Biomedical subjects

K G Wigg

Publications and source records attributed to K G Wigg.

11 recordsLinked to original sources

PubMed2006

Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder.

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.

Adult↗

PubMed2004

Support for EKN1 as the susceptibility locus for dyslexia on 15q21.

Dyslexia has been linked to a number of chromosomal regions including 15q. Recently a gene, EKN1, with unknown function in the linked region, was identified via a translocation breakpoint. This gene was further supported as a susceptibility locus by association studies in a Finnish sample. We investigated the possibility of this locus as a susceptibility gene contributing to dyslexia, analyzed as a categorical trait, and analyzed key reading phenotypes as quantitative traits using six polymorphisms including the two previously reported to be associated with dyslexia. In our sample of 148 families identified through a proband with reading difficulties, we found significant evidence for an association to dyslexia analyzed as a categorical trait and found evidence of association to the reading and related processes of phonological awareness, word identification, decoding, rapid automatized naming, language ability, and verbal short-term memory. However, association was observed with different alleles and haplotypes than those reported to be associated in a Finnish sample. These findings provide support for EKN1 as a risk locus for dyslexia and as contributing to reading component processes and reading-related abilities. Based on these findings, further studies of this gene in independent samples are now required to determine the relationship of this gene to dyslexia.

Child↗

PubMed2001

5'-untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder.

Recently the molecular genetic basis of attention-deficit hyperactivity disorder (ADHD) has been the focus of a number of studies with the majority of these investigating the role of dopamine system genes. A great deal of attention has been focused on the possible involvement of the dopamine D4 receptor gene (DRD4) following a report of an association of ADHD with the allele containing seven copies of the 48-bp repeat in the third exon. In this paper we extended the search for the molecular explanation for the observed association by testing three polymorphisms in the region 5' to the dopamine receptor D4 gene transcription start site for linkage to ADHD. We specifically targeted polymorphisms in the region 5' to the start site of transcription as DNA variants in this region could alter the transcription level of the gene and hence the phenotype. We did not observe significant evidence for biased transmission of any of the alleles at these three polymorphisms to ADHD probands using the transmission disequilibrium test. We conclude that these three polymorphisms are not related to the ADHD phenotype.

5' Untranslated Regions↗

PubMed2000

Further evidence from haplotype analysis for linkage of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder.

Several studies have suggested a possible association of a polymorphism at the dopamine D4 receptor gene and attention-deficit hyperactivity disorder [LaHoste et al., 1996; Rowe et al., 1998; Smalley et al., 1998; Sunohara et al., submitted; Swanson et al., 1998]. The allele reported to be associated with attention-deficit hyperactivity disorder (ADHD) is the allele with seven copies of the 48 bp repeat in the third exon. We extend our study of the dopamine D4 gene and ADHD by testing for linkage using two additional polymorphisms in the dopamine D4 receptor gene and a polymorphism in the closely linked gene, tyrosine hydroxylase. We also searched for two previously reported deletions, a 13 bp and a 21 bp deletion in the first exon. We examined the haplotypes of three polymorphisms of the D4 receptor gene and observed biased transmission of two of these haplotypes. Our findings further support the role of the dopamine D4 gene in ADHD.

Adolescent↗

PubMed2000

Linkage study of two polymorphisms at the dopamine D3 receptor gene and attention-deficit hyperactivity disorder.

Data from animal studies suggest that the dopamine D3 receptor gene may have a role in locomotion and behavioral regulation. Therefore, this gene has been suggested as a candidate for attention-deficit hyperactivity disorder (ADHD). The dopamine D3 receptor gene (DRD3) has two common polymorphisms, one in exon I that changes a Serine to Glycine (Ser9Gly) and alters the recognition site for the restriction enzyme MscI [Lannfelt et al., 1992]. The other common polymorphism is located in intron 5 and results in the change of a restriction site for MspI [Griffon et al., 1996]. We investigated the possibility of linkage of the dopamine D3 receptor gene in 100 small, nuclear families consisting of a proband with ADHD, their parents, and affected siblings. We examined the transmission of the alleles of each of these polymorphisms and the haplotypes of both polymorphisms using the transmission disequilibrium test [Spielman et al., 1993]. We did not observe biased transmission of the alleles at either polymorphism or any haplotype. Our findings using this particular sample do not support the role of the dopamine D3 gene in ADHD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:114-117, 2000.

Attention Deficit Disorder with Hyperactivity↗

PubMed2000

Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor.

