| Summary |
BACKGROUND: The purpose of this study was to investigate the association between the ionotropic and glutamate receptors, N-methyl D-asparate 2A (GRIN2A) and 2B (GRIN2B), and the metabotropic glutamate receptor mGluR7 (GRM7) gene polymorphisms and attention-deficit hyperactivity disorder (ADHD) in Korean population. METHODS: We conducted a case-control analysis of 202 ADHD subjects and 159 controls, performed a transmission disequilibrium test (TDT) on 149 trios, and compared scores from the continuous performance test (CPT), the Children's Depression Inventory (CDI), and the State-Trait Anxiety Inventory for Children (STAIC) according to the genotype of the glutamate receptor genes. RESULTS: There were no significant differences in the genotype or allele frequencies of the GRIN2A rs8049651, GRIN2B rs2284411, or GRM7 rs37952452 polymorphisms between the ADHD and control groups. For 148 ADHD trios, the TDT analysis also showed no preferential transmission of the GRIN2A rs8049651 or GRIN2B rs2284411 polymorphisms. However, the TDT analysis of the GRM7 rs3792452 polymorphism showed biased transmission of the G allele (chi2=4.67, p=0.031). In the ADHD probands, the subjects with GG genotype in the GRM7 rs37952452 polymorphism had higher mean T-scores for omission errors on the CPT than did those with the GA or AA genotype (t=3.38, p=0.001). In addition, the ADHD subjects who were homozygous for the G allele in the GRM7 rs37952452 polymorphism had higher STAIC-T (t=5.52,p<0.001) and STAIC-S (t=2.74,p=0.007) scores than did those with the GA or AA genotype. CONCLUSIONS: These results provide preliminary evidence of an association between the GRM7 rs37952452 polymorphism and selective attention deficit and anxiety found within the Korean ADHD population. |
| Total Sample |
We recruited children with ADHD from three child psychiatric clinics at university hospitals in Korea: Seoul National, Kyungpook National, and Chungbuk National Hospitals.In addition, we recruited control group subjects from five different administrative regions in Korea: Seoul, Seongnam,Incheon, Ulsan, and Yeoncheon. The case-control analysis included 202 ADHD subjects , including 174 boys (86.1%);159 controls,including 111 boys (69.8%). The family-based analysis included 149 trios consisting of an affected subject and his or her biological father and mother.All participants were ethnically Korean.The case-control analysis included 202 ADHD subjects with a mean age of 9.0,SD=2.5 years and 159 controls with a mean age of 9.0,SD=2.7 years. Oppositional defiant disorder was the most common (14.4%) comorbid diagnosis, followed by anxiety disorder (6.5%),enuresis (5.5%), and depressive disorder (3.5%). |
| Sample Collection |
We recruited children with ADHD from three child psychiatric clinics at university hospitals in Korea: Seoul National, Kyungpook National, and Chungbuk National Hospitals.In addition, we recruited control group subjects from five different administrative regions in Korea: Seoul, Seongnam,Incheon, Ulsan, and Yeoncheon. |
| Diagnosis Description |
Diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR); Score above the 90th percentile on the ADHD Rating Scale-IV (ARS); a T-score greater than 60 on the attention Problems subscale of the Child Behavior Checklist (CBCL); and an intelligent quotient (IQ) higher than 71 on the Korean Educational Developmental Institute's Wechsler Intelligence Scale for Children (KEDI-WISC) were included into cases. The children were selected for the control group based on the following criteria:(1)did not meet the criteria for a DSM-IV diagnosis of ADHD according to the Korean version of the Diagnostic Interview Schedule for Children Version-IV (DISC-IV);(2)scored below the 90th percentile on the ARS;(3)had a T-score of less than 60 on the Attention Problem subscale of the CBCL; and (4)had an IQ score higher than 71 on the KEDI-WISC.Subjects were excluded from the study if they had one or more of the following: (1) past and/or current history of any neurological disorder, including a seizure disorder or brain damage; and (2) presence of a comorbid psychosis,Tourette's, bipolar, communication, learning, or pervasive developmental disorder. In the ADHD subjects, ADHD and comorbid disorders were diagnosed using the Korean version of the Kiddle Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. |
| Technique |
Genomic DNA was extracted from whole blood lymphocytes using a G-DEXTM II Genomic DNA Extraction Kit (Intron, Korea). The detection of a single nucleotide polymorphism was based on an analysis of primer extension products generated from previously amplified genomic DNA using a chip-based matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform (Sequenom, California, USA). Primers in the PCR and homogeneous Mass Extend (hME) reactions were designed using Assay Designer 3.1 (Sequenom) |
| Analysis Method |
All data analyses were performed using the Statistical Package for Social Sciences (Version 19.0 for Windows;SPSS, Inc., Chicago, IL, USA).For all data from 202 patients with ADHD and 159 controls, allele frequencies were calculated, and the occurrence of Hardy-Weinberg equilibrium was established by way of goodness-of-fit X2 tests. Genotype distribution for each polymorphism was in agreement with the expected values of the Hardy-Weinberg equilibrium (p>0.05).A family-based study was performed to assess genetic association by transmission disequilibrium test (TDT) statistics.Subjects with ADHD were divided into genotype groups on the basis of their GRIN2A rs8049651, GRIN2B rs2284411, or GRM7 rs37952452 polymorphism.Due to the small number of individuals having two rare alleles,subjects were dichotomized according to whether they possessed the rare A allele (recessive model). Group differences in the continuous clinical variables were examined using an independent two sample t-test.Between-group comparisons with categorical data were assessed using the X2 test or Fisher`s exact test.The significance level was set at p=0.05 (two-tailed). |
| Result Description |
There were no significant differences in the genotype or allele frequencies of the GRIN2A rs8049651, GRIN2B rs2284411, or GRM7 rs37952452 polymorphisms between the ADHD and control groups. For 148 ADHD trios, the TDT analysis also showed no preferential transmission of the GRIN2A rs8049651 or GRIN2B rs2284411 polymorphisms. However, the TDT analysis of the GRM7 rs3792452 polymorphism showed biased transmission of the G allele (chi2=4.67, p=0.031). In the ADHD probands, the subjects with GG genotype in the GRM7 rs37952452 polymorphism had higher mean T-scores for omission errors on the CPT than did those with the GA or AA genotype (t=3.38, p=0.001). In addition, the ADHD subjects who were homozygous for the G allele in the GRM7 rs37952452 polymorphism had higher STAIC-T (t=5.52,p<0.001) and STAIC-S (t=2.74,p=0.007) scores than did those with the GA or AA genotype. CONCLUSIONS: These results provide preliminary evidence of an association between the GRM7 rs37952452 polymorphism and selective attention deficit and anxiety found within the Korean ADHD population. |
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