Neuroscience Letters 392 (2006) 72–74 The UBQLN1 polymorphism, UBQ-8i, at 9q22 is not associated with Alzheimer’s disease with onset before 70 years Nathalie Brouwers a , Kristel Sleegers a , Sebastiaan Engelborghs c , Veerle Bogaerts a , Cornelia M. van Duijn b , Peter Paul De Deyn c , Christine Van Broeckhoven a , Bart Dermaut a,∗ a Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology and Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, B-2610, Antwerpen, Belgium b Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands c Department of Neurology and Memory Clinic, Middelheim General Hospital (ZNA) and Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium Received 13 July 2005; received in revised form 29 August 2005; accepted 29 August 2005 Abstract An intronic polymorphism affecting alternative splicing of exon 8 of ubiquilin 1 (UBQLN1), that is located at a well established Alzheimer’s disease (AD) locus on chromosome 9q22, was recently associated with increased risk for late-onset AD. We analyzed this polymorphism in two independent AD samples consisting of patients with an onset age 70 years or less, but did not observe statistically significant association. Our study does not support a major role for this UBQLN1 polymorphism in AD patients with an earlier onset of disease. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Alzheimer’s disease; Ubiquilin 1; Chromosome 9; Genetic association study Alzheimer’s disease (AD) is the most common neurodegenera- tive brain disease and has a complex genetic etiology. Besides rare mutations in three genes (amyloid precursor protein, APP; presenilin 1 and 2, PS1 and PS2) causing autosomal dominant early-onset AD, the 4 allele of the apolipoprotein E (APOE) gene is the only well established AD risk gene (for review [10]). However, several studies have identified a region on chromo- some 9q22 as a promising AD risk locus [2,4,8,9]. Recently, Bertram et al. [1] reported significant association between AD and several single nucleotide polymorphisms (SNPs) in the gene encoding ubiquilin 1 (UBQLN1) at 9q22 in two independent samples using a family-based approach. The risk-conferring haplotype was defined by a single intronic C/T SNP, UBQ-8i, located 70 base pairs downstream of the 3’ splice site of exon 8. The UBQ-8i C-allele dose-dependently increased the risk of AD (1.5 and 2.1 times for hetero- and homozygotes, respectively) and partially explained the positive linkage signal observed at 9q22 in the original study [2]. In the same study, the UBQ- 8i C-allele was associated with a dose-dependent increase of an ∗ Corresponding author. Tel.: +32 3 820 23 32; fax: +32 3 265 10 12. E-mail address: bart.dermaut@ua.ac.be (B. Dermaut). alternatively spliced UBQLN1 exon 8 lacking transcript in brain. Since genetic factors are enriched in AD patients with an early disease onset [11], we have estimated the genetic contribution of UBQ-8i to AD with an onset before 70 years in a Belgian and Dutch population. Belgian AD patients and controls were derived from a prospective study of dementia [6], whereas Dutch patients and controls were derived from a population-based study of early-onset AD in four northern provinces of The Netherlands and the area of metropolitan Rotterdam [5,12]. Characteristics of these study samples are shown in Table 1. Belgian and Dutch AD patients included in this study had an age at onset of 70 years or less. Clinical diagnosis of probable AD was based on consensus by at least two neurologists in the Belgian study, or a neurologist and a member of the research team in the Dutch study, according to the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria [7]. Belgian and Dutch control individuals had no neurological or psychiatric antecedents and consisted of subjects without organic dis- ease involving the central nervous system based on clinical examination. Six Belgian patients (3%) carried a missense mutation (three in PS1, two in PS2 and one in APP; Brouwers 0304-3940/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2005.08.064