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Study Report
Reference | Hawi Z, 200312660802 |
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Citation | Hawi Z., Lowe N., Kirley A., Gruenhage F., Nothen M., Greenwood T., Kelsoe J., Fitzgerald M. and Gill M. (2003) "Linkage disequilibrium mapping at DAT1, DRD5 and DBH narrows the search for ADHD susceptibility alleles at these loci." Mol Psychiatry, 8(3): 299-308. |
Study Design | family-based |
Study Type | Candidate-gene association study |
Sample Size | 118 ADHD cases and their parents |
Predominant Ethnicity | Caucasian |
Population | Ireland |
Gender | 85% males |
Age Group | Children/Adolescents : 5-14 years |
Summary | In this investigation, they analyse additional markers creating a high-density map across and flanking these genes, and measure intermarker linkage disequilibrium (LD). None of the newly examined markers were more strongly associated with ADHD. At DAT1, the pattern of intermarker LD and haplotype association with the phenotype between exon 9 and the 3' of the gene suggests that the functional variant at DAT1 may be located to this region. For DRD5, three markers, covering a region of approximately 68 kb including the single DRD5 exon are all associated with disease, and thus do not provide localizing information. However, the data for DBH point to a region close to the centre of the gene. Correlation between D' and physical distance was observed between markers at DAT1 and DRD5 for distances less than 50 kb. This was not the case for DBH, where LD breakdown was observed between the intron 5 and intron 9 polymorphisms although they are only 9 kb apart. Further genetic analysis is unlikely to refine the location of susceptibility variants and functional assessment of variants within associated regions is required. |
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Total Sample | A total of 118 ADHD cases were recruited. The age range of the probands was between 5 and 14 years, with males accounting for 85%. The families were ethnically Irish with the exception of two families (in one, the father was Arabian and in the other the father was Croatian). |
Sample Collection | A total of 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. |
Diagnosis Description | Consensus diagnoses were made according to DSM-IV ADHD or UADD either with or without comorbidity. These diagnoses were based on all available clinical information18 and the rating scales described below. The rating scales used were as follows: (1) the Child Behavioural Checklist (CBCL), (2) The Connors Parents and Teachers Rating Scales, (3) The Comprehensive Teachers Rating Scale (ACTeRS) |
Technique | genotyping of polymorphisms at the DAT1, DBH and DRD5 genes were performed by PCR |
Analysis Method | They used the haplotype-based haplotype relative risk (HHRR) design to avoid any potential population stratification. They also used the program TRANSMIT to test for the transmission of multilocus haplotypes and the association between genetic markers and disease. All chi-square statistics and P-values were presented without correction for multiple testing. |
Result Description | At DAT1, the pattern of intermarker LD and haplotype association with the phenotype between exon 9 and the 3' of the gene suggests that the functional variant at DAT1 may be located to this region. For DRD5, three markers, covering a region of approximately 68 kb including the single DRD5 exon are all associated with disease, and thus do not provide localizing information. However, the data for DBH point to a region close to the centre of the gene. Correlation between D' and physical distance was observed between markers at DAT1 and DRD5 for distances less than 50 kb. This was not the case for DBH, where LD breakdown was observed between the intron 5 and intron 9 polymorphisms although they are only 9 kb apart. |