A recent study has suggested a possible association of a polymorphism near the dopamine D5 receptor gene (DRD5) and attention-deficit hyperactivity disorder. The polymorphism studied was a (CA)n repeat located in the cosmid containing the D5 receptor gene2 and the allele that was reported to be associated with attention-deficit hyperactivity disorder (ADHD) was the 148-bp allele. In this study we sought to replicate this finding by testing for biased transmission of the alleles at this same polymorphism in a sample of 92 families with an ADHD proband. We did not observe significant evidence for biased transmission of the 148-bp allele, however we did observe biased transmission of two other alleles, the 136-bp allele and the 146-bp allele. For these two alleles the bias was for these two alleles not to be transmitted to the ADHD children. The number of informative transmissions for these two alleles was small, therefore it would be premature to make any conclusions from our study concerning the role of DRD5 in ADHD.

Adolescent↗

PubMed2000

Genetics and sleep disorders.

This review describes the recent growth of our knowledge in the genetics of these sleep disorders and reports some of our preliminary molecular studies in restless legs syndrome.

Chromosome Mapping↗

PubMed1999

Genome scan for linkage to Gilles de la Tourette syndrome.

Gilles de la Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics. Despite clear evidence for a genetic predisposition to TS from family, twin, and adoption studies, there have been no confirmed linkage findings. In this article we test for linkage to TS in multigenerational families segregating TS using a panel of 386 markers with the largest interval between any two markers being 28 cM and an average distance between markers of 10 cM. We tested for linkage using an autosomal dominant model with reduced penetrance and using nonparametric methods. No significant evidence for linkage was found with parametric analysis. A logarithm of the odds (LOD) score of greater or equal to one under the autosomal dominant model was observed in 24 of these markers in at least one of the families tested. No LOD scores greater than two were observed with any of the markers. For the nonparametric analysis, eight markers were observed with a P-value less than 0.00005 for significance evidence of linkage in at least one family. However caution should be used in the interpretation of the nonparametric analyses as this statistic (the affected-pedigree-member method) is know to have a high false-positive rate. Further support for linkage in these regions is required before linkage can be assumed.

Female↗

PubMed1999

Catechol-O-methyltransferase and Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics. Individuals with TS often have symptoms of obsessive compulsive disorder (OCD) and these symptoms are thought to be an alternative expression of the TS gene(s) in TS families. In this paper we test for linkage of the functional polymorphism in the catechol-O-methyltransferase (COMT) gene to TS and OCD in five multi-generational families ascertained through a TS proband. This polymorphism (valine to methionine at codon 158) has been previously reported to influence the activity of COMT by three to four-fold and has recently been reported to be associated with OCD.1 We tested for linkage using an autosomal dominant model with reduced penetrance and non-parametric methods. No significant evidence for linkage was found for the COMT gene and the TS/CMT, or OCD phenotypes in these pedigrees.

Catechol O-Methyltransferase↗

PubMed1997

Linkage study of the dopamine D5 receptor gene and Gilles de la Tourette syndrome.

A defect in the dopamine system has been hypothesized as the etiological defect in Gilles de la Tourette syndrome (TS). In this report, we test the hypothesis that the dopamine D5 receptor locus (DRD5) is linked to the genetic susceptibility to TS in five families studied in Canada. We tested for linkage to the dopamine D5 receptor gene using a microsatellite polymorphism located in the same cosmid clone. Using an autosomal dominant model with reduced penetrance, we were able to exclude linkage in four of the five families for the TS and chronic multiple tics (CMT) phenotype. Also, no evidence for linkage was found using nonparametric methods in all five families.

Canada↗

PubMed1996

No evidence for a major gene effect of the dopamine D4 receptor gene in the susceptibility to Gilles de la Tourette syndrome in five Canadian families.

Gilles de la Tourette Syndrome (TS) is neuropsychiatric disorder characterized by both motor and vocal tics affecting approximately 1/10,000 females and 1/2000 males. Because of the success of neuroleptics and other agents interacting with the dopaminergic system in the suppression of tics, a defect in the dopamine system has been hypothesized in the etiology of TS. In this paper we test the hypothesis that the dopamine D4 receptor (DRD4) is linked to the genetic susceptibility to TS in five families. We tested three polymorphisms in the DRD4 gene and a polymorphism in the closely linked locus, tyrosine hydroxylase (TH). We found no evidence for linkage of DRD4 or TH to TS using an autosomal dominant model with reduced penetrance or using non-parametric methods. The presence of a mutation that results in a truncated non-functional D4 receptor protein was also tested for, but was not observed in these families.

Canada↗