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

Detail ...

Study Report

Basic Info

Reference	Nyman ES, 200718030083
Citation	Nyman E. S., Ogdie M. N., Loukola A., Varilo T., Taanila A., Hurtig T., Moilanen I. K., Loo S. K., McGough J. J., Jarvelin M. R., Smalley S. L., Nelson S. F. and Peltonen L. (2007) "ADHD candidate gene study in a population-based birth cohort: association with DBH and DRD2." J Am Acad Child Adolesc Psychiatry, 46(12): 1614-21.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	188 cases and 166 controls
Predominant Ethnicity	Caucasian
Population	Finland
Gender	228 males and 126 females
Age Group	Children/Adolescents : aged 15

Detail Info

Summary	So far, the most promising candidate genes for ADHD have been those involved in dopamine and serotonin pathways. This study tests a series of allelic variants within such candidate genes to determine their potential influence on ADHD susceptibility. They used a population sample ascertained from a birth cohort of a subpopulation of Finland, characterized by founder effect and isolation, thus minimizing genetic heterogeneity. The subjects were systematically ascertained using DSM-IV diagnostic criteria for ADHD from the Northern Finland Birth Cohort 1986 of more than 9,000 individuals, resulting in the study sample of 188 ADHD cases and 166 controls. They genotyped markers in 13 candidate genes, including critical components of dopamine and serotonin pathways. Evidence for association of ADHD with allelic variants of the dopamine B-hydroxylase (DBH) and dopamine receptor D2 (DRD2) genes was reported. This study supports the involvement of the dopamine pathway in the etiology of ADHD; specifically the genes DBH and DRD2 deserve more attention in further studies.
Total Sample	In the total study sample, 188 cases and 166 controls were identified. Of these, at least 159 cases and 151 controls were genotyped for each of the attempted markers. All of the genotyping occurred without knowledge of case-control status.
Sample Collection	The ADHD study sample was ascertained as described in detail by Smalley et al. (2007), using DSM-IV diagnostic criteria for ADHD cases and controls from the Northern Finland Birth Cohort 1986 (N=9,432 live-born individuals), a 1-year population-based birth cohort from the two northernmost provinces of Finland. This regional subpopulation of Finland represents an isolated population characterized by founder effect and more genetic homogeneity. Prospective longitudinal collection of an extensive amount of phenotype data has been carried out on the cohort members from the prenatal period onward (Jarvelin et al., 1993).
Diagnosis Description	At age 15 the subjects' parents were requested to complete the Strengths and Weaknesses of ADHD-Symptoms and Normal-Behaviors (SWAN) rating scale (Swanson et al., 2001a, 2001b). Based on SWAN screening, subjects were invited for further evaluation to determine their participation as either cases or controls. Clinical assessment included the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, a semistruc- tured interview for the assessment of ADHD and other psychiatric disorders (Kaufman et al., 1997). Final ADHD diagnoses were based on all of the information gathered on subjects using a best estimate procedure and DSM-IV criteria. Cases included in this study met a definite or probable lifetime diagnosis of ADHD. Probable cases fell one symptom short of diagnosis but met age of onset and impairment criteria. Controls were included if they met best estimate criteria as unaffected and were classified as SWAN controls. For a more detailed description of the sample and assessments, see Smalley et al. (2007). All of the study subjects provided informed consent under the University of Oulu and University of California, Los Angeles institutional review boards.
Technique	DNA was extracted from study participants' blood according to standard protocols (Vandenplas et al., 1984). SNPs in DRD1-DRD5 were genotyped using Sequenom's MassARRAY technology (Sequenom, San Diego, CA). Polymerase chain reaction (PCR) and extension primers were designed using SpectroDESIGNER 2.0 software (sequences available on request), and SNPs were genotyped in 3- to 6-plex reactions using the standard protocols. The average success rate for the Sequenom SNP data was 97%. SNPs in DAT1, DBH, TH, 5HTT, COMT, GRIN2A, MAOA, and SNAP25 were genotyped using TaqMan SNP Genotyping Assays and the 7900HT Fast Real-Time PCR System for fluorescent read detection and allelic discrimination using the