Study Report
Basic Info
Reference |
Park J, 201020347913
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Citation |
Park J., Willmott M., Vetuz G., Toye C., Kirley A., Hawi Z., Brookes K. J., Gill M. and Kent L. (2010) "Evidence that genetic variation in the oxytocin receptor (OXTR) gene influences social cognition in ADHD." Prog Neuropsychopharmacol Biol Psychiatry, 34(4): 697-702.
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Study Design |
family-based |
Study Type |
Candidate-gene association study |
Sample Size |
450 ADHD probands (inclusive of twelve affected siblings) and their parents |
Predominant Ethnicity |
Caucasian |
Population |
United Kingdom, Ireland |
Gender |
90.1% male |
Age Group |
Children/Adolescents
:
aged 4-16 years
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Detail Info
Summary |
Some children with ADHD also have social and communication difficulties similar to those seen in children with autistic spectrum disorders and this may be due to shared genetic liability. As the oxytocin receptor (OXTR) gene has been implicated in social cognition and autistic spectrum disorders, this study investigated whether OXTR polymorphisms previously implicated in autism were associated with ADHD and whether they influenced OXTR mRNA expression in 27 normal human amygdala brain samples. The family-based association sample consisted of 450 DSM-IV diagnosed ADHD probands and their parents. Although there was no association with the ADHD phenotype, an association with social cognitive impairments in a subset of the ADHD probands (N=112) was found for SNP rs53576 (F=5.24, p=0.007) with post-hoc tests demonstrating that the AA genotype was associated with better social ability compared to the AG genotype. Additionally, significant association was also found for rs13316193 (F=3.09, p=0.05) with post-hoc tests demonstrating that the CC genotype was significantly associated with poorer social ability than the TT genotype. No significant association between genotype and OXTR mRNA expression was found. This study supports previous evidence that the OXTR gene is implicated in social cognition. |
Total Sample |
All 450 probands were white and born in the United Kingdom or Ireland (age range 4-16 years). The sample was predominantly male (90.1%) with no significant difference in sex ratio between the two study recruitment centres. All probands fulfilled DSM-IV diagnostic criteria for ADHD. Of these N=42 (9.3%) had the inattentive subtype, and N=38 (8.4%) had the hyperactive impulsive subtype, the remainder had combined subtype (82.3%). For information about Human post-mortem brain sample, please refer to the original publication. |
Sample Collection |
For this study 450 ADHD probands (inclusive of twelve affected siblings) and their parents were recruited from several child psychiatry clinics in the United Kingdom (N=183) and Ireland (N=267), following approval from the appropriate research ethics committees. After complete description of the study to the subjects, written informed consent was obtained from parents and children (some younger children gave assent). |
Diagnosis Description |
For 380 of the probands from the United Kingdom and Ireland, parents were interviewed by trained psychiatrists or psychologists employing the Child and Adolescent Psychiatric Assessment (CAPA). Consistent interview procedures were employed across the two centres with researchers from each centre receiving a common training in the use of the CAPA. Inter-rater reliability kappa coefficients were calculated for ADHD subtype diagnoses (k=0.82; CI=0.71-0.94). The remaining 70 United Kingdom probands were interviewed with the parent version of the K-SADS interview by a trained psychologist. In addition teacher ratings were obtained for children by the Conners Teacher Rating Scale (CTRS). Established cut-off points for possible and likely ADHD caseness on the CTRS were adhered to i.e. a T score above 55 was required. All probands fulfilled DSM-IV diagnostic criteria for ADHD. Children with an IQ below 70, or significant medical conditions such as epilepsy were excluded. Specifically, children with diagnosed autism, atypical autism or Aspergers syndrome were excluded as were any children who required further assessment of possible autistic spectrum disorder after the research interview procedure used in this study. Two hundred and eleven children (46.9%) had comorbid oppositional defiant disorder (ODD) and 69 children (15.3%) ful filled criteria for comorbid conduct disorder. Frequencies of subtype and comorbidity were similar across the two recruitment centres. The social cognition phenotype was assessed by the Social and Communication Disorders Checklist completed by parents. |
Technique |
