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	Turic D, 2004 (a)14966475
Citation	Turic D., Langley K., Mills S., Stephens M., Lawson D., Govan C., Williams N., Van Den Bree M., Craddock N., Kent L., Owen M., O'Donovan M. and Thapar A. (2004) "Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD." Mol Psychiatry, 9(2): 169-73.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	238 families
Predominant Ethnicity	Caucasian
Population	United Kingdom
Gender	90% male and 10% female
Age Group	Children/Adolescents : aged 5-15 years, mean age 9.6 years

Detail Info

Summary	Linkage findings suggested evidence of a susceptibility locus on chromosome 16p13 (maximum LOD score of 4.2, P=5E-6) was reported. The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage. As this is also a good functional candidate gene for ADHD, they undertook family-based association analysis in a sample of 238 families. Significant evidence of association with a GRIN2A exon 5 polymorphism (P=0.01) was found. The data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al. They conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted.
Total Sample	The sample in this study consisted of 238 families. A total of 157 of these families were complete trios (child and both parents). Subjects were of Caucasian origin. The study was originally based on 161 families but sample collection is ongoing and given the positive findings, genotyping was later extended to include more recently collected families to expand the sample size.
Sample Collection	The study was originally based on 161 families but sample collection is ongoing and given the positive findings, genotyping was later extended to include more recently collected families to expand the sample size.
Diagnosis Description	The sample in this study consisted of 238 families in which the children met full diagnostic criteria for DSM-III-R/DSM-IV ADHD or ICD-10 hyperkinetic disorder after comprehensive assessment using standard research diagnostic interviews (full details of assessment and diagnostic procedures are described in Holmes et al.). Those with IQ test scores below 70, autism (screened using the Autism Screening Questionnaire), Tourette's syndrome and any neurological condition were excluded.
Technique	Three SNPs (Grin2a_5, Grin2a_10, Grin2a_13) were genotyped in the original association sample (n=161 families) by single nucleotide primer extension using a fluorescence polarisation (FP) assay based upon AcycloPrimet reagents (Perkin Elmer Life Science Products, Boston, MA, USA) according to the manufacturer's recommendations. Analyses were performed using a LJL Biosystems Analystt platform.
Analysis Method	The genotypic data were analysed for complete parent/child trios and mother/child duos using the statistical package TRANSMIT. Data from all available families were analysed and we also used the option of specifying a maximum allowable ambiguity for parental haplotypes of two. However, as the use of incomplete families may lead to spurious association, TDT analysis for complete trios only was also undertaked. Evidence for association between haplotypes constructed from the three markers and ADHD was sought using TRANSMIT. Linkage disequilibrium (LD) between markers (D' and r²) was calculated from the estimated haplotype probabilities produced by TRANSMIT.
Result Description	Initially, the study was based on a sample of 161 families. The exon 5 synonymous SNP (Grin2a_5) yielded evidence for association (P=0.01). No significant evidence was obtained for the exon 13 SNP #5765C/T (Grin2a_13; P=0.13) or the exon 10 SNP (Grin2a_10; P=0.08). Construction of the haplotypes from the three SNPs in the initial sample yielded weaker evidence for association (P=0.34) than did the exon 5 SNP alone in the same sample. Similarly, haplotypes of all combinations of pairs of markers also yielded no extra association evidence beyond that achieved with the exon 5 SNP alone. Each of the markers showed moderate to strong LD. In particular, the exon 5 and exon 10 SNPs were in strong LD. Given that the exon 13 SNP #5765C/T and the exon 10 SNP add no further information to the analysis, these were not followed up further in the newly recruited sample. However, they further genotyped 77 additional, newly recruited families for the exon 5 SNP CTG(L)325CTA(L). The enlarged sample continued to provide evidence for association (P=0.01) with this SNP. More conservatively, when the analysis was restricted to complete trios (n=157 families), the results remained significant (G allele; 78 transmissions, 55 nontransmissions; P=0.04; 10000 simulations). The estimate for the odds ratio was 1.4.

Other variant reported by this study (count: 3)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
GRIN2A exon5 G325A	G/A	G	TDT P-value=0.01 for initial 161 families; P-value=0.01 for ...... TDT P-value=0.01 for initial 161 families; P-value=0.01 for the enlarged sample; P-value=0.04 (OR=1.4) for complete trios More...	Evidence for association was found based on the initial 161 families. The enlarged sample continued to provide evidence for association with this SNP. More conservatively, when the analysis was restricted to complete trios, the results remained significant.	Significant
GRIN2A 3'-UTR #5765C/T	C/T		TDT P-value=0.13 for initial 161 families; P-value=0.13 for ...... TDT P-value=0.13 for initial 161 families; P-value=0.13 for all available families More...	No significant evidence was obtained	Non-significant
GRIN2A exon10 G695A	G/A		TDT P-value=0.08 for initial 161 families; P-value=0.11 for ...... TDT P-value=0.08 for initial 161 families; P-value=0.11 for all available families More...	No significant evidence was obtained	Non-significant

Genes reported by this study (count: 1)