Variant Name | Allele Change | Risk Allele | Statistical Values | Author Comments | Result of Statistical Analysis |
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SLC6A3 exon9 1342A>G | A/G | HHRR P-value=0.22, X^{2}=1.45, RR=1.18 for allele2 HHRR P-value=0.22, X^{2}=1.45, RR=1.18 for allele2 | no association was detected with the markers in exons 9 | Non-significant | |
SLC6A3 exon15 G/C | G/C | HHRR P-value=0.7, X^{2}=0.15, RR=1.1 for allele1 HHRR P-value=0.7, X^{2}=0.15, RR=1.1 for allele1 | no association was detected with the markers in exons 15 | Non-significant | |
DBH intron9 MspI | HHRR P-value=0.5, X^{2}=0.45, RR=1.1 for allele1 HHRR P-value=0.5, X^{2}=0.45, RR=1.1 for allele1 | no significant transmission of any allele to ADHD was reported | Non-significant | ||
DBH intron5 C/T TaqI | C/T | HHRR P-value=0.0027, X^{2}=9, RR=1.38 for allele1 HHRR P-value=0.0027, X^{2}=9, RR=1.38 for allele1 | showed highly significant association with ADHD | Significant | |
DBH exon2 444G/A EcoNI | HHRR P-value=0.34, X^{2}=0.91, RR=1.11 for allele1 HHRR P-value=0.34, X^{2}=0.91, RR=1.11 for allele1 | a slight but non-significant increase in the transmission was observed | Non-significant | ||
DBH 5'-flanking (GT)n | Global X^{2}=0.98; X^{2}=0, RR=1 for allele1...... Global X^{2}=0.98; X^{2}=0, RR=1 for allele1; HHRR P-value=0.73, X^{2}=0.1, RR=0.94 for allele2; HHRR P-value=0.69, X^{2}=0.16, RR=1.04 for allele3; HHRR P-value=0.8, X^{2}=0.06, RR=0.97 for allele4; HHRR P-value=0.99, RR=1 for allele5 More... | no significant transmission of any allele to ADHD was reported | Non-significant | ||
SLC6A3 5'-flanking D5S1981 | Global X^{2}=0.069; HHRR P-value=0.65, X^{2}...... Global X^{2}=0.069; HHRR P-value=0.65, X^{2}=0.2, RR=0.67 for allele1; HHRR P-value=0.009, X^{2}=6.75, RR=0.71 for allele2; HHRR P-value=0.016, X^{2}=5.8, RR=1.34 for allele3; HHRR P-value=0.84, X^{2}=0.04, RR=1.04 for allele4; HHRR P-value=0.87, X^{2}=0.03, RR=1.03 for allele5; HHRR P-value=0.65, X^{2}=0.2, RR=1.2 for allele6 More... | increased and significant transmission of allele 3 to the cases was observed | Significant | ||
SLC6A3 3'-UTR VNTR | Global X^{2}=0.02; HHRR P-value=0.56, X^{2}=...... Global X^{2}=0.02; HHRR P-value=0.56, X^{2}=0.34, RR=0.66 for allele1; HHRR P-value=0.0062, X^{2}=7.5, RR=1.4 for allele2 More... | significant association between allele 2 (480 bp) of the SLC6A3 VNTR polymorphism and ADHD was reported | Significant | ||
SLC6A3 3'-flanking D5S678 | Global X^{2}=0.20; HHRR P-value=1, X^{2}=0, ...... Global X^{2}=0.20; HHRR P-value=1, X^{2}=0, RR=1 for allele1; HHRR P-value=1, X^{2}=0, RR=1 for allele2; HHRR P-value=0.8, X^{2}=0.07, RR=0.88 for allele3; HHRR P-value=0.32, X^{2}=0.95, RR=0.64 for allele4; HHRR P-value=0.36, X^{2}=0.82, RR=0.75 for allele5; HHRR P-value=0.13, X^{2}=2.23, RR=1.21 for allele6; HHRR P-value=0.3, X^{2}=1.06, RR=0.6 for allele7; HHRR P-value=0.67, X^{2}=0.18, RR=1.18 for allele8 More... | no significant transmission of any allele to ADHD was reported | Non-significant | ||
SLC6A3 3'-flanking D5S2005 | Global X^{2}=0.093; HHRR P-value=0.77, X^{2}...... Global X^{2}=0.093; HHRR P-value=0.77, X^{2}=0.08, RR=1.17 for allele1; HHRR P-value=1, X^{2}=0, RR=1 for allele2; HHRR P-value=0.18, X^{2}=1.77, RR=0.63 for allele3; HHRR P-value=0.25, X^{2}=1.32, RR=1.15 for allele4; HHRR P-value=0.99, X^{2}=0, RR=1.01 for allele5; HHRR P-value=0.09, X^{2}=2.77, RR=0.8 for allele6; HHRR P-value=0.7, X^{2}=0.15, RR=1.33 for allele7 More... | increased transmission of allele 2 of the D5S2005 [(X^{2}=5.07, P-value=0.024, RR=1.58) conflicted with the data in the table 2: HHRR P-value=1, X^{2}=0, RR=1 for allele2] to the cases was observed | Non-significant | ||
