ADHDgene Database

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Large-scale studies

Data Summary

Published Variant
- SNP: 1391
- CNV: 398
- Others: 173
Published Gene: 359
Published Region: 128
Pathway by PBA: 8
Study: 361

Study Report

Basic Info

Reference	Turic D, 2004 (b)15108183
Citation	Turic D., Langley K., Kirov G., Owen M. J., Thapar A. and O'Donovan M. C. (2004) "Direct analysis of the genes encoding G proteins G alpha T2, G alpha o, G alpha Z in ADHD." Am J Med Genet B Neuropsychiatr Genet, 127B(1): 68-72.
Study Design	case-control and family-based
Study Type	Candidate-gene association study and Mutational study
Sample Size	129 parent-proband trios and 32 duos
Predominant Ethnicity	Caucasian
Population	United Kingdom
Age Group	Children/Adolescents and Adults : aged 6-16 years

Detail Info

Summary	In this study, they followed up the extensive replicated evidence that the dopamine DRD4 receptor is involved in the aetiology of ADHD by undertaking direct analysis of genes encoding other proteins in this effector system. They prioritised the genes encoding G protein alpha subunits Galpha_T2 (GNAT2), Galpha_o (GNAO1), Galpha_Z (GNAZ) as these have been shown to transduce the effects of ligand binding at DRD4. They screened the exons of all three genes for sequence variation in 28 unrelated subjects with ADHD and identified 13 novel polymorphisms. All were tested for possible association with ADHD using a combination of pooled and individual genotyping. The results of this study do not suggest that polymorphisms in these genes contribute to susceptibility to ADHD.
Total Sample	The sample includes 129 parent-proband trios and 32 duos (all mother and affected child). All ADHD probands are of United Kingdom Caucasian origin and were aged between 6 and 16 years at the time of interview. Adult United Kingdom Caucasian blood donor controls were used in this study. The controls were not matched for age or gender, and therefore to allow for potential confounding effects due to stratification.
Sample Collection	Families of children with suspected or diagnosed ADHD were recruited from District Child and Adolescent Psychiatry and Paediatric Clinics in South Wales, Bristol and the South West of United Kingdom and Greater Manchester.
Diagnosis Description	Mothers were interviewed about their children, using the Child and Adolescent Psychiatric Assessment (CAPA), a research diagnostic interview. Reports of ADHD symptoms and impairment at school were also obtained using a semi-structured teacher telephone interview (Child ADHD Teacher Telephone Interview (CHATTI). Diagnoses were assigned according to ICD-10, DSM-IV, and DSM-III-R criteria. Those with IQ test scores of below 70, measured using the Wechsler Intelligence Scale for Children, version III (WISC-III), Tourette's syndrome, any major medical or neurological disorder, pervasive developmental disorder, or fragile X syndrome were excluded.
Technique	DNA was obtained from venous blood or mouthwash samples using standard techniques. The genomic structures of each gene was obtained by aligning each of their respective reference mRNA sequences with genomic sequence data available in GenBank using the BLAST suite of software. Mutation analyses were performed using a WAVE DHPLC platform (Transgenomic). This study was divided in two stages. In the first stage, all detected polymorphisms (apart from non-synonymous changes and for technical reasons an insertion deletion polymorphism 1259_1282del) were initially genotyped in three sets of DNA pools to determine allele frequencies using the SNaPshot^TM (Perkin Elmer Applied Biosystems) modification of primer extension protocol described by Norton et al. [2002]. One pool contained 100 ADHD cases, and two pools each contained 184 different adult United Kingdom Caucasian blood donor controls. The controls were not matched for age or gender, and therefore to allow for potential confounding effects due to stratification, the design of the study required that polymorphisms showing evidence for association with ADHD in the pools would be individually genotyped. Individual genotyping was triggered by a relaxed P value (P<0.1). For more information about mutation screening and individual genotyping, please refer to the original publication.
Analysis Method	Marker data from complete trios were tested for allelic association with ADHD using TDT (transmission disequilibrium test) as described by Sham and Curtis [1995]. All family samples, complete and incomplete, were analysed using TRANSMIT [Clayton, 1999]. Where individual genotypes were available we tested for association between haplotypes using TRANSMIT. Marker-marker LD was calculated using the estimated haplotype frequencies derived from TRANSMIT.
Result Description	13 sequence variants were found; 6 in Galpha_T2, 4 in Galpha_Z, and 3 in Galpha_o. Galpha_T2 was the only gene in which non-synonymous changes were detected. These were (L)319(I) and (V)370(M). Bboth non-synonymous variants were individually genotyped in family sample. The deletion 1259_1283del polymorphism was also individually genotyped. None of these three polymorphisms yielded evidence for association. Pooled genotyping of the remaining polymorphisms produced evidence for association for a single variant (-32A>G; P=0.001). Given the pooled data, the -32A>G was individually genotyped and tested for association in the family sample. Haplotypes constructed from all permutations of the four markers that were individually genotyped in this sample were also tested. No significant single marker or multi-marker haplotypic association were observed. A restricted analysis of complete trios with combinations of two, three, and four markers gave similar results.

