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 ...

Gene Report

Basic Info

Approved Symbol	DRD4
Approved Name	dopamine receptor D4
Location	11p15.5
Position	chr11:637293-640706, +
External Links	HGNC: 3025 Entrez Gene: 1815 Ensembl: ENSG00000069696 UCSC: uc001lqp.1
No. of Studies	67 (significant: 49; non-significant: 18; trend: 0)
Source	Literature-origin; Mapped by literature SNP

Gene related studies (count: 67)

Reference	Statistical Values/Author Comments	Result of Statistical Analysis
Spencer, T. J., 2012	the gene frequencies of each of the gene polymorphisms assessed did not differ between the ADHD and control groups.	Non-significant
Carpentier, P. J., 2012	No significant association was found.	Non-significant
Sanchez-Mora C, 2011	chi-square test P-value>0.05 for haplotype frequencies, showed no association in any of the four separate cohorts; meta-analysis: P-value=0.01, OR=0.78 showed an under representation of the S-4R allelic combination in the ADHD sample; P-value=0.04, OR=0.73 in females; S-4R P-value=0.01, OR=0.75; L-4R P-value=0.02, OR=1.29, showed an increased frequency of carriers of the L-4R risk haplotype in addition to an under-representation of the S-4R allelic combination in this clinical dataset. P-value=3.04e-05, OR=1.66; P-value=2.66e-05, OR=1.74 of DRD4 L-4R and SLC6A3 9R-6R increased the risk for ADHD in both the ADHD sample as a whole and in the combined clinical subtype respectively which suggested additive effects of the DRD4 risk haplotype and the SLC6A3 gene	Significant
Nyman ES, 2007	No evidence of association was seen.	Non-significant
Johansson S, 2008	no association between ADHD and the DRD4 polymorphism	Non-significant
Lasky-Su J, 2007	One of the four SNPswas associatedwith the quantitative phenotypes generated fromthe ADHDsymptoms.	Significant
Yang JW, 2008	there was a significant association between the -521 C/T SNP and ADHD in Korean boys	Significant
Oades RD, 2008	1 SNP and 1 polymorphism showed significant association	Significant
Niederhofer H, 2008	they did not observe an association of ADHD with DRD4 polymorphism neither by the haplotype relative risk (HRR) method nor by the transmission disequilibrium test (TdT) method.	Non-significant
Johnson KA, 2008	a significant association between possession of the 7-repeat allele and diagnosis	Significant
Langley K, 2009	significant association between the DRD4 48 bp VNTR 7-repeat allele and 'persistent ADHD'.	Significant
Nikolaidis A, 2010	the Caucasian group showed a positive relationship between ADHD and the DRD4 7R allele; the Middle Eastern group showed a negative relationship between ADHD and the DRD4 7R allele; The South American group also demonstrated a positive relationship between ADHD and the DRD4 7R allele; The Asian group demonstrated a positive relationship between the DRD4 2R allele and ADHD, but the results were insignificant	Significant
Smith TF, 2010	consistent with previous meta-analytic work, the DRD4 7R allele was associated with AD/HD across studies. Combined type individuals within the AD/HD sample was associated with a significant increase in the magnitude of association between the DRD4 7R allele and AD/HD.	Significant
Gabriela ML, 2009	genotype analysis P-value=0.19; allelic analysis P-value=0.18 \| TDT P-value=0.59. No significant differences between groups of comparison.	Non-significant
Gizer IR, 2009	The present study provides significant evidence suggesting an association between childhood ADHD and this gene.	Significant
Das M, 2011	minimum UNPHASED P-value=0.29 for haplotype frequencies in the case-control analysis showed no significant difference; minimum ETDT P-value=0.02, X²(1df)=5.54, RR=5.18e+008, which showed significant over transmission of the 7R-T haplotypes from parents	Significant
Tovo-Rodrigues L, 2011	Findings in this study suggest an association between ADHD and DRD4 rare variants.	Significant
Ilott NE, 2010	1 SNP showed modest, nominally significant association in the AT and AW tests at age 3	Significant
Bidwell LC, 2011	In the current study, the DRD4 VNTR 4-repeat allele was associated with increased ADHD symptomatology.	Significant
Holmes J, 2000	A significant increase in the DRD4 7 repeat allele amongst ADHD probands and their parents was observed, compared to ethnically matched controls. However TDT analysis showed no preferential transmission of allele 7 to ADHD probands.	Significant
