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Study Report
Reference | Kirley A, 200212377397 |
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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 |
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. |
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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. |
SNP | Allele Change | Risk Allele | Statistical Values | Author Comments | Result of Statistical Analysis |
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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 |
Variant Name | Allele Change | Risk Allele | Statistical Values | Author Comments | Result of Statistical Analysis |
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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 |
Gene | Statistical Values/Author Comments | Result of Statistical Analysis |
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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 |
Copyright: Bioinformatics Lab, Institute of Psychology, Chinese Academy of Sciences Feedback
Last update: Feb 26, 2014