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	Xu X, 2008(b)18937296
Citation	Xu X., Hawi Z., Brookes K. J., Anney R., Bellgrove M., Franke B., Barry E., Chen W., Kuntsi J., Banaschewski T., Buitelaar J., Ebstein R., Fitzgerald M., Miranda A., Oades R. D., Roeyers H., Rothenberger A., Sergeant J., Sonuga-Barke E., Steinhausen H. C., Faraone S. V., Gill M. and Asherson P. (2008) "Replication of a rare protective allele in the noradrenaline transporter gene and ADHD." Am J Med Genet B Neuropsychiatr Genet, 147B(8): 1564-7.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	ST2: 435 trios; Dublin: 222 families; and 382 controls
Predominant Ethnicity	Caucasian
Population	Belgium, Germany, the Netherlands, Ireland, Israel, Spain, Switzerland, United Kingdom
Age Group	Children/Adolescents : 4-17 years

Detail Info

Summary	Using two independent samples of ADHD DSM-IV combined subtype trios they attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant. The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.
Total Sample	In this report they include new data from the IMAGE stage 2 sample (ST2) that consists of 435 combined type ADHD cases, including 376 probands and 59 of their affected siblings, with both parents present for 290 of the ADHD probands and only the mother included for 77 of the probands. Two hundred twenty-two families with clinically diagnosed ADHD children were recruited from child guidance clinics and ADHD support groups around Ireland. In this study 382 controls of Northern European ancestry were genotyped for rs11568324.
Replication Size	ST1: 752 trios, MGH: 474 trios
Sample Collection	European Caucasian
Diagnosis Description	IMAGE sample: the diagnosis of ADHD was made following a parent interview with the Parental Account of Child Symptoms that asks about ADHD symptoms in various settings. An algorithm was used to derive each of the DSM-IV ADHD symptoms from the PACS interview data and these were combined with items that scored 2 or more from teacher ratings of DSM-IV items taken from the long version of the Conners' Teacher Rating Scale. The diagnosis of ADHD was made if sufficient items were identified to fulfill DSM-IV criteria, and both impairment and pervasiveness were present. Dublin sample: To confirm DSM-IV diagnoses of ADHD, one or both parents of each child were interviewed using the child and adolescent psychiatric assessment (CAPA). To fulfill ICD-10 and 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 class teacher about DSM-IV symptoms of ADHD and impairment shown in class. DSM-IV diagnostic criteria were then applied using the parent and teacher interview data to derive the ADHD diagnostic subtypes.
Technique	The SNP markers rs11568324 and rs3785143 were included in a 48-SNP multiplex designed by Applied Biosystems as part of their SNPlex chemistry for genotyping. Additional genotyping was performed using the ABI TaqMan protocol under standard conditions provided by ABI with a pre-designed TaqMan1 SNP genotyping Assay. Genotyping for the samples from Dublin were performed on a commercial platform by KBiosciences.
Analysis Method	Genotype data were analyzed using the UNPHASED software with implementation of the option to handle missing parental genotypes for the ST1 and ST2 samples. To clarify the evidence for association from the four available studies they completed a combined TDT analysis for the two markers.
Result Description	Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant. The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.

SNPs reported by this study (count: 2)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs3785143			TDT P-value=0.02, OR=1.4 in ST1; TDT P-value=0.8, OR=0.93 in ST2; TDT P-value=0.02, OR=1.45 in MGH; TDT P-value=0.62, OR=0.85 in Dublin; TDT P-value=0.008, OR=1.27 in TOTAL	the overall evidence of association was significant across a...... the overall evidence of association was significant across all four datasets More...	Significant
rs11568324	T/C		TDT P-value=0.004, OR=0.26 in ST1; TDT P-value=0.22, OR=0.54 in ST2; TDT P-value=0.03, OR=0.31 in MGH; TDT P-value=0.16, OR=0.33 in Dublin; TDT P-value=0.00008, OR=0.34 in TOTAL; P-value=0.003, OR=0.21 in ST1; P-value=0.3, OR=0.59 in ST2, P-value=0.12, OR=0.32 in Dublin; P-value=0.007, OR=0.34 in Total, for allele counts	the overall evidence of association was significant across a...... the overall evidence of association was significant across all four datasets More...	Significant

Genes reported by this study (count: 1)