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	Ribases M, 200818179783
Citation	Ribases M., Hervas A., Ramos-Quiroga J. A., Bosch R., Bielsa A., Gastaminza X., Fernandez-Anguiano M., Nogueira M., Gomez-Barros N., Valero S., Gratacos M., Estivill X., Casas M., Cormand B. and Bayes M. (2008) "Association study of 10 genes encoding neurotrophic factors and their receptors in adult and child attention-deficit/hyperactivity disorder." Biol Psychiatry, 63(10): 935-45.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	216 adult cases and 330 children, 546 unrelated controls
Predominant Ethnicity	Caucasian
Population	Spain
Gender	seventy-nine percent of patients were male (73.1% of adults and 82.4% of children
Age Group	Children/Adolescents and Adults : 9.3 years (SD=2.6) for childhood ADHD patients, 29.6 years (SD=12.06) for adulthood ADHD patients, and 39.9 years (SD=17.0) for the control group

Detail Info

Summary	They performed a population-based association study in 546 ADHD patients (216 adults and 330 children) and 546 gender-matched unrelated control subjects with 183 single nucleotide polymorphisms covering 10 candidate genes that encode four neurotrophins (NGF, BDNF, NTF3, and NTF4/5), a member of the cytokine family of NTFs (CNTF), and their receptors (NTRK1, NTRK2, NTRK3, NGFR, and CNTFR). The single-marker and haplotype-based analyses provided evidence of association between CNTFR and both adulthood and childhood ADHD and also suggested a childhood-specific contribution of NTF3 and NTRK2 to ADHD. The data suggest that variations in NTFs might be involved in the genetic susceptibility to ADHD, support the contribution of the CNTFR locus as a predisposition factor for the disorder, and suggest that NTF3 and NTRK2 might be involved in the molecular basis of the age-dependent changes in ADHD symptoms throughout life span.
Total Sample	The clinical sample consisted of 546 Caucasoid patients with ADHD recruited from two centers in the Barcelona area (Spain) between 2004 and 2007. All subjects met DSM-IV criteria for ADHD and consisted of 216 adult cases and 330 children. The control sample consisted of 546 unrelated Caucasoid blood donors recruited from the Blood and Tissue Bank at Hospital Universitari Vall d¡¯Hebron for whom DSM-IV ADHD symptoms were retrospectively excluded.
Sample Collection	Caucasoid
Diagnosis Description	The diagnosis of ADHD in adulthood was evaluated with the Structured Clinical Interview for DSM-IV Axis I and II Disorders (SCID-I and SCID-II) and the Conners' Adult ADHD Diagnostic Interview for DSM-IV (CAADID Part I and II). All children were evaluated with the present and lifetime version of the Schedule for Affective Disorders and Schizophrenia for School-age children (KSADS-PL) reported by parents. All subjects met DSM-IV criteria for ADHD and consisted of 216 adult cases (66.7% combined ADHD, 28.7% inattentive ADHD, and 4.6% hyperactive- impulsive ADHD patients) and 330 children (73.3% combined ADHD, 21.8% inattentive ADHD, and 4.9% hyperactive- impulsive ADHD patients).
Technique	Genomic DNA was isolated from peripheral blood lymphocytes by the salting-out procedure or with magnetic bead technology with the Chemagic Magnetic Separation Module I and the Chemagic DNA kit, according to the manufacturer's recommendations. All SNPs were genotyped with the SNPlex platform as described by Tobler et al. Finally, the specifically bound fluorescent probes were eluted and analyzed with an Applied Biosystems 3730xl DNA Analyzer.
Analysis Method	The analysis of HWE and the comparison of both genotype and allele frequencies between cases and control subjects were performed with the SNPassoc R library. For the multiple comparison correction, they considered all tests performed and assumed a false discovery rate (FDR) of 10% with the Q-value R library, which corresponds to a significance threshold of P-value<8.1e-04. The Bonferroni correction, taking into account 166 SNPs and both adult and childhood samples, set the significance threshold at P-value<1.5e-04. To evaluate potential additive and epistatic effects between the risk haplotypes identified, they first assigned specific estimated haplotypes to individuals considering cases and control subjects separately with the PHASE 2.0 software. Then they implemented a stepwise logistic regression procedure with the SPSS 12.0 statistical package. Epistasis analysis was performed by taking genes two-by-two and comparing two different regression models by a likelihood ratio test.
