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	Kirley A, 200212377397
Citation	Kirley A., Hawi Z., Daly G., McCarron M., Mullins C., Millar N., Waldman I., Fitzgerald M. and Gill M. (2002) "Dopaminergic system genes in ADHD: toward a biological hypothesis." Neuropsychopharmacology, 27(4): 607-19.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	118 ADHD cases
Predominant Ethnicity	Caucasian
Population	Ireland
Gender	85% male
Age Group	Children/Adolescents : aged 4-14 years

Detail Info

Summary	In a recent article, they confirmed the previously reported association of DAT1 (480bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD5 (148bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4bp deletion in the untranslated exon 1 of the DOPA decarboxylase gene was also observed but was of marginal significance. Nonsignificant trends of association were found for TH and DRD2 (Ser-311). No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD1, DRD2 (Taq I), DRD3, DRD4, and COMT. Analyzing the data by sex of transmitting parent showed significant preferential paternal transmission of alleles at TH and a nonsignificant trend for paternal transmission for DRD2 (Ser-311). They attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses.
Total Sample	The families were 98% ethnically Irish. Approximately 80% of the children in this study with ADHD also met diagnostic criteria for other disorders such as Oppositional Defiant Disorder and Conduct Disorder.
Sample Collection	118 ADHD cases were recruited from child psychiatric clinics and schools in West County, Dublin, and from the Hyperactive and Attention Deficit Children's Support Group of Ireland. Informed consent was obtained from all participants and patient confidentiality was maintained.
Diagnosis Description	Details of diagnosis and clinical criteria can be found in Daly et al. (1999). Briefly, consensus diagnoses were made according to DSM-IV ADHD or UADD, either with or without comorbidity. These diagnoses were based on all available clinical information and the rating scales described below. The rating scales used were (1) the Child Behavior Checklist (CBCL), a widely based behavioral symptom measure, and the records of child behavior problems and social competencies as reported by parents; (2) the Connors Parents and Teachers Rating Scales, 48-item parent and 39-item teacher rating scales; (3) the Comprehensive Teachers Rating Scale (ACTeRS) which includes 24 items relevant to classroom behavior. The 25-item Wender-Utah rating scale (WURS) (Ward et al. 1993) was applied to all parents. This rating scale seeks retrospectively to make a diagnosis of ADHD during childhood. A cutoff score of 36 or higher is 96% sensitive and 96% specific for adults with ADHD as children (Ward et al. 1993). Familiality, for the purposes of the present study, was defined as the presence of one or more parents with a score on the WURS of >36.
Technique	DNA was extracted either from buccal cells as described in Gill et al. (1997) or from EDTA blood using the standard phenol chloroform procedure. DAT1 and DRD4 alleles were detected using silver staining as described in Gill et al. (1997) and Hawi et al. (2000a). All genotypes were scored independently by two investigators who were blind to the identity of the sample or family relationships.
Analysis Method	In this study, a family based design was used to avoid any potential population stratification. In this method, which seeks to detect departure from Mendel's first law, the nontransmitted parental alleles are used as controls for comparison with transmitted parental alleles. For the Transmission Disequilibrium Test, alleles from heterozygous parents were identified as transmitted or not transmitted and tabulated. The X² test was used to assess the significance of the resulting tables, and odds ratios were calculated. Significance levels are presented without correction for multiple testing. For comparison with previous work (Gill et al. 1997; Daly et al. 1999), they calculated the haplotype-based haplotype relative risk (HHRR) statistic. Further exploratory analyses were conducted by examining transmission of risk alleles by gender of transmitting parent and by family history. A transmission variable was created, coded 1 or 0 for transmission and nontransmission, respectively, of the risk allele from a heterozygous parent. This enabled exploration of the relationship between allelic transmission and the categorical variables of sex of transmitting parent and presence or absence of family history.
Result Description	Significant preferential transmission of DAT1, DBH, and DRD5 were observed. An increased frequency of transmission of DOPA-decarboxylase allele 1 was also observed which was of marginal statistical significance. The DRD2 Ser-311 and TH (allele 2) polymorphisms showed trends for association. Analyses of DRD1, DRD3, DRD4, and COMT showed no significant differences between transmitted and non-transmitted alleles. They observed that for DAT1, DBH, and DRD2 (Ser-311), the transmission of the associated alleles appeared stronger when at least one of the parents was respectively diagnosed as ADHD. For DAT1, the relative risk in family history positive cases (FH+) was 1.50 compared with 1.33 in the family history negative cases (FH-). For DBH, the FH+ RR was 1.55 and the FH- RR was 1.26. For DRD2 (Ser-311), the FH+ RR was 2.32 and the FH- RR was 1. Formal statistical testing of transmissions according to family history showed, however, a trend for greater transmission of DBH to FH+ cases than FH- cases but no evidence of preferential transmission of DAT1 or DRD2 to FH+ cases compared with FH- cases. TH also displayed a trend for greater transmission of the associated allele to FH+ cases compared with FH- cases. They also observed (in HHRR analyses) that transmission of the associated allele for DAT1 appeared to be stronger for fathers than for mothers (RR 1.73 and 1.33, respectively). For DBH and DRD5, the excess transmission of associated alleles appeared to be distributed equally between parents. For TH and DRD2, analysis by sex of parent also appeared to be stronger for fathers. Formal statistical comparison of transmissions from fathers versus mothers revealed significant preferential transmission from fathers of TH (allele 2), and marginally significant transmission from fathers of DRD2 (Ser-311). There was, however, no evidence of preferential transmission of DAT1 (480bp allele) from fathers to ADHD children.

