| Summary |
Genes involved in neuronal development and growth are important etiological candidates and neurotrophic factors have been hypothesized to play a role in the pathogenesis of ADHD. Glial derived neurotrophic factor (GDNF), nerve growth factor (NGF (beta subunit)), and neurotrophic factor 3 (NT3) are members of the neurotrophin family and are involved in the survival, differentiation, and maintenance of neuronal cells. Ten coding and intronic SNPs across GDNF, NGF, and NT3 were examined in a family-based association sample of 120 DSM-IV ADHD probands and their biological parents, as well as a case-control analysis with 120 sex-matched controls. Borderline significant overtransmission of the C allele of a non-synonymous C/T SNP(rs6330) in NGF which codes an alanine/valine change was found in the family-based sample (Chi-square=3.69, OR=1.65, P-value=0.05). Although this SNP is located in the 5' pro-NGF sequence and not the mature NGF protein, it may affect intracellular processing and secretion of NGF. |
| Total Sample |
All probands fulfilled DSM-IV diagnostic criteria for ADHD. Of these, 97 (81%) had ADHD combined type, 11 (9%) had the inattentive subtype, and 12 (10%) had the hyperactive impulsive subtype. In addition to the family-based sample, a control group of 120 ethnically and sex-matched adolescents from schools and colleges, local to the ADHD clinics were also employed for a case-control analysis. |
| Sample Collection |
For this study, 120 ADHD probands and their parents were recruited from two child psychiatry clinics in the United Kingdom, following approval from the appropriate research ethics committees. Of these, 72 were full trios with DNA available from both parents. All 120 probands were white and born in the United Kingdom. |
| Diagnosis Description |
Parents were interviewed by trained psychiatrists or psychologists employing the Child and Adolescent Psychiatric Assessment (CAPA) [Angold et al., 1995]. In addition, Conners Teacher Rating Scale (CTRS) [Conners, 1998] were completed on all children to confirm that symptomsmet the criterion of pervasiveness. Established cut-off points for possible and likely ADHD caseness on the CTRS were adhered to, that is, a T score above 55 was required. Children with an IQ below 70, autistic spectrum disorder, or significant medical conditions such as epilepsy were excluded. Twenty-nine children (24%) had comorbid oppositional defiant disorder and 15 children (13%) fulfilled criteria for comorbid conduct disorder. Control subjects were psychiatrically screened with the Strengths and Difficulties Questionnaire [Goodman, 2001]. |
| Technique |
For this study, all cases, controls, and only parents which contributed to full trios were genotyped. High molecular weight genomic DNA was extracted from either whole blood or cheek swab according to routine procedures. Single nucleotide polymorphisms (SNPs) for the three genes were chosen from the ABI assay on demand or assay by design service and all genotyping was performed by Geneservice, blind to affection status. Known coding SNPs with a minor allele frequency greater than 0.1 were chosen where possible, otherwise intronic SNPs were genotyped. Additionally, 20 Geneservice control samples were typed in duplicate with 100% concordance and 98.5% of all genotyping was successful. |
| Analysis Method |
The transmission disequilibriumtest (TDT) [Spielman et al., 1993] was used to test for the presence of non-random transmission of alleles to ADHD probands at each polymorphism, indicative of allelic association and case-control data were analyzed using Pearson Chi-squared test. |
| Result Description |
Parental, proband, and control allele frequencies were not significantly different from frequencies reported in Caucasian/CEPH populations from several databases including Hapmap (www.hapmap.org). Genotype frequencies demonstrated no significant departure from Hardy Weinberg equilibrium. There was no significant difference in allele or genotype frequencies between cases and controls for each polymorphism. TDT analysis demonstrated borderline significant overtransmission of the C allele of rs6330, a non-synonymous SNP in NGF. |
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