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, Jun Ichi Satoh, Taksushi Toda, Jian Wang, John P.A. Ioannidis, Mariza De Andrade, Walter A. Rocca

Research output: Contribution to journalArticlepeer-review

206 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)512-521
Number of pages10
JournalAnnals of neurology
Issue number4
StatePublished - Apr 2004

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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