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Gilles de la Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics. In our previous genome scan for TS we identified evidence for linkage to the centromeric region of chromosome 5 in a single large family of 32 individuals with 10 family members with TS or chronic multiple tics (CMT). In this paper we report further analyses of the 5p-centromeric region in this pedigree. An additional 11 family members were identified and screened for TS. Using a set of 14 microsatellite markers we refined the linked region to a ∼28 Mb interval between the markers D5S1506 and D5S76. A set of six candidate genes located in this region were selected to be tested for genetic association with TS. These genes were GDNF, ITGA1, ISL1, FGF10, HCN1 and SLC1A3. The TDT statistic was used for the association tests in a sample of 171 independent nuclear families with 241 affected children with TS. We found no evidence for an association between TS and markers in these genes in this sample of families. This study represents the first efforts to narrow the linkage region in the extended pedigree and the first tests of candidate genes in the chromosome 5 region linked to TS. © 2008 Wiley-Liss, Inc.

Linkage of attention deficit hyperactivity disorder (ADHD) to the short arm-centromeric region of chromosome 5 has been reported in multiple studies. The overlapping region (5p13-q11) contains a number of strong candidate genes for ADHD, based on their role in brain function or neurodevelopment. The aim of this study was to investigate some of the top candidates among these genes in relation to ADHD in a sample of 245 nuclear families from the Toronto area. We investigated the genes for the glial cell-derived neurotropic factor (GDNF), the fibroblast growth factor 10 (FGF10), islet-1 (ISL1), the hyperpolarized potassium channel (HCN1) and the integrin alpha 1 (ITGA1). In addition to these genes, we assessed the 3'region of the SLC1A3 gene, a glutamate transporter implicated in ADHD by a previous association study. A total of 36 polymorphisms were selected across the six genes. We performed family-based association and haplotype analyses. ADHD is a dimensional disorder, with symptoms of inattention and hyperactivity-impulsivity therefore, we also conducted quantitative analysis in relation to symptom scores for both dimensions. Single marker and haplotype analyses yielded little evidence of association for any of the genes tested in this study. Moreover, we were unable to replicate the positive association findings reported for SLC1A3. Our results suggest that these six genes are unlikely to be susceptibility genes in the chromosome 5p13-q11 region and other genes should now be considered for priority study.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental childhood psychiatric disorder. Brain-derived neurotropic factor (BDNF) has been suggested to play a role in the pathogenesis of ADHD and two family-based association studies demonstrated an association of BDNF polymorphisms with ADHD. The aim of the current study was to investigate the BDNF gene for association with ADHD in a large sample of families from Toronto. The transmission of three polymorphisms of the BDNF gene (rs6265, rs11030104, and rs2049046) was examined in 266 nuclear families ascertained through a proband with ADHD (315 affected children) using the transmission/disequilibrium test (TDT). In addition, we conducted quantitative analysis to assess the relationship between these marker alleles and the symptom dimensions of ADHD (inattention and hyperactivity/impulsivity) and cognitive measures of working memory. None of the individual marker alleles showed significant evidence of association with ADHD, dimensional symptom scores, or working memory ability in our sample of ADHD families. There was no significant evidence for biased transmission of individual haplotypes with frequency10% (global chi2 for these three haplotypes: chi2 = 6.349, df = 3, P = 0.096). One uncommon haplotype (A-G-G; frequency 2.2%) showed a significant association with ADHD in the categorical (chi2 = 5.293, df = 1, P = 0.021) and quantitative analyses (parents' rated inattention: Z = -2.504, P = 0.012; and hyperactivity/impulsivity: Z = -2.651, P = 0.008). These results should be interpreted cautiously, however, because of the low haplotype frequency. In light of the evidence for an involvement of BDNF in ADHD, further analysis of the BDNF gene in ADHD is warranted.