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	Sheehan K, 200515940290
Citation	Sheehan K., Lowe N., Kirley A., Mullins C., Fitzgerald M., Gill M. and Hawi Z. (2005) "Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD." Mol Psychiatry, 10(10): 944-9.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	179 nuclear families
Predominant Ethnicity	Irish
Population	Ireland
Gender	88% male
Age Group	Children/Adolescents : 5-14 years

Detail Info

Summary	They examined eight single nucleotide polymorphisms (SNP) in the TPH2 gene for association with ADHD in 179 Irish nuclear families. Transmission disequilibrium test analysis revealed significant association between the T allele of marker rs1843809 with the disorder. Stratifying data by the sex of the transmitting parent showed that this association was enhanced when paternal transmission was considered. In addition, several haplotypes (all including the associated marker) were associated with ADHD. These preliminary findings suggest that TPH2 is a susceptibility locus for ADHD.
Total Sample	A total of 179 children and their families took part in the study. Families with clinically diagnosed ADHD children were recruited from child guidance clinics and ADHD support groups around Ireland. The age range of the probands was between 5 and 14 years, with males accounting for 88% of the cases.
Sample Collection	Families with clinically diagnosed ADHD children were recruited from child guidance clinics and ADHD support groups around Ireland.
Diagnosis Description	One or both parents were interviewed using the Child and Adolescent Psychiatric Assessment (CAPA). To fulfil DSM-IV ADHD criteria for symptom pervasiveness, information about ADHD symptoms at school was obtained from teachers using a semi-structured teacher telephone interview, which involved asking the teacher about DSM-IV symptoms of ADHD and impairment shown in class. ADHD diagnostic subtypes were derived from DSM-IV diagnostic classification. A 25-item subscale is present in which a cutoff score of 36 or greater is 96% sensitive and specific for a retrospective diagnosis of childhood ADHD in a parent. Of these, 144 (80.3%) met research criteria for ICD-10 Hyperkinetic Disorder (HKD) or DSM-IVADHD (combined, inattentive or hyperactiveimpulsive subtype). Of all, 36 (20.2%) had a clinical diagnosis of ADHD but failed to meet research criteria for ADHD due to lack of information, usually on pervasiveness. With regard to DSM-IV ADHD, 112 children (62.6%) met research criteria for ADHD combined type, 21 (11.7%) for ADHD inattentive type and 11 (6.1%) for ADHD hyperactive-impulsive type.
Technique	Genomic DNA was extracted from whole blood using a standard phenol/chloroform method or from buccal cells as described in Gill et al. PCR amplification of the examined markers was carried out in a 12.5 ul reaction using 1X PCR reaction buffer containing 10mM of Tris-HCl (pH 8.9), 30 ng of genomic DNA, 20 pmol of each primer, 200 ul of each dNTP and 0.5U of Taq polymerase. Genotyping of all SNPs was performed using the SNaPshot Method^TM (Applied Biosystems) as described in Norton et al. This involves extending unlabelled primers by a single base using fluorescently tagged ddNTP's. Each of the four bases is labelled with a different coloured fluorescent dye that can be detected when run on an ABI Genetic Analyser (ABI PRISM 3100 genetic analyzer).
Analysis Method	The transmission disequilibrium test (TDT) was used to examine the association between the examined SNPs and ADHD. Haplotype analysis to test for the transmission of multilocus haplotypes was conducted using the program TRANSMIT (www.hgmp.mrc. ac.United Kingdom/Menu/transmit.html). All X² statistics and P-values are presented without correction for multiple testing.
Result Description	Transmission disequilibrium test analysis revealed significant association between the T allele of marker rs1843809 with the disorder (X²=12.2, P=0.0006, OR=2.36). Stratifying data by the sex of the transmitting parent showed that this association was enhanced when paternal transmission was considered (OR=3.7). In addition, several haplotypes (all including the associated marker) were associated with ADHD. These preliminary findings suggest that TPH2 is a susceptibility locus for ADHD.

