Neuroscience Letters 381 (2005) 131–134 UCHL1 is associated with Parkinson’s disease: A case-unaffected sibling and case-unrelated control study Maurizio Facheris a , Kari J. Strain b , Timothy G. Lesnick b , Mariza de Andrade b , James H. Bower a , J. Eric Ahlskog a , Julie M. Cunningham c , Sarah Lincoln d , Mathew J. Farrer d , Walter A. Rocca a, b , Demetrius M. Maraganore a, ∗ a DepartmentofNeurology,MayoClinicCollegeofMedicine,200FirstStreetSW,Rochester,MN55905,USA b DepartmentofHealthSciencesResearch,MayoClinicCollegeofMedicine,USA c DepartmentofLaboratoryMedicineandPathology,MayoClinicCollegeofMedicine,USA d DepartmentofNeuroscience,MayoClinicCollegeofMedicine,Jacksonville,FL,USA Received 1 October 2004; received in revised form 1 February 2005; accepted 5 February 2005 Abstract To avoid the possible confounding effect of population stratification, we employed a discordant sibling study design and a liberalization of the sibling transmission disequilibrium test to confirm the association of the S18Y variant of the ubiquitin carboxi-terminal hydrolase L1 (UCHL1) gene with Parkinson’s disease (PD). The study included 497 case–control pairs (427 case-unaffected sibling pairs and 70 case- unrelated control pairs). Analyses confirmed a significant inverse association of the UCHL1 S18Y polymorphism with PD overall (OR = 0.18, 95% CI = 0.05–0.64, p = 0.002, recessive model) and in several strata. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Ubiquitin proteasomal system; Transmission disequilibrium test; Association study; Parkinson’s disease; UCHL1; Genetics An I93M mutation in the ubiquitin carboxy-terminal hydro- lase L1 gene (UCHL1) was initially reported as the cause of Parkinson’s disease (PD) in a single German family [2].A common S18Y variant in the gene was subsequently found to be inversely associated with PD [5]. The inverse association of the S18Y variant with PD was recently confirmed in a collaborative-pooled analysis that included 1970 cases and 2224 unrelated controls from 11 sites [6]. The frequency of gene polymorphisms, including UCHL1 S18Y, may vary across ethnic groups [6]. In out bred popula- tions such as the United States it is problematic to match cases and controls for ethnicity, and the reliability of self-reported ethnicity is not established. Population stratification may, therefore, be a source of spurious findings in studies restricted to cases and unrelated controls [1]. A safeguard against the confounding effect of population stratification is to match ∗ Corresponding author. Tel.: +1 507 538 1038; fax: +1 507 284 3665. E-mailaddress: dmaraganore@mayo.edu (D.M. Maraganore). cases with their unaffected siblings, as they are likely to share the same ethnic origins (in the absence of non-paternity). To our knowledge, this is the first study of the UCHL1 S18Y variant and PD using discordant case-sibling pairs and a lib- eralization of the sibling transmission disequilibrium test. All subjects were recruited as part of an ongoing study of the molecular epidemiology of PD. Case subjects were PD patients sequentially referred to the Department of Neurology at the Mayo Clinic in Rochester, MN, after June 1996, and were residents of Minnesota or of one of the surrounding four states (Wisconsin, Iowa, South Dakota, or North Dakota). Control subjects consisted primarily of unaffected siblings of PD cases who screened negative for PD or parkinsonism via telephone interview [7] or who were confirmed not to have PD or parkinsonism via clinical assess- ment (after they screened positive). A movement disorders specialist performed standardized clinical assessments for all the cases and for those siblings who screened positive, using a set of clinical diagnostic criteria previously reported [5]. 0304-3940/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2005.02.008