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	Hawi Z, 200312660802
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

Detail Info

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.
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.

Other variant reported by this study (count: 14)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
SLC6A3 3'-flanking D5S678			Global X²=0.20; HHRR P-value=1, X²=0, ...... Global X²=0.20; HHRR P-value=1, X²=0, RR=1 for allele1; HHRR P-value=1, X²=0, RR=1 for allele2; HHRR P-value=0.8, X²=0.07, RR=0.88 for allele3; HHRR P-value=0.32, X²=0.95, RR=0.64 for allele4; HHRR P-value=0.36, X²=0.82, RR=0.75 for allele5; HHRR P-value=0.13, X²=2.23, RR=1.21 for allele6; HHRR P-value=0.3, X²=1.06, RR=0.6 for allele7; HHRR P-value=0.67, X²=0.18, RR=1.18 for allele8 More...	no significant transmission of any allele to ADHD was reported	Non-significant
SLC6A3 exon9 1342A>G	A/G		HHRR P-value=0.22, X²=1.45, RR=1.18 for allele2 HHRR P-value=0.22, X²=1.45, RR=1.18 for allele2	no association was detected with the markers in exons 9	Non-significant
DBH intron9 MspI			HHRR P-value=0.5, X²=0.45, RR=1.1 for allele1 HHRR P-value=0.5, X²=0.45, RR=1.1 for allele1	no significant transmission of any allele to ADHD was reported	Non-significant
DRD5 5'-flanking D4S2928			Global X²=0.22; HHRR P-value=0.56, X²=...... Global X²=0.22; HHRR P-value=0.56, X²=0.34, RR=0.5 for allele1; HHRR P-value=0.25, X²=1.29, RR=0.62 for allele2; HHRR P-value=0.112, X²=2.52, RR=1.22 for allele3; HHRR P-value=0.58, X²=0.38, RR=0.89 for allele4; HHRR P-value=0.73, X²=0.11, RR=1.25 for allele5; HHRR P-value=0.25, X²=1.32, RR=0.4 for allele7; HHRR P-value=0.65, X²=0.2, RR=0.67 for allele8; HHRR P-value=0.56, X²=0.34, RR=2 for allele9 More...	no association was detected with D4S2928	Non-significant
SLC6A3 3'-UTR VNTR			Global X²=0.02; HHRR P-value=0.56, X²=...... Global X²=0.02; HHRR P-value=0.56, X²=0.34, RR=0.66 for allele1; HHRR P-value=0.0062, X²=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
DRD5 5'-flanking D4S1582			Global X²=0.49; HHRR P-value=0.8, X²=0...... Global X²=0.49; HHRR P-value=0.8, X²=0.06, RR=1.13 for allele1; HHRR P-value=0.37, X²=0.78, RR=1.15 for allele2; HHRR P-value=1, X²=0, RR=1 for allele3; HHRR P-value=0.03, X²=4.58, RR=1.48 for allele4; HHRR P-value=1, X²=0, RR=1 for allele5; HHRR P-value=0.29, X²=1.1, RR=0.73 for allele6; HHRR P-value=0.89, X²=0.02, RR=0.97 for allele7; HHRR P-value=0.032, X²=4.59, RR=0.36 for allele8 More...	weak associations with allele 4 and allele 8 were observed	Significant
DBH 5'-flanking (GT)n			Global X²=0.98; X²=0, RR=1 for allele1...... Global X²=0.98; X²=0, RR=1 for allele1; HHRR P-value=0.73, X²=0.1, RR=0.94 for allele2; HHRR P-value=0.69, X²=0.16, RR=1.04 for allele3; HHRR P-value=0.8, X²=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
DBH exon2 444G/A EcoNI			HHRR P-value=0.34, X²=0.91, RR=1.11 for allele1 HHRR P-value=0.34, X²=0.91, RR=1.11 for allele1	a slight but non-significant increase in the transmission was observed	Non-significant
SLC6A3 5'-flanking D5S1981			Global X²=0.069; HHRR P-value=0.65, X²...... Global X²=0.069; HHRR P-value=0.65, X²=0.2, RR=0.67 for allele1; HHRR P-value=0.009, X²=6.75, RR=0.71 for allele2; HHRR P-value=0.016, X²=5.8, RR=1.34 for allele3; HHRR P-value=0.84, X²=0.04, RR=1.04 for allele4; HHRR P-value=0.87, X²=0.03, RR=1.03 for allele5; HHRR P-value=0.65, X²=0.2, RR=1.2 for allele6 More...	increased and significant transmission of allele 3 to the cases was observed	Significant
SLC6A3 exon15 G/C	G/C		HHRR P-value=0.7, X²=0.15, RR=1.1 for allele1 HHRR P-value=0.7, X²=0.15, RR=1.1 for allele1	no association was detected with the markers in exons 15	Non-significant
DRD5 3'-UTR 1481T/C	T/C		HHRR P-value=0.0093, X²=6.76, RR=1.41 for allele2 HHRR P-value=0.0093, X²=6.76, RR=1.41 for allele2	association with allele C (DRD5-1481) was observed	Significant
DRD5 5'-flanking (CT/GT/GA)n			Global X²=0.009; HHRR P-value=0.73, X²...... Global X²=0.009; HHRR P-value=0.73, X²=0.11, RR=1.25 for allele3; HHRR P-value=1, X²=0.11, RR=1 for allele4; HHRR P-value=0.22, X²=1.46, RR=0.68 for allele5; HHRR P-value=0.00005, X²=16.36, RR=1.6 for allele6; HHRR P-value=0.48, X²=0.5, RR=1.38 for allele7; HHRR P-value=0.18, X²=1.75, RR=0.5 for allele8; HHRR P-value=0.36, X²=0.85, RR=0.57 for allele9; HHRR P-value=0.028, X²=4.78, RR=0.27 for allele10; HHRR P-value=0.14, X²=2.2, RR=0.6 for allele11; HHRR P-value=0.018, X²=5.6, RR=0.13 for allele12; HHRR P-value=0.35, X²=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
DBH intron5 C/T TaqI	C/T		HHRR P-value=0.0027, X²=9, RR=1.38 for allele1 HHRR P-value=0.0027, X²=9, RR=1.38 for allele1	showed highly significant association with ADHD	Significant
SLC6A3 3'-flanking D5S2005			Global X²=0.093; HHRR P-value=0.77, X²...... Global X²=0.093; HHRR P-value=0.77, X²=0.08, RR=1.17 for allele1; HHRR P-value=1, X²=0, RR=1 for allele2; HHRR P-value=0.18, X²=1.77, RR=0.63 for allele3; HHRR P-value=0.25, X²=1.32, RR=1.15 for allele4; HHRR P-value=0.99, X²=0, RR=1.01 for allele5; HHRR P-value=0.09, X²=2.77, RR=0.8 for allele6; HHRR P-value=0.7, X²=0.15, RR=1.33 for allele7 More...	increased transmission of allele 2 of the D5S2005 [(X²=5.07, P-value=0.024, RR=1.58) conflicted with the data in the table 2: HHRR P-value=1, X²=0, RR=1 for allele2] to the cases was observed	Non-significant

Genes reported by this study (count: 3)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
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, X²(1df)=12.37, global X²(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, X²(1df)=9.1413, global X²(13df)=19.4, P-value=0.11 which showed a significant preferential transmission to ADHD cases More...	Significant
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, X²(1df)=14.2, global X²=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, X²(1df)=10.458, global X²=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, X²=4.0143; global X²=14, 3 df, P-value=0.0029 which showed preferential transmission More...	Significant