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	Hawi Z, 200212192616
Citation	Hawi Z., Dring M., Kirley A., Foley D., Kent L., Craddock N., Asherson P., Curran S., Gould A., Richards S., Lawson D., Pay H., Turic D., Langley K., Owen M., O'Donovan M., Thapar A., Fitzgerald M. and Gill M. (2002) "Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample." Mol Psychiatry, 7(7): 718-25.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	273 nuclear families
Predominant Ethnicity	Caucasian
Population	United Kingdom, Ireland
Age Group	Children/Adolescents

Detail Info

Summary	In this study, they investigated polymorphisms in HTR_1B and HTR_2A (which encode the serotonin receptors 5-HT_1B and 5-HT_2A respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, they observed significant preferential transmission of the allele 861G of the HTR_1B in the total sample (for HHRR: X²=7.4, P=0.0065 and TDT: X²=6.4, P= 0.014). Analysis of HTR_2A failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone (X²= 4.9, P= 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings.
Total Sample	273 nuclear families (80 from Ireland, 90 from Wales/Manchester, 48 from United Kingdom/Birmingham, 55 from United Kingdom/London) including 193 heterozygous parents
Sample Collection	ADHD cases were recruited from child psychiatric clinics and schools from three centres in the United Kingdom and one in Ireland.
Diagnosis Description	Details of the clinical assessment procedure, assignment of diagnosis and the clinical description of each sample have been published previously in the Irish by Daly et al; Welsh /Manchester in Holmes et al, London in Mill et al and Birmingham in Kent et al. Briefly, for the three United Kingdom centres, consensus diagnoses were made according to DSM-IV criteria for ADHD using the Child and Adolescence Psychiatric Assessment (CAPA), a semi-structured instrument.
Technique	DNA amplification of HTR_1B and HTR_2A His452Tyr were carried out by PCR. For more details, please refer to the original paper.
Analysis Method	In this study, the haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) designs were used to avoid any potential population stratification. In this method, the non-transmitted parental alleles are used as 'controls' for evaluating allele transmission in the case of HHRR. In contrast, the TDT is a test of linkage and association which only uses alleles transmitted from heterozygous parents. The X² test was used to examine the significance of the resulting tables.
Result Description	Allele frequencies for both markers did not show any significant deviation from that expected according to Hardy-Weinberg disequilibrium. A significant preferential transmission of allele 861G of HTR_1B was observed in the total sample. This was also the case for the Irish sample alone, which shows the most significant preferential transmission of this allele to ADHD cases. Increased transmission of the same allele was also seen in the samples from Wales/Manchester and Birmingham but this did not reach statistical significance in either case. However, in the sample from London, the allele 861G was less frequently transmitted to ADHD cases compared to 861C. The result of the TDT analysis confirmed the previous analysis indicating the presence of linkage as well as association between the HTR_1B and ADHD. Once again, the Irish sample exhibited the highest level of significance compared to the remainder of the sample. Similarly, the Cardiff and Birmingham samples showed a trend in the same direction. In contrast, the London sample showed a trend in the opposite direction. In addition, HHRR and TDT analyses of transmission by parent of origin were conducted. The increased transmission observed in the total sample was largely due to the transmission of allele 861G of paternal origin to ADHD cases. The opposite trend of transmission observed in the London sample was reversed and excess transmission of the allele 861G was observed though this was not significant. Transmission from maternal origin to ADHD cases was not significant in the total sample but was statistically significant in the Irish sample alone. HHRR analysis of the HTR_2A/His452Tyr did not show any preferential transmission in the total sample. However, an increased preferential transmission of the 452His allele was observed in the Irish sample alone. This has also been confirmed by TDT analysis suggesting the presence of linkage as well as association between this marker and ADHD in the Irish population. An inconsistent pattern of transmissions was observed with regard to other groups; while the Birmingham sample showed a similar trend (preferential transmission of 452His allele to ADHD cases) to that of the Irish sample, Cardiff/Manchester and London samples showed the opposite trend.

Other variant reported by this study (count: 2)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
HTR2A His452Tyr	His/Tyr		HHRR P-value=0.82 (RR [95% CI]= 0.98 [0.79-1.21], TDT P-valu...... HHRR P-value=0.82 (RR [95% CI]= 0.98 [0.79-1.21], TDT P-value=1 (OR=0.98) in Total sample; HHRR P-value=0.026 (RR [95% CI]= 1.9 [0.95-3.80], TDT P-value=0.052 (OR=2.76) in Ireland sample; HHRR P-value=0.29 (RR [95% CI]=1.19 [0.88-1.61], TDT P-value=0.26 (OR=0.61) in Wales/Manchester sample; HHRR P-value=0.26 (RR [95% CI]= 1.84 [0.70-2.96], TDT P-value=0.42 (OR=1.8) in England/Birmingham sample; HHRR P-value=0.17 (RR [95% CI]= 0.76 [0.54-1.08], TDT P-value=0.13 (OR=2.14) in England/London sample More...	Analysis of HTR2A failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone.	Significant
HTR1B G861C	G/C		HHRR P-value=0.0065 (RR [95% CI]=1.24 [1.05-1.45], TDT P-val...... HHRR P-value=0.0065 (RR [95% CI]=1.24 [1.05-1.45], TDT P-value=0.014 (OR=1.44) in Total sample; HHRR P-value=0.0018 (RR [95% CI]=1.57 [1.15-2.16], TDT P-value=0.0037 (OR=2.2) in Ireland sample; HHRR P-value=0.08 (RR [95% CI]=1.26 [0.96-1.65], TDT P-value=0.14 (OR=1.52) in Wales/Manchester sample; HHRR P-value=0.33 (RR [95% CI]= 1.29 [0.73-2.27], TDT P-value=0.6 (OR=1.27) in England/Birmingham sample; HHRR P-value=0.44 (RR [95% CI]= 0.89 [0.67-1.19], TDT P-value=0.51 (OR=0.76) in England/London sample More...	Significant preferential transmission of the allele 861G of the HTR1B was observed in the total sample	Significant

Genes reported by this study (count: 2)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
HTR1B	Significant preferential transmission of the allele 861G of ...... Significant preferential transmission of the allele 861G of the HTR1B was observed in the total sample More...	Significant
HTR2A	Analysis of HTR2A failed to reveal evidence of association o...... Analysis of HTR2A failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone. More...	Significant