| Summary |
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, they 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 their sample of ADHD families. There was no significant evidence for biased transmission of individual haplotypes with frequency >10%. One uncommon haplotype (A-G-G; frequency 2.2%) showed a significant association with ADHD in the categorical and quantitative analyses (parents' rated inattention: P-value=0.012; and hyperactivity/impulsivity: P-value=0.008). These results should be interpretedcautiously, 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. |
| Total Sample |
The study sample comprised 266 nuclear families recruited in the Toronto area, including 49 affected siblings of the probands, for a total of 315 affected children (80.8% boys). |
| Sample Collection |
Briefly, probands and affected siblings were referred to the Child Development and Neuropsychiatry Clinics at the Hospital for Sick Children, Toronto. |
| Diagnosis Description |
Subject assessment and diagnostic criteria for inclusion in this study are described in detail elsewhere [Barr et al., 1999; Quist et al., 2000; Laurin et al., 2005]. Diagnosis was based on information from semi-structured interviews of parents and teachers: Parent Interview for Child Symptoms (PICS-IV) [Ickowicz etal., 2006] and Teacher Telephone Interview (TTI-IV) [Tannock et al., 2002]. Children who met DSM-IV criteria for ADHD were included in the study. All children were free of medication for 24 hr before assessment. This protocol was approved by the Hospital for Sick Children's Research Ethics Board and informed written consent or assent was obtained for all participants. For the quantitative analysis, the symptom scores obtained for both ADHD dimensions (inattention and hyperactivity/impulsivity) from the PICS-IV and TTI-IV semi-structured interviews were used. Verbal short-term and working memory were assessed using the digit span subtest of the WISC-III [Wechsler, 1991; Kaplan et al., 1999]. This test provides two subscale scores (digits span forward and digits span backward) which index the ability to store and manipulate auditory-verbal information, respectively, as well as an overall memory score. |
| Technique |
DNA was extracted from blood lymphocytes using a standard high salt extraction method [Miller et al., 1988]. A total of three SNPs (rs6265, rs11030104, rs2049046) were genotyped using the ABI 7900-HT Sequence Detection Systems (Applied Biosystems, Foster City, CA) and TaqMan 5' nuclease assays for allelic discrimination [Livak et al., 1995]. |
| Analysis Method |
The allelic transmission of the three individual markers were examined using the TDT statistic calculated with the extended TDT (ETDT) program [Sham and Curtis, 1995]. Paternal and maternal transmission were also assessed separately for all markers. Evidence for linkage disequilibrium (LD) between the three makers was examined by calculating the D' and Delta2 coefficients using the Haploview program [Barrett et al., 2005]. For the analysis of the haplotypes, the TRANSMIT program version 2.5 was employed, using the robust estimator of variance option [Clayton, 1999]. Quantitative trait TDT analyses, examining the transmission of individual alleles or haplotypes in relation to symptom scores of inattention and hyperactivity/ impulsivity and to short-term memory and working memory measures, were carried out using the FBAT program version 1.5.5, with the additive model of inheritance [Laird et al., 2000; Horvath et al., 2001].Population-based mean scores for the tests were used as an offset value to mean center the trait. The P-values reported in this study were not corrected for multiple tests. No significant departure from Hardy-Weinberg equilibrium was observed for the genotype frequencies. |
| Result Description |
Pairwise LD coefficients D' and Delta2 to assess the strength of LD support the high correlation between the three markers in the sample of families. When considering ADHD as a categorical trait, no significant evidence of biased transmission of these three individual markers was observed. Moreover, no preferential transmission of the paternal Val66Met allele was observed after separate analysis of paternal and maternal transmissions. No significant evidence for biased transmission of any of the three haplotypes with frequency >10% was found. No significant evidence was found for a relationship between individual alleles or common haplotypes (with frequency >10%) and the two ADHD symptom dimensions or short-term and working memory scores. Of note, one uncommon haplotype, A-G-G (frequency 2.2%), demonstrated a significant association with ADHD in categorical and quantitative analyses. However, the number of transmission for this haplotype was considered too low to provide a definitive result (i.e., quantitative analysiswas based on 12 informative families). |
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