Meta-analysis of Parkinson disease: Identification of a novel locus, RIT2

• Type of Material: Article
• Authors: Nathan Pankratz, Indiana University; Gary W. Beecham, University of Miami; Anita L. DeStefano, Boston University; Ted M. Dawson, Johns Hopkins University; Kimberly F. Doheny, Johns Hopkins University; Stewart Factor, Emory University; Taye H. Hamza, New York State Department of Health; Albert Y. Hung, Massachusetts General Hospital; Bradley T. Hyman, Massachusetts General Hospital; Adrian J. Ivinson, Harvard University; Dmitri Krainc, Massachusetts General Hospital; Jeanne C. Latourelle, Boston University; Lorraine N. Clark, Columbia University; Karen Marder, Columbia University; Eden R. Martin, University of Miami; Richard Mayeux, Columbia University; Owen A. Ross, Mayo Clinic; Clemens R. Scherzer, Harvard University; David K. Simon, Beth Israel Deaconess Medical Center; Caroline Tanner, Parkinsons Institute; Jeffery M. Vance, University of Miami; Zbigniew K. Wszolek, Mayo Clinic; Cyrus P. Zabetian, VA Puget Sound Health Care System; Richard H. Myers, Boston University; Haydeh Payami, New York State Department of Health; William K. Scott, University of Miami; Tatiana Foroud, Indiana University; Boadie W Dunlop, Emory University
• Language: English
• Date: 2012-03-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Neurological Association.
• Final Published Version (URL): http://dx.doi.org/10.1002/ana.22687
• Title of Journal or Parent Work: Annals of Neurology
• ISSN: 0364-5134
• Volume: 71
• Issue: 3
• Start Page: 370
• End Page: 384
• Grant/Funding Information: PD and control brain samples provided by the Sun Health Research Institute in Sun City, Arizona, which is supported by the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011 and 05-901 to the Arizona Parkinson’s Disease Consortium) and the Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson’s Research; the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number R24 MH 068855, and the Human Brain and Spinal Fluid Resource Center VA West Los Angeles Healthcare Center, 11301 Wilshire Blvd. Los Angeles, CA 90073, which is sponsored by NINDS/NIMH, National Multiple Sclerosis Society, Department of Veterans.; Control samples and clinical data were provided from the National Cell Repository for Alzheimer’s Disease (U24 AG021886) and the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds).; This project was supported by R01CA141668, R01NS37167, R01NS065070, R56NS037167, MO1RR00750, R01NS36960, P50NS39764, R01NS064155, U10NS44482, NIH/NINDS 1RC2NS070276, NS057567, P50NS072187-02, IH NS36630, UL1 RR024156, NS050487, NS060113, U24AG026395, 1I01BX000531, NS24778, R01NS36711, Harvard NeuroDiscovery Center, The Michael J. Fox Foundation Edmond J Safra Michael J Fox Foundation Global Genetic Consortium Initiative, Bumpus Foundation, Robert P. and Judith N. Goldberg Foundation, National Parkinson Foundation; Parkinson’s Disease Foundation Joseph R. Mazzulli and Grace Bwala, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052018 and MCF #90052030) (ZKW), and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052) (ZKW, OAR), and Dystonia Medical Research Foundation (ZKW).
• Keywords: GENETICS; CALMODULIN; SNCA; RISK-FACTORS; VARIANTS; Clinical Neurology; HAPLOTYPES; ALPHA-SYNUCLEIN; Neurosciences; Science & Technology; SEQUENCE; GENOME-WIDE ASSOCIATION; Life Sciences & Biomedicine; SUSCEPTIBILITY; Neurosciences & Neurology
• Research Categories: Biology, Genetics; Biology, Neuroscience

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 × 10-8Combined Sample) (N370; OR = 3.08; p = 7 × 10-5Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p = 5 × 10-5Discovery Sample; p = 1.52 × 10-7Replication sample; p = 2 × 10-10Combined 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. Copyright