SNPs reported by this study (count: 2)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs6280			HHRR: P-value=0.56 (RR=1.07, OR=1.15); TDT: P-value=0.893 (OR=1.07); TDT by presence of family history: P-value=1 (OR[95%CI]=1.22[0.31-4.80]); TDT of Paternal and Maternal transmissions: P-value=0.976 (OR[95%CI]=1.02[0.30-3.44])	no significant differences between transmitted and non-trans...... no significant differences between transmitted and non-transmitted alleles More...	Non-significant
rs4680	G(Val)/A(Met)		HHRR: P-value=0.59 (RR=1.06, OR=1.12); TDT: P-value=0.482 (OR=1.21); TDT by presence of family history: P-value=0.1 (OR[95%CI]=0.28[0.07-1.11]); TDT of Paternal and Maternal transmissions: P-value=0.368 (OR[95%CI]=1.58[0.58-4.31])	no significant differences between transmitted and non-trans...... no significant differences between transmitted and non-transmitted alleles More...	Non-significant

Other variant reported by this study (count: 7)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
SLC6A3 3'-UTR VNTR		480bp	HHRR: P-value=0.0062 (RR=1.4, OR=1.88); TDT: P-value=0.042 (...... HHRR: P-value=0.0062 (RR=1.4, OR=1.88); TDT: P-value=0.042 (OR=1.63); TDT by presence of family history: P-value=0.494 (OR[95%CI]=1.87[0.47-7.35]); TDT of Paternal and Maternal transmissions: P-value=0.403 (OR[95%CI]=1.56[0.55-4.44]) More...	Significant preferential transmission	Significant
DRD2 TaqI			HHRR: P-value=0.18 (RR=1.2, OR=1.5); TDT: P-value=0.511 (OR=...... HHRR: P-value=0.18 (RR=1.2, OR=1.5); TDT: P-value=0.511 (OR=1.31); TDT by presence of family history: P-value=0.238 (OR[95%CI]=0.32[0.06-1.64]); TDT of Paternal and Maternal transmissions: P-value=0.67 (OR[95%CI]=0.71[0.15-3.33]) More...	trends for association	Non-significant
DRD4 exon3 VNTR		7 repeat	HHRR: P-value=0.58 (RR=1.07, OR=1.15); TDT: P-value=0.677 (O...... HHRR: P-value=0.58 (RR=1.07, OR=1.15); TDT: P-value=0.677 (OR=1.17); TDT by presence of family history: P-value=0.441 (OR[95%CI]=2.2[0.47-10.35]); TDT of Paternal and Maternal transmissions: P-value=0.207 (OR[95%CI]=0.44[0.12-1.57]) More...	no significant differences between transmitted and non-transmitted alleles	Non-significant
TH intron1 (TCAT)n			HHRR: P-value=0.34 (RR=1.1, OR=1.21); TDT: P-value=0.331 (OR...... HHRR: P-value=0.34 (RR=1.1, OR=1.21); TDT: P-value=0.331 (OR=1.36); TDT by presence of family history: P-value=0.27 (OR[95%CI]=3[0.68-13.31]); TDT of Paternal and Maternal transmissions: P-value=0.015 (OR[95%CI]=4.29[1.32-13.88]). More...	no significant differences between transmitted and non-transmitted alleles	Non-significant
DRD5 5'-flanking (CT/GT/GA)n		148bp	HHRR: P-value=0.000052 (RR=1.57, OR=2.52); TDT: P-value=0.00...... HHRR: P-value=0.000052 (RR=1.57, OR=2.52); TDT: P-value=0.0088 (OR=1.79); TDT by presence of family history: P-value=1 (OR[95%CI]=1.14[0.35-3.78]); TDT of Paternal and Maternal transmissions: P-value=0.62 (OR[95%CI]=1.24[0.53-2.92]) More...	Significant preferential transmission	Significant
DRD2 exon7 Ser311Cys			HHRR: P-value=0.18 (RR=1.5, OR=2.05); TDT: P-value=0.301 (OR...... HHRR: P-value=0.18 (RR=1.5, OR=2.05); TDT: P-value=0.301 (OR=2); TDT by presence of family history: P-value=1 (OR[95%CI]=0.75[0.04-14.97]); TDT of Paternal and Maternal transmissions: P-value=0.07 (OR[95%CI]=10.5[0.67-165.11]) More...	trends for association	Non-significant
DBH intron5 C/T TaqI	C/T		HHRR: P-value=0.0027 (RR=1.38, OR=1.87); TDT: P-value=0.01 (...... HHRR: P-value=0.0027 (RR=1.38, OR=1.87); TDT: P-value=0.01 (OR=1.88); TDT by presence of family history: P-value=0.307 (OR[95%CI]=2.44[0.59-10.04]); TDT of Paternal and Maternal transmissions: P-value=0.98 (OR[95%CI]=1.01[0.36-2.90]) More...	Significant preferential transmission	Significant

