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	Smith KM, 200515635701
Citation	Smith K. M., Bauer L., Fischer M., Barkley R. and Navia B. A. (2005) "Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder." Am J Med Genet B Neuropsychiatr Genet, 133B(1): 57-63.
Study Design	case-control and family-based
Study Type	Candidate-gene association study
Sample Size	103 cases and 66 controls; 35 families composed of trios or affected sib pairs (ASP)
Predominant Ethnicity	Caucasian
Population	USA
Gender	case-control: 91% male, 9% female
Age Group	Children/Adolescents and Adults : case-control: 25-32 years; family-based: 7-18 years

Detail Info

Summary	This study aimed to identify polymorphisms in NR4A2 and test their association to ADHD. Database analysis revealed a CA repeat polymorphism in the 3' UTR of NR4A2 that was confirmed by PCR. SSCP screening revealed a common DeltaC polymorphism, 254 bp 5' to the transcriptional start site. These polymorphisms were tested for an association with ADHD in both a case control study of individuals from the MilwaUnited Kingdomee Longitudinal Study of ADHD (103 cases and 66 controls), and in 35 families composed of trios or affected sib pairs (ASP) with ADHD. Functional effects of the promoter polymorphism were tested in vitro. The non-deleted allele was significantly more active in undifferentiated SK-N-MC cells compared to differentiated SK-N-MC and HeLa cells while a trend for increased activity for the DeltaC allele was observed in undifferentiated SK-N-MC cells. Identification of these polymorphisms may aid future candidate gene studies in disorders with altered dopamine signaling, such as schizophrenia Parkinson's disease and ADHD.
Total Sample	Genotyping results from a subgroup of 103 Caucasian hyperactive and 66 Caucasian control individuals were included in this study. The gender composition of this group was 91% male and 9% female. The subjects from both groups are 25-32 years of age and are being re-evaluated in an ongoing follow-up phase of this project. Subjects for the ASP and trios (32 ASP and 3 trios) were recruited from two clinics in Massachusetts between 1997 and 2001.
Sample Collection	Case-control: subject recruitment for the MilwaUnited Kingdomee longitudinal study of ADHD has been previously described [Barkley et al., 1990; Smith et al., 2003]. Family-based: subjects for the ASP and trios (32 ASP and 3 trios) were recruited from two clinics in Massachusetts between 1997 and 2001.
Diagnosis Description	For the MilwaUnited Kingdomee (case-control) cohort, at the time of initial ascertainment, it is likely that all subjects would have met DSM-IV criteria for the Combined subtype of ADHD since all subjects were 2 standard deviations above the norm for hyperactivity and inattention at the time of ascertainment [Barkley et al., 1990; Smith et al., 2003]. The subjects from both groups are 25¨C32 years of age and are being re-evaluated in an ongoing follow-up phase of this project. Families with more than one child between 7 and 18 years of age who met clinical diagnostic criteria for ADHD (Combined, Inattentive, or Hyperactive type) were initially identified by review of clinic records, contacted, and those interested in participating were sent a rating scale of ADHD symptoms based on DSM-IV criteria. For more research diagnosis descriptions, please refer to the original publication.
Technique	DNA was extracted from whole blood using Gentra System's Puregene Kit (Minneapolis, MN).DNA from 32 MilwaUnited Kingdomee Study control subjects, 56 ADHD subjects, and two CEPH reference individuals (1331-1 and 1331-2, obtained through Coriell Cell Repositories),and used to screen for polymorphisms in the NR4A2 gene by SSCP. DNA was sequenced manually using the dsDNA Cycle Sequencing System (Gibco BRL) or by an automated sequencing system (ABI Prism Model 3100 version 3.4.1). Template PCR products were purified with the QIAquick PCR purification kit (Qiagen, Valencia, CA). Sequences were analyzed with the DNA Strider 1.2 software program.
Analysis Method	For case control studies, chi square analysis using the GENEPOP program was used to test for association between the NR4A2 alleles and ADHD. For family studies, TDT analysis (using both affected siblings) was performed in order to test for preferential transmission of alleles to affected individuals [Spielman et al., 1993]. For haplotype TDT analysis, the TRANSMIT program (version 2.5.4) was used to test for preferential transmission of the haplotypes [Clayton, 1999; Clayton and Jones, 1999].
Result Description	The non-deleted allele was significantly more active in undifferentiated SK-N-MC cells compared to differentiated SK-N-MC and HeLa cells while a trend for increased activity for the DeltaC allele was observed in undifferentiated SK-N-MC cells. Identification of these polymorphisms may aid future candidate gene studies in disorders with altered dopamine signaling, such as schizophrenia Parkinson's disease and ADHD.

Other variant reported by this study (count: 2)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
NR4A2 3'-UTR (CA)n	S/L		allelic TDT P-value=0.15, X²=2.083; genotypic chi...... allelic TDT P-value=0.15, X²=2.083; genotypic chi-square P-value=0.91 in two different study groups More...	chi square analysis comparing allele frequencies did not reveal significant differences; for the family association studies, TDT analysis revealed a weak trend towards increased transmission of short allele	Non-significant
NR4A2 upstream deltaC BglI	non-deleted/DeltaC		allelic TDT P-value=0.40, X²=0.714; genotypic chi...... allelic TDT P-value=0.40, X²=0.714; genotypic chi-square P-value=1.0 in two different study groups More...	no association between ADHD and either allele was observed	Non-significant

Genes reported by this study (count: 1)