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	Landaas ET, 201020113357
Citation	Landaas E. T., Johansson S., Jacobsen K. K., Ribases M., Bosch R., Sanchez-Mora C., Jacob C. P., Boreatti-Hummer A., Kreiker S., Lesch K. P., Kiemeney L. A., Kooij J. J., Kan C., Buitelaar J. K., Faraone S. V., Halmoy A., Ramos-Quiroga J. A., Cormand B., Reif A., Franke B., Mick E., Knappskog P. M. and Haavik J. (2010) "An international multicenter association study of the serotonin transporter gene in persistent ADHD." Genes Brain Behav, 9(5): 449-58.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	448 cases and 580 controls
Predominant Ethnicity	Caucasian
Population	Norway, Germany, the Netherlands, Spain, USA
Gender	Norway, 53% male; the Netherlands, 49% male; Germany, 53% male; Spain, 72% male, USA 41% male
Age Group	Adults : >18 years

Detail Info

Summary	They tested the functional promoter polymorphism 5-HTTLPR and seven single nucleotide polymorphisms in SLC6A4 for association with ADHD in 448 adult ADHD patients and 580 controls from Norway. Replication attempts were performed in a sample of 1454 Caucasian adult ADHD patients and 1302 controls from Germany, Spain, the Netherlands and USA, and a meta-analysis was performed also including a previously published adult ADHD study. They found an association between ADHD and rs140700 [odds ratio(OR)=0.67; P-value=0.01] and the short (S) allele of the 5-HTTLPR (OR=1.19; P-value=0.06) in the Norwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females (rs140700: OR=0.45; P-value=0.00084). However, the meta-analysis of 1894 cases and 1878 controls could not confirm the association for rs140700 [OR=0.85, 95% confidence interval (CI)=0.67-1.09; P-value=0.20]. For 5-HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta-analysis refuted a strong effect (OR=1.10, 95% CI=1.00-1.21; P-value=0.06). Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety. In conclusion, the results do not support a major role for SLC6A4 common variants in persistent ADHD, although a modest effect of the 5-HTTLPR and a role for rare variants cannot be excluded.
Total Sample	The Norwegian sample consists of 448 Caucasians of Norwegian ancestry (237 males and 211 females) of more than 18 years of age, diagnosed with ADHD or hyperkinetic disorder. The control group of 580 Norwegian adults (257 males and 323 females) consisted of 195 healthy blood donors (for whom only gender was known) and a random sample of 385 healthy volunteers (aged 18-40 years) recruited from all over Norway for the purpose of this study. The replication samples obtained through the IMpACT consortium included a total of 1454 cases and 1302 controls from Spain, Germany, the Netherlands and USA.
Replication Size	a total of 1454 cases and 1302 controls
Sample Collection	Caucasian
Diagnosis Description	The Norwegian samples were diagnosed with ADHD or hyperkinetic disorder using either the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) or International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) protocols. For the control group, no exclusion criteria were applied for the random controls. The replication samples were diagnosed in accordance with the DSM-IV criteria; onset before the age of 7, lifelong persistence and current diagnosis. For more detailed description, please refer to the original article.
Technique	Norwegian sample: The SNPs were genotyped using the MassARRAY iPLEX System. The promoter insertion/deletion polymorphism, 5-HTTLPR, was amplified by the polymerase chain reaction (PCR) and genotyped by fragment analysis on the ABI3100 using fluorescently labeled reverse primers. The genotypes were automatically called using the GENEMAPPER software, and they were subsequently manually inspected. Replication samples from Spain, Germany, the Netherlands and USA: The SNP rs140700 was either genotyped in Norway (samples from Norway, Spain and the Netherlands) or in Germany (German samples) using the MassARRAY iPLEX System as described above. Genotyping for the replication samples from USA was conducted at the Psychiatric and Neurodevelopmental Genetics Unit of the Massachusetts General Hospital using a single base extension reaction with allele discrimination by MassARRAY mass spectrometry system. In addition, ninety-three individuals from the Norwegian patient group were sequenced for the 13 protein-coding exons of SLC6A4 (exon 3-15, NM 001045), including exon-intron boundaries, aswell as the 3'UTR, all following a standard Sanger sequencing method.
Analysis Method	The statistical analyses of dichotomous traits were performed with the PLINK software. All analyses were based on an additive allelic model. Analyses and visualization of linkage disequilibrium (LD) was performed with the HAPLOVIEW software. The meta-analyses presented were performed with a random effects model. Similar results were also obtained using the PLINK meta-analysis option.
Result Description	They found an association between ADHD and rs140700 and the short (S) allele of the 5-HTTLPR in theNorwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females. However, the meta-analysis of 1894 cases and 1878 controls could not confirm the association for rs140700. For 5-HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta-analysis refuted a strong effect. Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety.

SNPs reported by this study (count: 7)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs2020942	A/G		P-value=0.43, OR=0.93 in the Norwegian samples; P-value=0.61, OR=0.94 in the Norwegian samples; P-value=0.63, OR=0.94 in the Norwegian males	no significant association no significant association	Non-significant
rs16965628	G/C		P-value=0.86, OR=0.97 in the Norwegian samples; P-value=0.45, OR=0.83 in the Norwegian samples; P-value=0.68, OR=1.1 in the Norwegian males	no significant association no significant association	Non-significant
rs140700	A/G		P-value=0.011, OR=0.67 in the Norwegian samples; P-value=0.00084, OR=0.45 in the Norwegian samples; P-value=0.68, OR=0.92 in the Norwegian males; meta-analysis P-value=0.20, OR=0.85 for A allele	showed an association between rs140700 and ADHD in the Norwe...... showed an association between rs140700 and ADHD in the Norwegian sample, and this association was mainly restricted to females; but the the meta-analysis did not support the association More...	Significant
rs11657536	A/G		P-value=0.3, OR=0.74 in the Norwegian samples; P-value=0.085, OR=0.48 in the Norwegian females; P-value=0.67, OR=1.2 in the Norwegian males	no significant association no significant association	Non-significant
rs8076005	G/A		P-value=0.27, OR=0.88 in the Norwegian samples; P-value=0.029, OR=0.69 in the Norwegian samples; P-value=0.59, OR=1.09 in the Norwegian males	associated with ADHD in females in the stratified analysis i...... associated with ADHD in females in the stratified analysis in the Norwegian sample More...	Significant
rs4583306	G/A		P-value=0.12, OR=1.15 in the Norwegian samples; P-value=0.047, OR=1.29 in the Norwegian samples; P-value=0.9, OR=1.02 in the Norwegian males	associated with ADHD in females in the stratified analysis i...... associated with ADHD in females in the stratified analysis in the Norwegian sample More...	Significant
rs4251417	A/G		P-value=0.3, OR=0.86 in the Norwegian samples; P-value=0.55, OR=0.89 in the Norwegian samples; P-value=0.42, OR=0.85 in the Norwegian males	no significant association no significant association	Non-significant

Other variant reported by this study (count: 1)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
5HTTLPR	short/long		P-value=0.061, OR=1.19 in the Norwegian samples; P-value=0.0...... P-value=0.061, OR=1.19 in the Norwegian samples; P-value=0.016, OR=1.36 in the Norwegian samples; P-value=0.98, OR=1 in the Norwegian males; meta-analysis P-value=0.06, OR=1.10 for S allele More...	a trend for an association between the 5-HTTLPR S allele and ADHD in the Norwegian sample, especially significant in females, but the meta-analysis refuted a strong effect	Significant

Genes reported by this study (count: 1)