manufacturers' specifications. The average success rate for the TaqMan SNP data was 99%. SNPs not failing the Hardy-Weinberg equilibrium (p<0.05) were included in the study. The 48-base pair variable number of tandem repeats (VNTR) polymorphism in DRD4 exon 3 was amplified in a modification of a previously described method (Lichter et al., 1993). The length of the fragments was determined using an ABI 3730 DNA analyzer (Applied Biosystems), called with GeneMapper version 3.0 software and verified manually. The DBH microsatellite (GT repeat) was genotyped according to previously described specifications (Wei et al., 1997). Genotypes were determined using an ABI 3700 DNA analyzer and called using Genotyper version 2.1 software. The 40-base pair (bp) VNTR in the DAT1 3'-untranslated region (UTR) was genotyped according to a method described previously (Cook et al., 1995). The length of the fragments was determined by 3% agarose gel electrophoresis. Genotypes were inspected visually and called twice independently. The 30-bp MAOA VNTR was genotyped according to a previously described procedure (Sabol et al., 1998). Products were separated on an ABI 3700 DNA analyzer and genotypes were called using Genotyper version 2.1 software. The 5HTTLPR was genotyped using a method described previously (Manor et al., 2001). VNTR, 5HTTLPR, and microsatellite polymorphisms were tested for Hardy-Weinberg equilibrium using the GENEPOP or PEDSTATS software program, and markers not failing the Hardy- Weinberg equilibrium ( p<0.05) were included in the study. The average success rate was 97%.
Analysis Method	The DRD4 VNTR was analyzed both as a multiallelic marker and as a biallelic marker based on carrier status of the long alleles (>=6 repeats). The DAT1 VNTR was analyzed as a biallelic marker after removing two individuals with a rare allele. Haploblocks were determined using HAPLOVIEW, and haplotypes were constructed using PHASE2.1.1 software (Adkins, 2004; Stephens and Donnelly, 2003; Stephens et al., 2001). Rare (frequency <0.05) haplotypes were clustered together into composite haplotypes. Analyses of biallelic marker data were performed using the SAS software package version 9.1.3. Logistic regression was used for testing association between genotypes or haplotypes and ADHD. Modeling was done using sex as a covariate and for males and females separately. Comparisons were made between different genotypes and carriers of different alleles for single markers, and between presence versus absence or different copy counts for haplotypes. Analyses of multiallelic marker data were done using LRTCC, an in-house program performing genotype- and allele-based likelihood ratio and randomization tests for calculating P- values. Power calculations were performed using the Genetic Power Calculator program (Purcell et al., 2003). Results were not corrected for type I errors due to limitations of sample size and magnitude of gene effects investigated. Instead, reliability of the findings is to be evaluated based on independent replications or refutations.
Result Description	Logistic regression analyses provide evidence of association with ADHD for markers in four genes, DRD2, DBH, DAT1, and 5HTT. Association for rs2073837 in the DBH intron 12 was detected. The minor homozygote was risk conferring compared with the major homozygote adjusted for sex and an even stronger effect was seen in males. Association was also observed in males only for three intronic DRD2 SNPs and an SNP in the 3'-UTR, the DRD2 Taq1A RFLP. For all of the SNPs the minor allele was risk conferring, giving odds ratios between 1.9 and 2.1. No evidence of association was seen in the complete sample or in females. For DAT1, some evidence of association was found for an SNP (rs12516948) in the 3'-UTR. However, the result is only marginally significant, and no evidence of association is seen for the other DAT1 markers. Although four SNPs in 5HTT are nominally associated, including an SNP in the 3' flanking region (rs1979572) and three intronic SNPs (rs4325622, rs140701, rs2066713), the results were considered inconclusive because the effect was seen only for heterozygotes, and no risk (or protective) allele could be identified. Allelic haplotypes were constructed using associated DRD2 SNPs. These SNPs belong to the same haploblock. The DRD2 minor allelic haplotype gave evidence of association for males, being risk-conferring. The odds ratio of the haplotype carriers compared to the rest was 2.1. No evidence of association was seen in the complete sample or in females.