McCracken JT, 2000	TDT of haplotype: P=0.04 for 120/-7; P=0.196 for 120/+7; P=0.297 for 240/-7; P=0.165 for 240/+7. Results in this study suggest that the 240-bp (long) allele of the 120-bp repeat polymorphism in the 5' untranslated region of DRD4 is preferentially transmitted from parents to their ADHD offspring.	Significant
Sunohara GA, 2000	The results of this study further support the possibility of a role of the dopamine D4 receptor locus in ADHD	Significant
Barr CL, 2001(d)	allele-wise TDT P-value>0.059, the result was not significant for any of the haplotypes of the 5' polymorphisms; the overall allele-wise TDT X² and genotype-wise TDT X² for the haplotypes of the 5' polymorphisms were not significant. Allele-wise TDT X²=3.903, d.f.=1, P-value=0.048 for haplotype composed of 2 repeats of the 120 bp polymorphism, allele 2 (T) of the FspI polymorphism, allele 1 (C) of the AvaII polymorphism and the 7-repeat allele of exon III (2-2-1-7) showed significant evidence for biased transmission; The overall genotype-wise TDT X² for the haplotypes of the 5' polymorphisms and the exon III polymorphism was significant (TDT X²=68.282, 43 d.f., P=0.009) but the overall allele-wise TDT X² was not	Significant
Barr CL, 2000 (b)	TDT of DRD4 haplotypes: smallest P=0.02; the current study of additional polymorphisms and haplotypes at the DRD4 locus further suggests that it is a susceptibility factor in ADHD.	Significant
Hawi Z, 2000 (a)	no significant differences in the frequency of the DRD4 alleles transmitted or not transmitted to ADHD cases from their parents nor when comparing case allele frequencies to ethnically matched controls.	Non-significant
Muglia P, 2000	The results of this study suggest a role of the 7-repeat allele of DRD4 in adult subjects suffering from ADHD.	Significant
Kotler M, 2000	there was a significant excess of the long DRD4 repeat alleles in the HRR control group.	Significant
Faraone SV, 1999	The results suggest that there may be an association between ADHD and the 7-repeat allele of the dopamine D4 gene in this sample	Significant
Comings DE, 1999	48bp repeat polymorphism is significantly associated with ADHD	Significant
Tahir E, 2000 (b)	increased transmission of the DRD4 7-repeat allele was found	Significant
Eisenberg J, 2000	Current study failed to observe preferential transmission of the DRD4 exon III long 7 repeat allele (P<0.1). Nor was any preferential transmission observed when genotypes were compared (P>0.1)	Non-significant
Swanson JM, 1998	The HRR contingency statistic of allele 7 repeat was significant. This provides additional evidence that the DRD4 gene is associated with a refined phenotype of ADHD.	Significant
Rowe DC, 1998	Findings in this study were most positive for the questionnaire-based diagnosis of ADHD-inattentive type.	Significant
Smalley SL, 1998	In this study, they found evidence that the 7-repeat allele of DRD4 VNTR in exon 3 is transmitted to affected offspring more than non-7 repeat alleles suggesting that the 7-repeat allele is a susceptibility gene in ADHD.	Significant
Castellanos FX, 1998	There were no significant differences between cases and controls in the frequency of any allele and genotype	Non-significant
Kirley A, 2004	there was no association between the investigated variants and ADHD	Non-significant
Bakker SC, 2005	haplotype DRD4, TDT P-value=0.65; DRD4 did not contribute substantially to ADHD in the Dutch population	Non-significant
Qian Q, 2004	no evidence for association for either the entire sample or for DSM-IV subtypes of ADHD, but stratification by gender yielded intriguing results. Long repeat alleles were associated with ADHD in males but short repeats were associated with ADHD in females.	Significant
Arcos-Burgos M, 2004 (b)	PDT smallest P=0.0467 for haplotype 240bp/7R, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype with ADHD.	Significant
Kustanovich V, 2004	The DRD4 gene 120-bp insertion/deletion promoter polymorphism displayed a significant bias in transmission of the insertion. The seven repeat allele of the DRD4 48-bp repeat polymorphism was not significantly associated with ADHD.	Significant
Mill J, 2003	haplotype (2-C-C-142-4) P-value=0.04, X²=4.073, 1 df, showed marginal evidence for biased transmission to ADHD probands; of which haplotype (2-C-C) P-value=0.03, X²=4.68, 1 df, was over-transmitted to affected ADHD probands	Significant
Smith KM, 2003	no polymorphism was significantly associated with ADHD	Non-significant