Result Description	The single-marker and haplotype-based analyses provided evidence of association between CNTFR and both adulthood (P-value= .0077, odds ratio [OR]=1.38) and childhood ADHD (P-value=9.1e-04, OR=1.40) and also suggested a childhood-specific contribution of NTF3 (P-value=3.0e¨C 04, OR=1.48) and NTRK2 (P-value=.0084, OR=1.52) to ADHD. The data suggest that variations in NTFs might be involved in the genetic susceptibility to ADHD, support the contribution of the CNTFR locus as a predisposition factor for the disorder, and suggest that NTF3 and NTRK2 might be involved in the molecular basis of the age-dependent changes in ADHD symptoms throughout life span.

SNPs reported by this study (count: 18)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs10780695			genotypic P-value=0.067; genotypic P-value=0.083 in dominant model; genotypic P-value=0.048, OR=1.78 (1.02-1.61) in recessive model; allelic P-value=0.03, OR=1.28 (1.02-1.59) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs1080750			genotypic P-value=0.12; genotypic P-value=0.14 in dominant model; genotypic P-value=0.063 in recessive model; allelic P-value=0.048, OR=1.23 (1-1.51) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs1073049			genotypic P-value=0.009; genotypic P-value=0.018, OR=1.47 (1.06-2.04) in dominant model; genotypic P-value=0.015, OR=4.5 (1.05-20) in recessive model; allelic P-value=0.0054, OR=1.51 (1.12-2.04) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs1387926			genotypic P-value=8e-04; genotypic P-value=0.0011, OR=1.75 (1.23-2.44) in dominant model; genotypic P-value=0.012, OR=7.14 (.96-50) in recessive model; allelic P-value=3.6e-04, OR=1.75 (1.27-2.4) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs1491850			genotypic P-value=0.11; genotypic P-value=0.05, OR=1.42 (1.00-2.02) in dominant model; genotypic P-value=0.18 in recessive model; allelic P-value=0.04, OR=1.26 (1.01-1.59) in Adults; genotypic P-value=0.12; genotypic P-value=0.057 in dominant model; genotypic P-value=0.15 in recessive model; allelic P-value=0.037, OR=1.24 (1.01-1.51) in Children	provided evidence of association with adulthood and childhoo...... provided evidence of association with adulthood and childhood ADHD More...	Significant
rs11030096			genotypic P-value=0.14; genotypic P-value=0.15 in dominant model; genotypic P-value=0.074 in recessive model; allelic P-value=0.044, OR=1.22 (1-1.49) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs11795386			genotypic P-value=0.018; genotypic P-value=0.0076, OR=1.56 (1.12-2.17) in dominant model; genotypic P-value=0.13 in recessive model; allelic P-value=0.0049, OR=1.12 (1.54-2.08) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs2381164			genotypic P-value=0.03; genotypic P-value=0.083 in dominant model; genotypic P-value=0.015, OR=1.69 (1.11-2.56) in recessive model; allelic P-value=0.015, OR=1.28 (1.05-1.59) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs2856811			genotypic P-value=0.025; genotypic P-value=0.01, OR=1.46 (1.09-1.94) in dominant model; genotypic P-value=0.96 in recessive model; allelic P-value=0.076 in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs1545285			genotypic P-value=0.077; genotypic P-value=0.14 in dominant model; genotypic P-value=0.034, OR=1.47 (1.02-2.13) in recessive model; allelic P-value=0.029, OR=1.25 (1.02-1.52) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs2254404			genotypic P-value=0.005; genotypic P-value=0.003, OR=1.52 (1.15-2.01) in dominant model; genotypic P-value=0.65 in recessive model; allelic P-value=0.038, OR=1.25 (1.01-1.54) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs6332			genotypic P-value=3.7e-04; genotypic P-value=7.7e-04, OR=1.77 (1.26-2.48) in dominant model; genotypic P-value=0.0022, OR=1.65 (1.20-2.27) in recessive model; allelic P-value=1.2e-04, OR=1.47 (1.21-1.78) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs6327			genotypic P-value=0.036; genotypic P-value=0.44 in dominant model; genotypic P-value=0.04, OR=1.49 (1.02-2.16) in recessive model; allelic P-value=0.48 in Adults	provided evidence of association with adulthood ADHD provided evidence of association with adulthood ADHD	Significant
