Abstract
Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 × 10-6; OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 × 10-5; OR = 1.35) and MAPT (recessive model: p = 2.0 × 10-5; OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case-control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 × 10-7) and the MAPT region (recessive model: p = 9.8 × 10-6; additive model: p = 4.8 × 10-5). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 593-605 |
| Number of pages | 13 |
| Journal | Human Genetics |
| Volume | 124 |
| Issue number | 6 |
| DOIs | |
| State | Published - 2009 |
Bibliographical note
Funding Information:Acknowledgments This project was supported by R01 NS37167, R01 NS036711, the Robert P. & Judith N. Goldberg Foundation, the Bumpus Foundation and the Harvard NeuroDiscovery Center. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), as well as clinical data. DNA samples contributed by the Parkinson Institute—Is-tituti Clinici di Perfezionamento, Milan, Italy were from the “Human genetic bank of patients aVected by PD and parkinsonisms”, supported by Italian Telethon grant n. GTB07001 and by the “Fondazione Grigi-oni per il Morbo di Parkinson”. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. We particularly thank Justin Paschall from the NCBI dbGaP staV for his assistance in developing the dataset available at dbGaP. The data generated from this case–control study are available at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession number: phs000126.v1.p1. Data from the Fung et al. study were obtained from dbGaP. Funding support for “NINDS-Genome-Wide Genotyping in Parkinson’s Disease: First Stage Analysis and Public Release of Data” was provided by intramural programs of the National Institute on Aging and the National Institute on Neurological Disorders and Stroke (NINDS) and the genotyping of samples was provided by NINDS. The dataset used for the meta-analyses described in this manuscript were obtained from the NINDS Database found at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession number phs000089.v1.p1. The following are members of the PROGENI Steering Committee. University of Tennessee Health Science Center: R. F. PfeiVer; University of Rochester: F. Marshall, D. Oakes, A. Rudolph, A. Shinaman; Columbia University Medical Center: K. Marder; Indiana University School of Medicine: P. M. Conneal-ly, T. Foroud, C. Halter; University of Kansas Medical Center: K. Lyons; Eli Lilly & Company: E. Siemers; Medical College of Ohio: L. Elmers; University of California, Irvine: N. Hermanowicz. The following are members of the GenePD Steering Committee. University of Virginia Health System: G. F. Wooten; UMDNJ-Robert Wood Johnson Medical School: L. Golbe; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School: J. F. Gusel-la; Boston University School of Medicine: R. H. Myers. We thank the subjects for their participation in this research study.