Maher BS, 2002	for DRD4, positive association was demostrated with ADHD in the meta-analysis and there was no support for hetergeneity between studies	Significant
Kirley A, 2002	No preferential transmission of alleles to ADHD children was observed	Non-significant
Manor I, 2002 (a)	preferential transmission of the short allele of DRD4 exon 3 VNTR was observed	Significant
Holmes J, 2002	evidence of linkage and association between DRD4 and ADHD was found in this study	Significant
Roman T, 2001	an excess of the 7-repeat allele was observed when both ADHD probands and their parents were compared with an ethnically matched control sample, no main effects of DRD4 and ADHD by using dimensional Analyses	Significant
Payton A, 2001	there was no evidence of preferential transmission of any marker allele for the polymorphism examined in this study	Non-significant
Todd RD, 2001(b)	combined haplotype of 5' 120bp RP and exon3 48bp RP, ETDT P-value>0.08 in DSM-IV subtype; haplotype (1-7) ETDT P-value=0.04, corrected P-value=0.25 in DSM-IV any ADHD; there was suggestive evidence for biased transmission	Significant
Mill J, 2001	there was evidence of association between 7 repeat allele of a 48 base-pair repeat in the dopamine D4 receptor gene in the case-control sample, but no evidence of linkage in the family-based UK sample	Significant
Faraone SV, 2001	both the case-control and family-based studies supported for the association between ADHD and DRD4	Significant
Kereszturi E, 2007	haplotype frequency analysis: P-value=0.093 (df=9) under an unequal distribution; P-value=0.002 (OR=2.33) for 1-C-A-T haplotype. The 1-repeat form of the 120-bp dup in this gene was significantly higher in the ADHD group compared to controls. The 1-C-A-T haplotype was overrepresented in the cases.	Significant
Brookes KJ, 2008(c)	DRD4 7-repeat allele is associated with ADHD	Significant
Qian Q, 2007	Logistic Regression Analysis: P-value=0.039, OR=2.805, 95%CI=1.056-7.452. Result show that the effects of the risk alleles of DRD4 found in the univariate analyses remained significant after partialing out the effects of the other putative risk alleles.	Significant
Gornick MC, 2007	The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls.	Significant
Brookes K, 2006	UNPHASED TDT P-value=0.055, global P-value=0.182, WHAP TDT P_sum P-value=0.132; OR=1.7, one or more SNPs with nominal P-value<0.05 located in this gene	Significant
Cheuk DK, 2006(a)	4/4 repeat genotype chi-square P-value=0.26, OR=1.52; 2/4 repeat genotype chi-square P-value=0.15, OR=0.55; the longer repeat genotypes chi-square P-value=0.01; P-value=0.013 in the male subgroup; P-value=0.005 in the inattentive subtype; a significant trend between the longer repeat alleles and ADHD	Significant
Hawi Z, 2005	one marker showed significant overtransmission of paternal alleles; paternal versus maternal transmissions, combined TDT P-value=0.0019, X²=9.6 (1df), OR=1.56; TDT P-value=0.0011, X²=10.6 when DRD4 was removed in sensitivity analysis	Significant
Li D, 2006	DRD4 4-repeat, 5-repeat, 7-repeat showed significant associations, there is a statistically significant association between ADHD and DRD4	Significant
Bhaduri N, 2006 (a)	haplotype 1-1-1 of the 5' flanking 120-bp duplication, exon 1 12-bp duplication, and exon 3 48-bp VNTR, haplotype frequencies P-value=0.0009, X² (1df)=10.93 in cases, P-value=0.0091, X² (1df)=6.8 in controls	Significant
Carrasco X, 2006	DRD4 7-repeat alleles Fisher¡¯s exact test P-value>0.25, DRD4 7-repeat heterozygosity and SLC6A3 10 allele homozygosity Fisher¡¯s exact test P-value=0.0096; OR=12.71, suggested evidence of gene-gene interaction effects on the prevalence of ADHD in the Chilean population	Significant
Kim YS, 2005	did not show preferential transmission of any allele or gene-gene interaction	Non-significant
Todd RD, 2005	no significant associations were found for DRD4 polymorphisms using DSM-IV ADHD subtypes	Non-significant
Bobb AJ, 2005	no polymorphism was associated with ADHD	Non-significant
Brookes KJ, 2005 (a)	two-marker haplotype, TDT P-value=0.45; HHRR P-value=0.45; did not find either global or haplotype-specific evidence for association	Non-significant
Lowe N, 2004 (a)	significant over transmission of SNP in DRD4 was observed.	Significant
Leung PW, 2005	chi-square analysis confirmed a significant increase in the frequency of the 2R allele of DRD4 in the Han Chinese ADHD probands compared to ethnically-matched controls from the five Han Chinese communities	Significant