rs550942			genotypic P-value=0.019; genotypic P-value=0.006, OR=1.64 (1.15-2.38) in dominant model; genotypic P-value=0.77 in recessive model; allelic P-value=0.013, OR=1.48 (1.08-2.04) in Adults	provided evidence of association with adulthood ADHD provided evidence of association with adulthood ADHD	Significant
rs3763613			genotypic P-value=0.004; genotypic P-value=0.01, OR=1.54 (1.10-2.13) in dominant model; genotypic P-value=0.2 in recessive model; allelic P-value=0.094 in Adults	provided evidence of association with adulthood ADHD provided evidence of association with adulthood ADHD	Significant
rs719452			genotypic P-value=0.1; genotypic P-value=0.033, OR=1.35 (1.02-1.78) in dominant model; genotypic P-value=0.45 in recessive model; allelic P-value=0.046, OR=1.25 (1-1.56) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant
rs7036351			genotypic P-value=2.5e-04; genotypic P-value=0.0037, OR=1.69 (1.18-2.44) in dominant model; genotypic P-value=0.058 in recessive model; allelic P-value=0.062 in Adults; genotypic P-value=0.073; genotypic P-value=0.022, OR=1.41 (1.05-1.92) in dominant model; genotypic P-value=0.057 in recessive model; allelic P-value=0.03, OR=1.33 (1.02-1.75) in Children	provided evidence of association with adulthood and childhoo...... provided evidence of association with adulthood and childhood ADHD More...	Significant
rs6537860			genotypic P-value=0.023; genotypic P-value=0.0067, OR=1.46 (1.11-1.93) in dominant model; genotypic P-value=0.7 in recessive model; allelic P-value=0.026, OR=1.27 (1.03-1.56) in Children	provided evidence of association with childhood ADHD provided evidence of association with childhood ADHD	Significant

Genes reported by this study (count: 6)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
NTF3	a four-marker haplotype (rs4074967-rs6332-rs6489630-rs795618...... a four-marker haplotype (rs4074967-rs6332-rs6489630-rs7956189) global P-value=2.3e-04, Best Haplotype P-value=2.1e-05, adjusted P-value=1.0e-04, OR=1.48 (1.20-1.84) in children; Haplotype-Specific(TACA) P-value=2.1e-05; OR(CI)=1.6 (1.28-2.00), Haplotype-Specific (TGCA) P-value=3.0e-04; OR(CI)=1.48 (1.20-1.84) in children More...	Significant
CNTFR	a three-marker haplotype (rs7036351-rs1080750-rs1124882) glo...... a three-marker haplotype (rs7036351-rs1080750-rs1124882) global P-value=0.042, Best Haplotype P-value=0.0077, Adjusted P-value=0.031, OR=1.38 (1.10-1.74) in adults; global P-value=0.0069, Best Haplotype P-value=9.1e-04, Adjusted P-value=0.0052, OR=1.40 (1.15-1.72) in children; global P-value=0.0019, Best Haplotype P-value=2.0e-04, Adjusted P-value=0.0014, OR=1.39 (1.17-1.66) in adults and children; Haplotype-Specific(CGC) P-value=0.0077; OR(CI)=1.38(1.10-1.74) in adults; Haplotype-Specific(CGC) P-value=9.1e-04; OR(CI)=1.40(1.15-1.72) in children; Haplotype-Specific(CGC) P-value=2.0e-04; OR(CI)=1.39(1.17-1.66) in children and adults More...	Significant
NTRK2	a four-marker haplotype(rs7816-rs11795386-rs1387926-rs158668...... a four-marker haplotype(rs7816-rs11795386-rs1387926-rs1586681) global P-value=2.1e-04, Best Haplotype P-value=1.5e-04, adjusted P-value=0.0030, OR=1.52 (1.16-1.98) in children; Haplotype-Specific (ACGA) P-value=0.0084; OR(CI)=1.52 (1.17-1.98), Haplotype-Specific(ATAA) P-value=1.5e-04; OR(CI)=3.92 (1.85-8.32) in children More...	Significant
CNTF	1 SNP showed significant association with both adulthood and...... 1 SNP showed significant association with both adulthood and childhood ADHD; 2 SNP showed significant association with childhood ADHD; 1 SNP showed significant association with adulthood ADHD More...	Significant
BDNF	1 SNP showed significant association with both adulthood and...... 1 SNP showed significant association with both adulthood and childhood ADHD; 1 SNP showed significant association with childhood ADHD More...	Significant
NGF	4 SNP showed significant association with childhood ADHD; 1 ...... 4 SNP showed significant association with childhood ADHD; 1 SNP showed significant association with adulthood ADHD More...	Significant