For association study samples, high molecular weight genomic DNA was extracted from whole blood, cheek swab or Oragene saliva collection systems according to standard procedures. Many of the SNPs across the OXTR gene are in high LD with each other and SNPs were chosen taking this into account so as to limit genotyping redundancy. Five SNPs (4 in intron 3 and 1 in the 3'UTR) were chosen based on previous findings: rs237885, rs13316193 and rs237995 were recently demonstrated to have functional consequences on OXTR mRNA; rs13316193 in addition to rs6770632 was also in several significant haplotypes associated with autistic spectrum disorder in Lerer et al. (2007); rs53576 has been previously associated with autism with several positive replications. Pre-designed SNP genotyping assays were obtained from Applied Biosystems for use on the Stratagene Mx3005P real-time PCR machine (Stratagene, CA) following standardised protocols provided with the assays. For information about mRNA expression, please refer to the original publication. |
Analysis Method |
For the association studies, TDT analysis for each sample was carried out using the programme software UNPHASED 3.1. Evidence for association was set at the 0.05 significance level. For the mRNA expression studies, mean values were obtained from the triplicate Ct values for each probe per sample. The target OXTR mRNA expression was normalised to endogenous reference genes (beta-2M and GAPDH) to generate a deltaCt value. The relationship between the deltaCt values (OXTR mRNA relative expression) and the different genotype groups were analysed by ANOVA with TUnited Kingdomey post-hoc analyses in the analytical programme SPSS Data Editor Version 17.0. All p values are reported as uncorrected. |
Result Description |
There were no Mendelian inheritance errors detected by Haploview. TDT analysis for the five SNP markers within the OXTR gene genotyped in an ADHD family-based sample did not demonstrate significant association of the gene with ADHD. There was minimal linkage disequilibrium (LD) between the genotyped markers as determined by Haploview with all marker pairs having an r2 <0.2, except between rs53576 and rs237895 (r2 = 0.43 ). TDT analysis for pair-wise haplotypes between all markers showed no significant associations. For result information about social cognitive score association and OXTR mRNA expression, please refer to the original publication. |
SNPs reported by this study (count: 5)
SNP |
Allele Change |
Risk Allele |
Statistical Values |
Author Comments |
Result of Statistical Analysis |
rs13316193 |
C/T |
C |
TDT P-value=0.72, OR=1.11, 95% CI=0.75-1.64. |
TDT analysis did not demonstrate significant association of ......
TDT analysis did not demonstrate significant association of this SNP with ADHD.
More...
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Non-significant
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rs237885 |
G/T |
T |
TDT P-value=0.69, OR=1.11, 95% CI=0.77-1.59. |
TDT analysis did not demonstrate significant association of ......
TDT analysis did not demonstrate significant association of this SNP with ADHD.
More...
|
Non-significant
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rs6770632 |
A/C |
C |
TDT P-value=0.51, OR=1.21, 95% CI=0.81-1.82. |
TDT analysis did not demonstrate significant association of ......
TDT analysis did not demonstrate significant association of this SNP with ADHD.
More...
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Non-significant
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rs237895 |
C/T |
C |
TDT P-value=0.64, OR=1.13, 95% CI=0.78-1.64. |
TDT analysis did not demonstrate significant association of ......
TDT analysis did not demonstrate significant association of this SNP with ADHD. But an association with social cognitive impairments in a subset of the ADHD probands (N=112) was found for this SNP (F=3.09, P-value=0.05).
More...
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Non-significant
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rs53576 |
A/G |
G |
TDT P-value=0.18, OR=1.47, 95% CI=0.99-2.18. |
TDT analysis did not demonstrate significant association of ......
TDT analysis did not demonstrate significant association of this SNP with ADHD. But an association with social cognitive impairments in a subset of the ADHD probands (N=112) was found for this SNP (F=5.24, P-value=0.007).
More...
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Non-significant
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Genes reported by this study (count: 1)
Gene |
Statistical Values/Author Comments |
Result of Statistical Analysis |
OXTR |
There was no association with the ADHD phenotype through TDT......
There was no association with the ADHD phenotype through TDT test, but an association with social cognitive impairments in a subset of the ADHD probands (N=112) was found.
More...
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Non-significant
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