Gene related SNPs (count: 8)

Literature-origin SNPs (count: 8)

rs_ID	Location	Functional Annotation	No. of Studies (significant/non-significant/trend)
rs936461	Chr11:636496(Fwd)	upstream_gene_variant	1(0/1/0)
rs7124601	Chr11:639273(Fwd)	downstream_gene_variant; intron_variant; nc_transcript_variant	1(1/0/0)
rs3758653	Chr11:636399(Fwd)	upstream_gene_variant	2(1/1/0)
rs1800955	Chr11:636784(Fwd)	upstream_gene_variant	3(2/1/0)
rs17758	Chr11:644325(Fwd)	3_prime_UTR_variant; NMD_transcript_variant; downstream_gene_variant; nc_transcript_variant; non_coding_exon_variant	1(0/1/0)
rs12720373	Chr11:636688(Fwd)	upstream_gene_variant	1(1/0/0)
rs916457	Chr11:637014(Fwd)	upstream_gene_variant	1(1/0/0)
rs916455	Chr11:636929(Fwd)	upstream_gene_variant	2(0/2/0)

LD-proxies (count: 0)

Gene related CNVs (count: 0)

Gene related other variant (count: 8)

Variant Name	Variant Type	Location in Gene	No. of Studies (significant/non-significant/trend)
DRD4_promoter_duplication_120bp	insertion/deletion	promoter	13 (4/9/0)
DRD4_exon3_VNTR	VNTR	exon 3	58 (33/25/0)
DRD4_intron1_(G)n	microsatellite	intron 1	3 (0/3/0)
DRD4_exon1_ins/del_12bp	insertion/deletion	exon 1	2 (0/2/0)
DRD4_promoter_-615A/G	point mutation	promoter	1 (0/1/0)
DRD4_promoter_-616C/G	point mutation	promoter	5 (1/4/0)
DRD4_promoter_-376C/T	point mutation	promoter	2 (0/2/0)
DRD4_promoter_-521C/T	point mutation	promoter	6 (0/6/0)

Gene related regions (count: 0)

Gene related GO terms (count: 43)