Genes reported by this study (count: 10)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
TH	Nonsignificant trends of association were found for TH, but ...... Nonsignificant trends of association were found for TH, but significant preferential paternal transmission of alleles at TH (allele 2) was found More...	Significant
SLC6A3	current study confirmed the previously reported association ...... current study confirmed the previously reported association of SLC6A3 (480bp allele) with ADHD More...	Significant
DRD5	Significant preferential transmission of allele at DRD5 (148...... Significant preferential transmission of allele at DRD5 (148bp allele) More...	Significant
DRD3	No preferential transmission of alleles to ADHD children was...... No preferential transmission of alleles to ADHD children was observed More...	Non-significant
DRD4	No preferential transmission of alleles to ADHD children was...... No preferential transmission of alleles to ADHD children was observed More...	Non-significant
COMT	No preferential transmission of alleles to ADHD children was...... No preferential transmission of alleles to ADHD children was observed More...	Non-significant
DBH	Significant preferential transmission of allele at DBH (alle...... Significant preferential transmission of allele at DBH (allele 2, Taq I polymorphism) More...	Significant
DRD1	HHRR: P=0.64 (RR=1.06, OR=1.1); TDT: P=0.708 (OR=1.13); TDT ...... HHRR: P=0.64 (RR=1.06, OR=1.1); TDT: P=0.708 (OR=1.13); TDT by presence of family history: P=0.509 (OR[95%CI]=1.78[0.48-6.62]); TDT of Paternal and Maternal transmissions: P=0.78 (OR[95%CI]=0.85[0.26-2.78]). No preferential transmission of alleles to ADHD children was observed More...	Non-significant
DDC	HHRR: P=0.1 (RR=1.24, OR=1.52); TDT: P=0.043 (OR=2); TDT by ...... HHRR: P=0.1 (RR=1.24, OR=1.52); TDT: P=0.043 (OR=2); TDT by presence of family history: P=1 (OR[95%CI]=1.43[0.26-7.74]); TDT of Paternal and Maternal transmissions: P=0.411 (OR[95%CI]=1.8[0.44-7.31]). Increased transmission of the 4bp deletion in the untranslated exon 1 of DOPA was observed with marginal significance More...	Significant
DRD2	No preferential transmission of alleles to ADHD children was...... No preferential transmission of alleles to ADHD children was observed More...	Non-significant