Please cite this article as follows: Kay DM, Factor SA, Samii A, Higgins DS, Griffith A, Roberts JW, Leis BC, Nutt JG, Montimurro JS, Keefe RG, Atkins AJ, Yearout D, Zabetian CP, Payami H. 2008. Genetic Association Between α-Synuclein and Idiopathic Parkinson's Disease. Am J Med Genet Part B 147B:1222–1230.
Genetic association between α-synuclein and idiopathic parkinson's disease†
Version of Record online: 10 APR 2008
Copyright © 2008 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 147B, Issue 7, pages 1222–1230, 5 October 2008
How to Cite
Kay, D. M., Factor, S. A., Samii, A., Higgins, D. S., Griffith, A., Roberts, J. W., Leis, B. C., Nutt, J. G., Montimurro, J. S., Keefe, R. G., Atkins, A. J., Yearout, D., Zabetian, C. P. and Payami, H. (2008), Genetic association between α-synuclein and idiopathic parkinson's disease. Am. J. Med. Genet., 147B: 1222–1230. doi: 10.1002/ajmg.b.30758
- Issue online: 18 SEP 2008
- Version of Record online: 10 APR 2008
- Manuscript Accepted: 3 MAR 2008
- Manuscript Received: 11 DEC 2007
- Michael J. Fox Foundation Edmond J. Safra Global Genetics Consortia Grant
- National Institutes of Health (NIH) National Institute for Neurological Disorders and Stroke grants. Grant Numbers: NS R01-36960, K08-NS044138
- VA Merit Award
- NIH National Institutes of Aging grant. Grant Number: AG 08017
- Mental Health and Geriatric Research Education and Clinical Centers at the VA Puget Sound Health Care System
- Genomics Institute of the New York State Department of Health Wadsworth Center
- age at onset;
- relative predispositional effects;
- mode of inheritance
Point mutations and copy number variations in SNCA, the gene encoding α-synuclein, cause familial Parkinson's disease (PD). A dinucleotide polymorphism (REP1) in the SNCA promoter may be a risk factor for common forms of PD. We studied 1,802 PD patients and 2,129 controls from the NeuroGenetics Research Consortium, using uniform, standardized protocols for diagnosis, subject recruitment, data collection, genotyping, and data analysis. Three common REP1 alleles (257, 259, and 261 bp, with control frequencies of 0.28, 0.65, and 0.06) and several rare alleles (combined frequency <0.01) were detected. We confirmed association of REP1 with PD risk [odds ratio (OR) = 0.86, P = 0.006 for 257-carriers; OR = 1.25, P = 0.022 for 261-carriers]. Using a normalization procedure, we showed that the 257 and 261 alleles are both independently associated with PD risk (for 257, P = 0.002 in overall data, 0.003 in non-familial PD, 0.001 in early-onset PD; for 261, P = 0.056 in overall data, 0.024 in non-familial PD, 0.052 in early-onset PD). The 257-associated risk was consistent with a dominant model [hazard ratio (HR) = 0.99, P = 0.91 for 257/257 vs. 257/X where X denotes all other common alleles; HR = 1.16, P = 0.004 for X/X vs. 257/X]. The 261-associated risk was consistent with a recessive model (HR = 1.89, P = 0.026 for 261/261 vs. 261/X; HR = 0.95, P = 0.42 for X/X vs. 261/X). Genotype-specific mean onset ages (±SD) ranged from 54.8 ± 12.1 for 261/261 to 59.4 ± 11.5 for 257/257, displaying a trend of decreasing onset age with increasing allele size (P = 0.055). Genetic variation in SNCA and its regulatory regions play an important role in both familial and sporadic PD. © 2008 Wiley-Liss, Inc.