GO terms by PBA (with statistical significance of FDR<0.05) (count: 0)

GO terms by database search (count: 43)

ID	Name	Type	Evidence[PMID]	No. of Genes in ADHDgene
GO:0001963	synaptic transmission, dopaminergic	Biological Process		7
GO:0001975	response to amphetamine	Biological Process		16
GO:0004952	dopamine neurotransmitter receptor activity	Molecular Function	IDA[8413587]	3
GO:0005515	protein binding	Molecular Function	IPI[12297500]	910
GO:0005886	plasma membrane	Cellular Component		772
GO:0005887	integral to plasma membrane	Cellular Component	IDA[15755724]	220
GO:0005938	cell cortex	Cellular Component		26
GO:0006874	cellular calcium ion homeostasis	Biological Process	IC[7921596]	16
GO:0000187	activation of MAPK activity	Biological Process	IDA[15755724]	21
GO:0001591	dopamine neurotransmitter receptor activity, coupled via Gi/Go	Molecular Function	IDA[1840645]	3
GO:0001662	behavioral fear response	Biological Process	NAS[12860355]	7
GO:0043195	terminal bouton	Cellular Component		11
GO:0043025	neuronal cell body	Cellular Component		51
GO:0046928	regulation of neurotransmitter secretion	Biological Process		5
GO:0043197	dendritic spine	Cellular Component		12
GO:0042053	regulation of dopamine metabolic process	Biological Process		5
GO:0035240	dopamine binding	Molecular Function	IDA[1319557]	8
GO:0042596	fear response	Biological Process		5
GO:0042417	dopamine metabolic process	Biological Process	IC[1840645]	5
GO:0051586	positive regulation of dopamine uptake involved in synaptic transmission	Biological Process	IC[1840645]	2
GO:0050848	regulation of calcium-mediated signaling	Biological Process		1
GO:1901386	negative regulation of voltage-gated calcium channel activity	Biological Process	IDA[7921596]	2
GO:0060080	regulation of inhibitory postsynaptic membrane potential	Biological Process		5
GO:0048149	behavioral response to ethanol	Biological Process	TAS[12888781]	4
GO:0048148	behavioral response to cocaine	Biological Process		6
GO:0050709	negative regulation of protein secretion	Biological Process	IDA[16839358]	5
GO:0050482	arachidonic acid secretion	Biological Process	IDA[7512953]	7
GO:0008144	drug binding	Molecular Function	IDA[8413587]	19
GO:0008344	adult locomotory behavior	Biological Process		12
GO:0008355	olfactory learning	Biological Process		1
GO:0012506	vesicle membrane	Cellular Component		3
GO:0007194	negative regulation of adenylate cyclase activity	Biological Process	IDA[7512953]	10
GO:0007195	adenylate cyclase-inhibiting dopamine receptor signaling pathway	Biological Process	IDA[7512953]	3
GO:0007212	dopamine receptor signaling pathway	Biological Process	IDA[1840645]	3
GO:0007614	short-term memory	Biological Process		2
GO:0032417	positive regulation of sodium:hydrogen antiporter activity	Biological Process	IDA[7512953]	1
GO:0033674	positive regulation of kinase activity	Biological Process	IDA[15755724]	2
GO:0034776	response to histamine	Biological Process	IDA[16839358]	3
GO:0035176	social behavior	Biological Process	NAS[11409696]	9
GO:0015459	potassium channel regulator activity	Molecular Function	NAS[12297500]	7
GO:0016020	membrane	Cellular Component	IDA[7512953]	139
GO:0017124	SH3 domain binding	Molecular Function	IDA[9843378]	22
GO:0030818	negative regulation of cAMP biosynthetic process	Biological Process	IDA[7512953]	7

Gene related KEGG pathways (count: 1)

ID	Name	No. of Genes in ADHDgene	Brief Description
hsa04080	Neuroactive ligand-receptor interaction	93

Genes shared at least 5 GO terms with DRD4 (count: 18)

