Journal ArticleDOI
UCHL1 is a Parkinson's disease susceptibility gene
Demetrius M. Maraganore,Timothy G. Lesnick,Alexis Elbaz,Marie-Christine Chartier-Harlin,Thomas Gasser,Rejko Krüger,Nobutaka Hattori,George D. Mellick,Aldo Quattrone,Aldo Quattrone,Jun Ichi Satoh,Taksushi Toda,Jian Wang,John P. A. Ioannidis,John P. A. Ioannidis,Mariza de Andrade,Walter A. Rocca +16 more
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TLDR
In a new large case-control study in white individuals, the S18Y variant was not protective against PD under any genetic model of inheritance, and a cumulative meta-analysis showed a trend toward a null effect.Abstract:
The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73-0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57-0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis-generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease-modifying therapies.read more
Citations
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Genetics of Parkinson disease: paradigm shifts and future prospects.
TL;DR: Genetic insights provide the rationale for new strategies for prevention or therapy, and have led to animal models of disease in which these strategies can be tested.
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The genetic epidemiology of neurodegenerative disease
Lars Bertram,Rudolph E. Tanzi +1 more
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