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	Kotler M, 200010898899
Citation	Kotler M., Manor I., Sever Y., Eisenberg J., Cohen H., Ebstein R. P. and Tyano S. (2000) "Failure to replicate an excess of the long dopamine D4 exon III repeat polymorphism in ADHD in a family-based study." Am J Med Genet, 96(3): 278-81.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size
Predominant Ethnicity	Jews
Population	Israel
Gender	42 males and 7 females
Age Group	Children/Adolescents : aged 6-17 years, mean age 9.89 years (SD=2.76)

Detail Info

Summary	In the current study they independently recruited an group of 49 triads from a different geographical location (Petak Tikvah) in Israel but having a similar ethnic background. In contrast to previous findings from a number of groups, in the current study an excess of the long DRD4 alleles was observed in the HRR control group compared to the ADHD subjects (Likelihood ratio = 5.50, P=0.02). In the expanded Israeli group of 98 triads examined for the DRD4 repeat polymorphism there is an excess of the long alleles in the HRR control group (Likelihood ratio = 3.81, P=0.05). These results attest to the complexity of ADHD inheritance and the likelihood that genetic heterogeneity characterizes this disorder especially across ethnic and cultural boundaries.
Total Sample	The probands consisted of 42 males and 7 females from 47 families. The percentage of probands with ADHD com-bined type was 87% and inattentive 13%.
Sample Collection	ADHD subjects and their famalies were recruited for participation in this study from the ADHD unit in the Children and Adolescents Division of Geha Mental Health Center that primarily serves the central part of Israel (greater municipal Tel-Aviv area). Triad families included all diagnosed ADHD children who had two biological parents, and included both Ashkenazi and non-Ashkenazi Jews. The Ethics Committee of the Israeli Health Ministry approved this study and written informed consent was obtained from participating subjects.
Diagnosis Description	ADHD diagnosis followed DSM IV guidelines that recognizes three types of ADHD: ADHD-Predominantly Inattentive (Type I), ADHD-Predominantly Hyperactive Impulse (Type II), and ADHD-Combined Type (III). The informants were the parents, the teacher, and the proband. The parents and the proband were interviewed by an experienced psychiatrist using a semi-structured interview based on DSM-IV criteria for ADHD and Conduct Disorder. When available, teachers were also informants and along with parents were interviewed using two instruments: the abbreviated Conners Rating Scales [Conners, 1998] and the Child Behavior Check List [Hudziak et al., 1999]. Probands were also administered the Test Of Variables of Attention (T.O.V.A.), which is a computerized Continuous Performance Test [Greenberg and Waldman, 1993]. Cases were excluded with a primary diagnosis of Pervasive Developmental Disorder, physically handicapped, psychosis, mental retardation, epilepsy, hyperthyroidism, evidence or history of child abuse, adoption. IQ was determined by WISC and children with an IQ less than 80 were excluded.
Technique	The exon III repeat region of the DRD4 receptor was characterized by PCR. The PCR products were resolved on a 2% Metaphor (FMC Bio products) gel. It should be noted that in the new cohort all probands with the long alleles (6-8 repeats) were distinguished by the seven repeat and in essence, they compared seven versus non-seven repeats.
Analysis Method	The haplotype relative risk (HRR)
Result Description	No difference was observed between the ADHD and HRR control group (Likelihood ratio=7.94, P=0.16). When the DRD4 repeat polymorphism is grouped by the short versus long alleles there is a significant excess of the DRD4 long repeat in the HRR control group (Likelihood ratio=5.50, P=0.02). Similarly, when the expanded group of 98 ADHD triads independently recruited from two geographical areas in Israel are examined, a significant excess of the DRD4 exon III long alleles is also observed (Likelihood ratio=3.81, P=0.05). A similar tendency for an excess of the DRD4 long repeat in the HRR control group, that did not reach statistical significance, was observed when the expanded sample was grouped by the two main DSM IV categories, combined (Likeli-hood ratio=1.93, P=0.17) and inattentive variety (Likelihood ratio=2.06, P=0.15) of ADHD.

Other variant reported by this study (count: 1)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
DRD4 exon3 VNTR	2-8 repeats, short(2-5)/long(6-8)		HRR test: P-value=0.02 for current 49 triads, P-value=0.05 f...... HRR test: P-value=0.02 for current 49 triads, P-value=0.05 for combined 98 triads; P-value=0.17 for ADHD combined type; P-value=0.15 for inattentive type More...	there is a significant excess of the DRD4 long repeat in the HRR control group	Significant

Genes reported by this study (count: 1)