Gene Symbol	Pathway Count	Pathway List
DRD2	20	synaptic transmission, dopaminergic; response to amphetamine; protein binding; plasma membrane; integral to plasma membrane; cellular calcium ion homeostasis; dopamine neurotransmitter receptor activity, coupled via Gi/Go; dopamine binding; dopamine metabolic process; positive regulation of dopamine uptake involved in synaptic transmission; negative regulation of voltage-gated calcium channel activity; behavioral response to ethanol; behavioral response to cocaine; negative regulation of protein secretion; arachidonic acid secretion; drug binding; negative regulation of adenylate cyclase activity; adenylate cyclase-inhibiting dopamine receptor signaling pathway; response to histamine; potassium channel regulator activity;
DRD3	17	synaptic transmission, dopaminergic; response to amphetamine; protein binding; plasma membrane; integral to plasma membrane; cellular calcium ion homeostasis; dopamine neurotransmitter receptor activity, coupled via Gi/Go; dopamine binding; dopamine metabolic process; behavioral response to cocaine; negative regulation of protein secretion; arachidonic acid secretion; drug binding; negative regulation of adenylate cyclase activity; adenylate cyclase-inhibiting dopamine receptor signaling pathway; response to histamine; social behavior;
DRD1	11	synaptic transmission, dopaminergic; response to amphetamine; dopamine neurotransmitter receptor activity; protein binding; plasma membrane; integral to plasma membrane; behavioral fear response; regulation of dopamine metabolic process; dopamine binding; dopamine metabolic process; behavioral response to cocaine;
ADORA2A	8	synaptic transmission, dopaminergic; response to amphetamine; protein binding; plasma membrane; integral to plasma membrane; neuronal cell body; regulation of inhibitory postsynaptic membrane potential; membrane;
DRD5	7	synaptic transmission, dopaminergic; response to amphetamine; dopamine neurotransmitter receptor activity; plasma membrane; integral to plasma membrane; cellular calcium ion homeostasis; dopamine binding;
SLC18A2	7	response to amphetamine; plasma membrane; integral to plasma membrane; terminal bouton; neuronal cell body; drug binding; membrane;
ADRB1	7	protein binding; plasma membrane; integral to plasma membrane; dopamine binding; fear response; regulation of inhibitory postsynaptic membrane potential; drug binding;
SLC6A3	7	protein binding; plasma membrane; integral to plasma membrane; neuronal cell body; regulation of dopamine metabolic process; dopamine binding; drug binding;
GRM7	7	plasma membrane; integral to plasma membrane; cell cortex; behavioral fear response; negative regulation of adenylate cyclase activity; short-term memory; negative regulation of cAMP biosynthetic process;
TH	6	synaptic transmission, dopaminergic; response to amphetamine; protein binding; terminal bouton; dopamine binding; social behavior;
ADRA2A	6	protein binding; plasma membrane; integral to plasma membrane; fear response; negative regulation of adenylate cyclase activity; negative regulation of cAMP biosynthetic process;
SNCA	6	protein binding; plasma membrane; cell cortex; terminal bouton; behavioral response to cocaine; adult locomotory behavior;
GRIN2A	5	response to amphetamine; protein binding; plasma membrane; integral to plasma membrane; dopamine metabolic process;
GHR	5	protein binding; plasma membrane; integral to plasma membrane; activation of MAPK activity; neuronal cell body;
ILK	5	protein binding; plasma membrane; terminal bouton; neuronal cell body; SH3 domain binding;
LPAR1	5	protein binding; plasma membrane; integral to plasma membrane; activation of MAPK activity; dendritic spine;
OPRM1	5	protein binding; plasma membrane; integral to plasma membrane; behavioral response to ethanol; negative regulation of adenylate cyclase activity;
P2RX3	5	integral to plasma membrane; terminal bouton; neuronal cell body; dendritic spine; membrane;

Genes shared at least 2 KEGG pathways with DRD4 (count: 0)

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Region: chr11:637293..640706 View in gBrowse