title: 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.
  
  
  CONCLUSIONS
  We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.forename: Gary W
authors.initials: GW
authors.lastname: Beecham
authors.forename: Anita L
authors.initials: AL
authors.lastname: DeStefano
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Factor
authors.forename: Taye H
authors.initials: TH
authors.lastname: Hamza
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Hung
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Ivinson
authors.forename: Dmitri
authors.initials: D
authors.lastname: Krainc
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Latourelle
authors.forename: Lorraine N
authors.initials: LN
authors.lastname: Clark
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Scherzer
authors.forename: David K
authors.initials: DK
authors.lastname: Simon
authors.forename: Caroline
authors.initials: C
authors.lastname: Tanner
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.forename: Haydeh
authors.initials: H
authors.lastname: Payami
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
mesh_terms: D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D020559:Monomeric GTP-Binding Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D006023:Glycoproteins; D009419:Nerve Tissue Proteins; C089283:Rit2 protein, mouse; D020559:Monomeric GTP-Binding Proteins