DRD5 5'-flanking D4S2928 | Global X^{2}=0.22; HHRR P-value=0.56, X^{2}=...... Global X^{2}=0.22; HHRR P-value=0.56, X^{2}=0.34, RR=0.5 for allele1; HHRR P-value=0.25, X^{2}=1.29, RR=0.62 for allele2; HHRR P-value=0.112, X^{2}=2.52, RR=1.22 for allele3; HHRR P-value=0.58, X^{2}=0.38, RR=0.89 for allele4; HHRR P-value=0.73, X^{2}=0.11, RR=1.25 for allele5; HHRR P-value=0.25, X^{2}=1.32, RR=0.4 for allele7; HHRR P-value=0.65, X^{2}=0.2, RR=0.67 for allele8; HHRR P-value=0.56, X^{2}=0.34, RR=2 for allele9 More... | no association was detected with D4S2928 | Non-significant | ||
DRD5 5'-flanking D4S1582 | Global X^{2}=0.49; HHRR P-value=0.8, X^{2}=0...... Global X^{2}=0.49; HHRR P-value=0.8, X^{2}=0.06, RR=1.13 for allele1; HHRR P-value=0.37, X^{2}=0.78, RR=1.15 for allele2; HHRR P-value=1, X^{2}=0, RR=1 for allele3; HHRR P-value=0.03, X^{2}=4.58, RR=1.48 for allele4; HHRR P-value=1, X^{2}=0, RR=1 for allele5; HHRR P-value=0.29, X^{2}=1.1, RR=0.73 for allele6; HHRR P-value=0.89, X^{2}=0.02, RR=0.97 for allele7; HHRR P-value=0.032, X^{2}=4.59, RR=0.36 for allele8 More... | weak associations with allele 4 and allele 8 were observed | Significant | ||
DRD5 5'-flanking (CT/GT/GA)n | Global X^{2}=0.009; HHRR P-value=0.73, X^{2}...... Global X^{2}=0.009; HHRR P-value=0.73, X^{2}=0.11, RR=1.25 for allele3; HHRR P-value=1, X^{2}=0.11, RR=1 for allele4; HHRR P-value=0.22, X^{2}=1.46, RR=0.68 for allele5; HHRR P-value=0.00005, X^{2}=16.36, RR=1.6 for allele6; HHRR P-value=0.48, X^{2}=0.5, RR=1.38 for allele7; HHRR P-value=0.18, X^{2}=1.75, RR=0.5 for allele8; HHRR P-value=0.36, X^{2}=0.85, RR=0.57 for allele9; HHRR P-value=0.028, X^{2}=4.78, RR=0.27 for allele10; HHRR P-value=0.14, X^{2}=2.2, RR=0.6 for allele11; HHRR P-value=0.018, X^{2}=5.6, RR=0.13 for allele12; HHRR P-value=0.35, X^{2}=1.01, RR=0.33 for allele13 More... | associations of 148 bp allele (allele 6 of the DRD5-PCR1) and allele 12 to ADHD cases were reported | Significant | ||
DRD5 3'-UTR 1481T/C | T/C | HHRR P-value=0.0093, X^{2}=6.76, RR=1.41 for allele2 HHRR P-value=0.0093, X^{2}=6.76, RR=1.41 for allele2 | association with allele C (DRD5-1481) was observed | Significant |
Gene | Statistical Values/Author Comments | Result of Statistical Analysis |
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DRD5 | 3 markers within this gene showed significant association wi...... 3 markers within this gene showed significant association with ADHD; minimal 2-marker_haplotype 2.6 (DRD5-1481, DRD5-PCR1) P-value=0.00016, X^{2}(1df)=14.2, global X^{2}=22.4, 11 df, P-value=0.021 which showed significant excess transmission to the ADHD cases; minimal 3-marker_haplotype 2.2.6 (DRD5-1481, D5S1582, DRD5-PCR1) P-value=0.0013, X^{2}(1df)=10.458, global X^{2}=41.8, 25 df, P-value=0.0189 which showed preferentially transmitted to the ADHD cases More... | Significant |
DBH | 1 marker within this gene showed significant association wit...... 1 marker within this gene showed significant association with ADHD; 2-marker haplotype_1.2 (DBH exon2, DBH intron5) P-value=0.045, X^{2}=4.0143; global X^{2}=14, 3 df, P-value=0.0029 which showed preferential transmission More... | Significant |
SLC6A3 | 2 markers within this gene showed significant association wi...... 2 markers within this gene showed significant association with ADHD; minimal 2-marker_haplotype 2.3 (VNTR-1981) P-value=0.0004, X^{2}(1df)=12.37, global X^{2}(13df)=21.3, P-value=0.067 which showed increased transmission to ADHD; minimal 3-marker_haplotype 4.2.3 (D5S2005-VNTR-D5S1981) P-value=0.0025, X^{2}(1df)=9.1413, global X^{2}(13df)=19.4, P-value=0.11 which showed a significant preferential transmission to ADHD cases More... | Significant |
Copyright: Bioinformatics Lab, Institute of Psychology, Chinese Academy of Sciences Feedback
Last update: Feb 26, 2014