SNPs reported by this study (count: 62)

SNP	Statistical Values	Author Comments	Result of Statistical Analysis
rs2073833	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs2070762	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs2076907	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs2073837	Logistic regression for single markers: adjusted for sex: P-value=0.0055, OR=2.69, 95%CI=1.34-5.43 for 22vs.11, P-value=0.0099, OR=0.44, 95%CI=0.23-0.82 for 11/12vs.22; Males: P-value=0.0027, OR=5.05, 95%CI=1.75-14.54 for 22vs.11, P-value=0.0036, OR=0.22, 95%CI=0.08-0.61 for 11/12vs.22	The minor homozygote was risk conferring compared with the m...... The minor homozygote was risk conferring compared with the major homozygote adjusted for sex and an even stronger effect was seen in males More...	Significant
rs1979572	Logistic regression for single markers: adjusted for sex: P-value=0.0258, OR=0.54, 95%CI=0.32-0.93 for 12vs.11; Males: P-value=0.0264, OR=0.43, 95%CI=0.20-0.91 for 12vs.22	nominally associated, but the results were considered inconc...... nominally associated, but the results were considered inconclusive because the effect was seen only for heterozygotes, and no risk (or protective) allele could be identified. More...	Significant
rs1800497	Logistic regression for single markers: Males: P-value=0.0333, OR=1.93, 95%CI=1.05-3.55 for 22/12vs.11	Association was observed in males. No evidence of associatio...... Association was observed in males. No evidence of association was seen in the complete sample or in females. More...	Significant
rs2066713	Logistic regression for single markers: adjusted for sex: P-value=0.0452, OR=0.54, 95%CI=0.29-0.99 for 12vs.22	nominally associated, but the results were considered inconc...... nominally associated, but the results were considered inconclusive because the effect was seen only for heterozygotes, and no risk (or protective) allele could be identified. More...	Significant
rs2020917	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs17758	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs167771	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs1800464	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs1799978	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs140701	Logistic regression for single markers: adjusted for sex: P-value=0.0393, OR=0.51, 95%CI=0.27-0.97 for 12vs.22; Males: P-value=0.0483, OR=0.53, 95%CI=0.28-1.00 for 12vs.11	nominally associated, but the results were considered inconc...... nominally associated, but the results were considered inconclusive because the effect was seen only for heterozygotes, and no risk (or protective) allele could be identified. More...	Significant
rs1354348	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs165728	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs1611125	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs1108581	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs1124491	Logistic regression for single markers: Males: P-value=0.0174, OR=2.08, 95%CI=1.14-3.80 for 22/12vs.11	Association was observed in males. No evidence of associatio...... Association was observed in males. No evidence of association was seen in the complete sample or in females. More...	Significant
rs12516948	Logistic regression for single markers: adjusted for sex: P-value=0.0468, OR=2.2, 95%CI=1.01-4.80 for 11vs.22	Some evidence of association was found. But the result is on...... Some evidence of association was found. But the result is only marginally significant, and no evidence of association is seen for the other DAT1 markers. More...	Significant
rs12920919	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs10064219	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs1079595	Logistic regression for single markers: Males: P-value=0.0287, OR=1.99, 95%CI=1.07-3.69 for 22/12vs.11	Association was observed in males. No evidence of associatio...... Association was observed in males. No evidence of association was seen in the complete sample or in females. More...	Significant
rs1079727	Logistic regression for single markers: Males: P-value=0.0393, OR=1.89, 95%CI=1.03-3.45 for 22/12vs.11	Association was observed in males. No evidence of associatio...... Association was observed in males. No evidence of association was seen in the complete sample or in females. More...	Significant
rs3859124	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs40184	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs3746544	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs3842753	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs4245149	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs4325622	Logistic regression for single markers: adjusted for sex: P-value=0.0112, OR=0.49, 95%CI=0.29-0.85 for 12vs.11, P-value=0.036, OR=0.58, 95%CI=0.34-0.97 for 22/12vs.11; Males: P-value=0.031, OR=0.48, 95%CI=0.25-0.94 for 12vs.11, P-value=0.0436, OR=0.46, 95%CI=0.21-0.98 for 12vs.22	nominally associated, but the results were considered inconc...... nominally associated, but the results were considered inconclusive because the effect was seen only for heterozygotes, and no risk (or protective) allele could be identified. More...	Significant
rs403636	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs4074905	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs6275	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs6279	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs5993882	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs6269	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs686	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs7197278	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs6350	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs6497730	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs2267770	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs226082	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs2234689	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs2134655	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs265973	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs2519152	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs2423486	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs2283724	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs324029	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs267418	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs265981	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs265975	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs363050	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs362988	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs362599	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs362569	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs740603	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs739398	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs8049651	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs765287	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs933271	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs916455	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant
rs936461	No available information.	No evidence of association was seen. No evidence of association was seen.	Non-significant

