e.g., it is not known if any given PD susceptibility gene is associated with all PD or a disease subtype. We also suspect that important disease genes may have escaped detection because of this heterogeneity. We used presence/absence of family history to subdivide the cases and performed genome-wide association studies (GWAS) in Sporadic-PD and Familial-PD separately. The aim was to uncover new genes and gain insight into the genetic architecture of PD.ResultsEmploying GWAS on the NeuroGenetics Research Consortium (NGRC) dataset stratified by family history (1565 Sporadic-PD, 435 Familial-PD, 1986 controls), we identified a novel locus on chromosome 1p21 in Sporadic-PD (PNGRC = 4 × 10(-8)) and replicated the finding (P(Replication) = 6 × 10(-3); P(Pooled) = 4 × 10(-10)) in 1528 Sporadic-PD and 796 controls from the National Institutes of Neurologic Disease and Stroke (NINDS) Repository. This is the fifth PD locus to be mapped to the short arm of chromosome 1. It is flanked by S1PR1 and OLFM3 genes, and is 200 kb from a multiple sclerosis susceptibility gene. The second aim of the study was to extend the stratified GWAS to the well-established PD genes. SNCA_ rs356220 was associated with both Sporadic-PD (OR = 1.37, P = 1 × 10(-9)) and Familial-PD (OR = 1.40, P = 2 × 10(-5)). HLA_rs3129882 was more strongly associated with Sporadic-PD (OR = 1.38, P = 5 × 10(-10)) than Familial-PD (OR = 1.12, P = 0.15). In the MAPT region, virtually every single nucleotide polymorphism (SNP) had a stronger effect-size and lower P-value in Familial-PD (peak P = 8 × 10(-7)) than in Sporadic-PD (peak P = 2 × 10(-5)).ConclusionsWe discovered and replicated a new locus for Sporadic-PD which had escaped detection in un-stratified GWAS. This demonstrates that by stratifying on a key variable the power gained due to diminished heterogeneity can sometimes outweigh the power lost to reduced sample size. We also detected distinct patterns of disease associations for previously established PD susceptibility genes, which gives an insight to the genetic architecture of the disease and could aid in the selection of appropriate study population for future studies.

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

Publications

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

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