SNPs reported by this study (count: 8)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs2129575	G/T		allelic TDT P-value=0.49, X²=0.62, OR=1.16; TDT P-value=0.8, X²=0.19, OR=1.1 of paternal origin; TDT P-value=0.53, X²=0.61, OR=1.3 of maternal origin	did not attain significance at P<0.05 did not attain significance at P<0.05	Non-significant
rs1487275	T/G		allelic TDT P-value=0.24, X²=1.6, OR=1.26; TDT P-value=0.7, X²=0.86, OR=1.2 of paternal origin; TDT P-value=0.16, X²=2.4, OR=0.6 of maternal origin	did not attain significance at P<0.05 did not attain significance at P<0.05	Non-significant
rs1487278	T/C		allelic TDT P-value=0.45, X²=0.7, OR=1.15; TDT P-value=0.13, X²=0.73, OR=1.4 of paternal origin; TDT P-value=0.01, X²=7.1, OR=2.2 of maternal origin	overtransmission of the T allele was detected for maternal t...... overtransmission of the T allele was detected for maternal transmissions More...	Significant
rs1487279	A/T		allelic TDT P-value=0.17, X²=2.1, OR=1.3; TDT P-value=0.02, X²=5.9, OR=2.1 of paternal origin; TDT P-value=1, X²=0.02, OR=0.96 of maternal origin	the trend towards association of allele A in the total sampl...... the trend towards association of allele A in the total sample was stronger for paternal transmissions More...	Significant
rs1386493	C/T		allelic TDT P-value=0.095, X²=3.4, OR=1.4; TDT P-value=0.04, X²=4.6, OR=1.9 of paternal origin; TDT P-value=0.8, X²=0.1, OR=1.1 of maternal origin	the trend towards association of allele C in the total sampl...... the trend towards association of allele C in the total sample was stronger for paternal transmissions More...	Significant
rs1843809	T/G		allelic TDT P-value=0.0006, X²=12.2, OR=2.36; TDT P-value=0.001, X²=10.9, OR=3.7 of paternal origin; TDT P-value=0.09, X²=3.5, OR=1.9 of maternal origin	a highly significant association between the T allele and AD...... a highly significant association between the T allele and ADHD was observed; association is enhanced when paternal transmission alone is considered More...	Significant
rs1386497	A/C		allelic TDT P-value=0.048, X²=4.2, OR=1.45; TDT P-value=0.3, X²=0.75, OR=1.4 of paternal origin; TDT P-value=0.06, X²=4.1, OR=1.8 of maternal origin	a weaker association was observed a weaker association was observed	Significant
rs1023990	T/C		allelic TDT P-value=1, X²=0.008, OR=1; TDT P-value=0.3, X²=0.75, OR=1.4 of paternal origin; TDT P-value=0.4, X²=0.92, OR=0.8 of maternal origin	did not attain significance at P<0.05 did not attain significance at P<0.05	Non-significant

Genes reported by this study (count: 1)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
TPH2	haplotype (G of rs2129575/T of rs1843809) TRANSMIT P-value=0...... haplotype (G of rs2129575/T of rs1843809) TRANSMIT P-value=0.0090, X²=6.8, df=1; global X²=14.9, df=3, P-value=0.002; haplotype (T of rs1843809/C of rs1386493) TRANSMIT P-value=0.0007, X²=11.62, df=1; global X²=19.5, df=3, P-value=0.0002 a highly significant association with ADHD was observed; a three-marker haplotype (G of rs2129575/T of rs1843809/C of rs1386493) TRANSMIT P-value=0.0027, X²=9, df=1; global X²=22.2, df=7, P-value=0.002 significantly associated with ADHD; a four-marker haplotype (G of rs2129575/T of rs1843809/C of rs1386493/T of rs1023990) TRANSMIT P-value=0.003, X²=8.9, df=1; global X²=36.2, df=14, P-value=0.001 transmitted more frequently to ADHD cases; an eight-marker (G of rs2129575/T of rs1843809/C of rs1386493/T of rs1023990/A of rs1386497/T of rs1487278/T of rs1487275/ A of rs1487279) individual X²=12.2, df=1, P-value=0.0005; global X² not calculated showed the association with ADHD More...	Significant