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Meta‐analysis of Parkinson's Disease: Identification of a novel locus, RIT2
Author(s) -
Pankratz Nathan,
Beecham Gary W.,
DeStefano Anita L.,
Dawson Ted M.,
Doheny Kimberly F.,
Factor Stewart A.,
Hamza Taye H.,
Hung Albert Y.,
Hyman Bradley T.,
Ivinson Adrian J.,
Krainc Dmitri,
Latourelle Jeanne C.,
Clark Lorraine N.,
Marder Karen,
Martin Eden R.,
Mayeux Richard,
Ross Owen A.,
Scherzer Clemens R.,
Simon David K.,
Tanner Caroline,
Vance Jeffery M.,
Wszolek Zbigniew K.,
Zabetian Cyrus P.,
Myers Richard H.,
Payami Haydeh,
Scott William K.,
Foroud Tatiana
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22687
Subject(s) - genome wide association study , single nucleotide polymorphism , imputation (statistics) , genetics , locus (genetics) , biology , snp , genetic association , odds ratio , logistic regression , genotype , gene , medicine , missing data , machine learning , computer science
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 .ANN NEUROL 2012;