| Summary |
Linkage of ADHD to 6p, an identified RD candidate locus, has previously been reported, suggesting the possibility of a pleiotropic gene at this locus. RD (Reading disabilities) has been previously associated with five genes in the region, particularly DCDC2 and KIAA0319. To test whether these genes also contribute to ADHD, they investigated markers previously associated with RD for association with ADHD and ADHD symptoms in a sample of families with ADHD (n=264). Markers were located in two subregions, VMP/DCDC2 and KIAA0319/TTRAP. Across all analyses conducted, strong evidence for association was observed in the VMP/DCDC2 region. Association was equally strong with symptoms of both inattention and hyperactivity/impulsivity, suggesting that this locus contributes to both symptom dimensions. Markers were also tested for association with measures of reading skills (word identification, decoding); however, there was virtually no overlap in the markers associated with ADHD and those associated with reading skills in this sample. Overall this study supports a previous linkage study of ADHD indicating a risk gene for ADHD on 6p and points to VMP or DCDC2 as the most likely candidates. |
| Total Sample |
The sample consisted of 264 nuclear families from the Toronto area, which includes 264 probands and 55 siblings between the ages of 7 and 16 selected on the basis of an ADHD diagnosis (described below). Of these, 192 were two-parent families, 157 with one child, 55 with two children, and two with three children. There were also 72 single-parent families, 55 with one child, 16 with two children, and one with three children. |
| Sample Collection |
The sample consisted of families from the Toronto area. Ninety percent of the participants described their ethnicity as 'European' and the other 10% were of 'other' or 'mixed' backgrounds. These included Chinese, African, Indian, and Native USAn. |
| Diagnosis Description |
Subjects were recruited following referral to the Child Development and Neuropsychiatry Clinics at the Hospital for Sick Children in Toronto. Children were included in the study if they met DSM-IV criteria for one of the three DSM-IV ADHD subtypes (IA, HI, and combined). The diagnosis of ADHD was based on semi-structured interviews with parents (Parent Interview for Child Symptoms [PICS-IV]) and teachers (Teacher Telephone Interviews [TTI-IV]), with additional information on behavior and academic skills collected from standardized questionnaires and assessments. Subjects were excluded if they showed evidence of neurological or chronic medical illness, bipolar affective disorder, psychotic symptoms, Tourette syndrome, or chronic multiple tics. Children were also excluded if they scored below 80 on both the Performance and Verbal Scales of the Wechsler Intelligence Scale for Children III. For detailed information, please refer to the original publication. |
| Technique |
DNA was extracted directly from blood lymphocytes using a high-salt extraction method. The assays employed here were either predesigned (Assay-on-Demand by Applied Biosystems, Foster City, California) or designed from flanking sequence (UCSC database builds 33-35; Assay-by-Design (Applied Biosystem)). Genotyping was conducted with the ABI 7900-HT Sequence Detection System (Applied Biosystems) using the TaqMan 5' nuclease assay for allelic discrimination and the end point analysis mode of SDS software package version 2.0 (Applied Biosystems). For detailed information, please refer to the original publication. |
| Analysis Method |
All markers were tested for Mendelian errors, crossovers, and Hardy-Weinberg equilibrium using Merlin. For the single marker categorical analysis, the transmission disequilibrium test (TDT) statistic was calculated using the extended TDT (ETDT) program. P-values from the TDT analysis of all 10 SNP were corrected using a permutation test, running 1000 permutations in UNPHASED . Haplotype transmission for ADHD defined as a categorical trait was analyzed using the TRANSMIT program . Analysis of the quantitative measures of IA and HI as reported by both parents and teachers was carried out using the Family Based Association Test (FBAT) program and the HBAT component for the quantitative analysis of haplotypes. For detailed information, please refer to the original publication. |
| Result Description |
Across all analyses conducted, strong evidence for association was observed in the VMP/DCDC2 region. Association was equally strong with symptoms of both inattention and hyperactivity/impulsivity, suggesting that this locus contributes to both symptom dimensions. Markers were also tested for association with measures of reading skills (word identification, decoding); however, there was virtually no overlap in the markers associated with ADHD and those associated with reading skills in this sample. |
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