Other variant reported by this study (count: 13)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
GNAT2 -32A>G	A/G	G	Pooled estimates allelic test P-value=0.001; TDT test P-valu...... Pooled estimates allelic test P-value=0.001; TDT test P-value=0.69 More...	sequence variant found in gene GNAT2; evidence for association was found in case-control analysis, but not in family-based TDT test.	Significant
GNAT2 1259 1282del		del	TDT test P-value=0.50 TDT test P-value=0.50	sequence variant found in gene GNAT2; no evidence for association was found.	Non-significant
GNAT2 G(T)546A(T)	G/A	A	Pooled estimates allelic test P-value=1 Pooled estimates allelic test P-value=1	sequence variant found in gene GNAT2; no evidence for association was found.	Non-significant
GNAT2 C(L)319A(I)	C/A	A	TDT test P-value=0.11 TDT test P-value=0.11	sequence variant found in gene GNAT2; non-synonymous change; no evidence for association was found.	Non-significant
GNAO1 -1214G>A	G/A	A		sequence variant found in gene GNAO1; no evidence for association was found.	Non-significant
GNAO1 T(T)513C(T)	T/C	T	Pooled estimates allelic test P-value=0.3 Pooled estimates allelic test P-value=0.3	sequence variant found in gene GNAO1; no evidence for association was found.	Non-significant
GNAO1 IVS4+22T>C	T/C	T	Pooled estimates allelic test P-value=0.6 Pooled estimates allelic test P-value=0.6	sequence variant found in gene GNAO1; no evidence for association was found.	Non-significant
GNAZ 2418A>G	A/G	G		sequence variant found in gene GNAZ; no evidence for association was found.	Non-significant
GNAZ 2529T>C	T/C	C	Pooled estimates allelic test P-value=0.21 Pooled estimates allelic test P-value=0.21	sequence variant found in gene GNAZ; no evidence for association was found.	Non-significant
GNAT2 G(V)370A(M)	G/A	A	TDT test P-value=1.0 TDT test P-value=1.0	sequence variant found in gene GNAT2; non-synonymous change; no evidence for association was found.	Non-significant
GNAT2 T(N)933C(N)	T/C	C		sequence variant found in gene GNAT2; no evidence for association was found.	Non-significant
GNAZ 1368G>C	G/C	C		sequence variant found in gene GNAZ; no evidence for association was found.	Non-significant
GNAZ 1479A>G	A/G	G	Pooled estimates allelic test P-value=0.32 Pooled estimates allelic test P-value=0.32	sequence variant found in gene GNAZ; no evidence for association was found.	Non-significant

Genes reported by this study (count: 3)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
GNAO1	3 sequence variants were found in this gene, but none of the...... 3 sequence variants were found in this gene, but none of them achieved even suggestive evidence for association. More...	Non-significant
GNAT2	6 sequence variants were found in this gene, only one of the...... 6 sequence variants were found in this gene, only one of them (-32A>G, synonymous change) achieved suggestive evidence for association. More...	Significant
GNAZ	4 sequence variants were found in this gene, but none of the...... 4 sequence variants were found in this gene, but none of them achieved even suggestive evidence for association. More...	Non-significant