Other variant reported by this study (count: 6)

Variant Name	Allele Change	Statistical Values	Author Comments	Result of Statistical Analysis
SLC6A3 3'-UTR VNTR		No available information. No available information.	No evidence of association was seen.	Non-significant
MAOA promoter VNTR		No available information. No available information.	No evidence of association was seen.	Non-significant
DBH 5'-flanking (GT)n		No available information. No available information.	No evidence of association was seen.	Non-significant
DRD4 exon3 VNTR		No available information. No available information.	No evidence of association was seen.	Non-significant
SNAP25 hCV2488338		No available information. No available information.	No evidence of association was seen.	Non-significant
5HTTLPR	short/long	No available information. No available information.	No evidence of association was seen.	Non-significant

Genes reported by this study (count: 13)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
DRD3	No evidence of association was seen. No evidence of association was seen.	Non-significant
MAOA	No evidence of association was seen. No evidence of association was seen.	Non-significant
GRIN2A	No evidence of association was seen. No evidence of association was seen.	Non-significant
DRD2	Association was observed in males only for three intronic DR...... Association was observed in males only for three intronic DRD2 SNPs (rs1079727, rs1079595, rs1124491) and an SNP in the 3'-UTR (rs1800497), the DRD2 Taq1A RFLPThe DRD2 minor allelic haplotype gave evidence of association for males, being risk-conferring. No evidence of association was seen in the complete sample or in females . More...	Significant
TH	No evidence of association was seen. No evidence of association was seen.	Non-significant
SLC6A4	Four SNPs in 5-HTT are nominally associated, including an SN...... Four SNPs in 5-HTT are nominally associated, including an SNP in the 3' flanking region (rs1979572) and three intronic SNPs. More...	Significant
DRD1	No evidence of association was seen. No evidence of association was seen.	Non-significant
DRD4	No evidence of association was seen. No evidence of association was seen.	Non-significant
DBH	Association for an SNP in the DBH intron 12 was detected. Association for an SNP in the DBH intron 12 was detected.	Significant
DRD5	No evidence of association was seen. No evidence of association was seen.	Non-significant
SLC6A3	Some evidence of association was found for a SNP (rs12516948...... Some evidence of association was found for a SNP (rs12516948) in the 3'-UTR of SLC6A3. More...	Significant
SNAP25	No evidence of association was seen. No evidence of association was seen.	Non-significant
COMT	No evidence of association was seen. No evidence of association was seen.	Non-significant