Nancy Laurin

Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget's disease of bone.

Mutations of the SQSTM1/p62 gene are commonly observed in PDB. Screening an updated sample from Quebec and using previously published data from other populations, we compared frequency estimates for SQSTM1/p62 mutations and haplotype distribution. The P392L mutation was the most prevalent, embedded in two different haplotypes, possibly shared by other populations. We also examined the phenotype and penetrance of P392L.

Association study of the nicotinic acetylcholine receptor α4 subunit gene, CHRNA4, in attention-deficit hyperactivity disorder

Attention‐deficit hyperactivity disorder (ADHD) is a common childhood‐onset psychiatric condition with a strong genetic component. Evidence from pharmacological, clinical and animal studies has suggested that the nicotinic system could be involved in the disorder. Previous studies have implicated the nicotinic acetylcholine receptor α4 subunit gene, CHRNA4, in ADHD. Particularly, a polymorphism in the exon 2–intron 2 junction of CHRNA4 has been associated with severe inattention defined by latent class analysis. In the current study, we used the transmission disequilibrium test (TDT) to investigate four polymorphisms encompassing this region of CHRNA4 for association with ADHD in a sample of 264 nuclear families from Toronto. No significant evidence of biased transmission was observed for any of the marker alleles for ADHD defined as a categorical trait (all subtypes included), although one haplotype showed marginal evidence of under‐transmission. No association was found with the ADHD predominantly inattentive subtype or with symptom dimension scores of inattention. On the contrary, nominally significant evidence of association of individual markers was obtained for the ADHD combined subtype and with teacher‐rated hyperactivity–impulsivity scores, with the same haplotype being under‐transmitted. Based on our results and others, CHRNA4 may be involved in ADHD; however, its role in ADHD symptomatology remains to be clarified.

Chromosome 5 and Gilles de la Tourette syndrome: Linkage in a large pedigree and association study of six candidates in the region†

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.

Association study for genes at chromosome 5p13-q11 in attention deficit hyperactivity disorder†

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.

No evidence for genetic association between DARPP-32 (PP1R1B) polymorphisms and attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests that a dopamine system dysfunction plays a role in the disorder pathophysiology. Several genes involved in dopamine neurotransmission have shown replicated genetic association with ADHD. These include the dopamine receptors D4 (DRD4), D5 (DRD5), and the dopamine transporter (DAT1) genes. Recently, evidence has also accumulated in favor of the dopamine receptor D1 gene (DRD1). The dopamine‐ and cAMP‐regulated phosphoprotein of relative molecular mass of 32 kDa (DARPP‐32) is a key component of dopamine signaling, acting as a converging point for several neurotransmitter systems influencing dopaminergic neurons and regulating a wide variety of downstream effectors. Here, we tested the DARPP‐32 gene, PPP1R1B, for association with ADHD using four polymorphic markers selected across the gene in a sample of 255 ADHD families. We did not detect evidence of association of individual marker alleles and haplotype analysis did not reveal significant association in this sample of families. Moreover, we found no relationship between the same alleles or haplotypes and symptom scores of inattention or hyperactivity/impulsivity in these families using a quantitative approach. In conclusion, albeit a key regulatory role in dopamine signaling, our data do not support a major contribution of the DARPP‐32 gene in ADHD.