Study Report
Basic Info
| Reference |
Dorval KM, 200717010153
|
| Citation |
Dorval K. M., Wigg K. G., Crosbie J., Tannock R., Kennedy J. L., Ickowicz A., Pathare T., Malone M., Schachar R. and Barr C. L. (2007) "Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder." Genes Brain Behav, 6(5): 444-52.
|
| Study Design |
family-based |
| Study Type |
Candidate-gene association study |
| Sample Size |
205 nuclear families |
| Predominant Ethnicity |
Caucasian |
| Population |
Canada |
| Gender |
204 boys and 48 girls |
| Age Group |
Children/Adolescents
:
aged 7-16
|
Detail Info
| Summary |
They 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-termmemorywere performed using the FBAT program. Three SNPs showed significantly biased transmission (P-value<0.05), with the strongest evidence of association found for rs2284411 (P-value=0.005). Quantitative trait analyses showed associations of thesemarkers 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. Their data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait. |
| Total Sample |
The study sample included 205 small nuclear families with 47 affected siblings. A total of 252 affected children were used in this study. Genotyping of both parents was achieved in 150 families, and in 55 families, only one parent was genotyped. |
| Sample Collection |
The study samples were from the Toronto area. The ethnic background of the sample was largely of European Caucasian descent, with 10% comprising other or mixed ethnic backgrounds including African, Chinese, Indian and Native USAn. |
| Diagnosis Description |
Probands and affected siblings meeting the criteria for ADHD as outlined in the DSM-IV (USAn Psychiatric Association, 1994) were recruited from the Child Development and Neuropsychiatry Clinics at the Hospital for Sick Children (Toronto, Canada). The criteria for assessment and diagnosis of subjects used for this study have been previously described (Adams et al. 2004; Barr et al. 1999). Division of the affected children among the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) ADHD subtypes was 27% predominantly IA, 14% predominantly HI and 59% of the combined subtype. The mean IQ of the sample as measured by the Wechsler Intelligence Scale for Children III (WISC-III) full-scale performance was 102.9(mean), SD=12.8. |
| Technique |
Single nucleotide polymorphisms (SNPs) were genotyped for this study using an ABI 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA, USA) using the TaqMan 5' nuclease assay for allelic discrimination. SNPs used in the analysis were selected from confirmed polymorphisms in public databases with probes and primers available commercially (Assay on Demand or Assay by Design) from Applied Biosystems. Results were obtained from the allelic discrimination end-point analysis mode of the ABI 7900HT software package version 2.0. |
| Analysis Method |
For the categorical analysis of ADHD, they used the extended TDT (ETDT) program to test for the biased transmission of individual alleles. Transmission of haplotypes was analyzed using the TRANSMIT program. Haplotypes with a frequency of less than 10% were not included in the analysis. To calculate the coefficients of linkage disequilibrium (LD), D' and r2, between marker alleles in the parental chromosomes, they used HAPLOVIEW v2.03. Permutation-based analysis was performed using the UNPHASED program. The FBAT program was used to analyze GRIN2B variants in relation to ADHD symptom dimensions of IA and HI, and the cognitive phenotypes of verbal shortterm memory and verbal working memory. As is recommended in the application of the FBAT statistic, an offset was used in the quantitative TDT analyses. The choice of offset varied by trait and was based on mean scores derived from the population. |
| Result Description |
Significant TDT results (P-value<0.05) or a trend toward significance was observed for four SNPs located in intron 3. Following permutation-based analysis to correct for multiple comparisons, the global significance level for rs2284411 was 0.03. No biased transmission of any of the remaining SNPs were observed. Five of the nine selected SNPs fall within separate haplotype blocks. The global transmit results were significant for haplotypes with a frequency greater than 10% and for all haplotypes. Symptom scores showed a significant association of markers rs2300256 and rs2284411 with IA and a trend for rs2268115 and rs2284407. For HI, a significant association was observed for rs2284407 and a trend toward significance for rs2268115. No significant association between the positive intron 3 SNPs and short-term or working memory was observed. |
SNPs reported by this study (count: 9)
| SNP |
Allele Change |
Risk Allele |
Statistical Values |
Author Comments |
Result of Statistical Analysis |
| rs1805502 |
A/G |
A |
Allelic TDT P-value=0.772 |
No biased transmission
No biased transmission
|
Non-significant
|
| rs2284411 |
T/C |
C |
Allelic TDT P-value=0.005 |
Significant TDT results
Significant TDT results
|
Significant
|
| rs2284407 |
G/T |
G |
Allelic TDT P-value=0.032 |
Significant TDT results
Significant TDT results
|
Significant
|
| rs2268115 |
T/G |
T |
Allelic TDT P-value=0.021 |
Significant TDT results
Significant TDT results
|
Significant
|
| rs2268097 |
A/G |
A |
Allelic TDT P-value=0.803 |
No biased transmission
No biased transmission
|
Non-significant
|
| rs2284416 |
T/G |
G |
Allelic TDT P-value=0.297 |
No biased transmission
No biased transmission
|
Non-significant
|
| rs2300256 |
G/A |
A |
Allelic TDT P-value=0.074 |
a trend toward significance was observed
a trend toward significance was observed
|
Non-significant
|
| rs4764031 |
A/C |
A |
Allelic TDT P-value=0.695 |
No biased transmission
No biased transmission
|
Non-significant
|
| rs890 |
A/C |
A |
Allelic TDT P-value=0.417 |
No biased transmission
No biased transmission
|
Non-significant
|
Genes reported by this study (count: 1)
| Gene |
Statistical Values/Author Comments |
Result of Statistical Analysis |
| GRIN2B |
In haplotype analysis, the most significant P-value=0.013 . ......
In haplotype analysis, the most significant P-value=0.013 . The global transmit results were significant for haplotypes with a frequency greater than 10%(P-value=0.008) and for all haplotypes(P-value=0.003).
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Significant
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Hot Results