Advertisement

The dopamine D4 receptor gene 48-base-pair-repeat polymorphism and mood disorders: A meta-analysis

      Background

      We conducted a meta-analysis to re-evaluate the role of the dopamine D4 receptor gene 48-base-pair- repeat (DRD4) polymorphism in mood disorders.

      Methods

      DRD4 allele frequencies were compared between 917 patients with unipolar (UP) or bipolar affective disorder (BP) and 1164 control subjects from 12 samples, using the Cochrane Review Manager.

      Results

      An association was found between all mood disorder groups and DRD4.2. After correcting for multiple testing, the association between DRD4.2 and BP dropped to insignificance; however, the evidence of an association between the DRD4.2 allele and UP (p < .001) and the combined group (p < .001) remained. There was no evidence for heterogeneity or publication bias.

      Conclusions

      These findings suggest that the DRD4.2 allele is a risk allele for depression symptomatology. Meta-analysis may be a valuable objective tool for a quantitative summary of evidence for association studies in psychiatric genetics.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ainsworth K.
        • Smith S.E.
        • Sharp T.
        Repeated administration of fluoxetine, desipramine and tranylcypromine increases dopamine D2-like but not D1-like receptor function in the rat.
        J Psychopharmacol. 1998; 12: 252-257
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. American Psychiatric Press, Washington, DC1987 (Revised)
        • Asghari V.
        • Sanyal S.
        • Buchwaldt S.
        • Paterson A.
        • Jovanovic V.
        • Van Tol H.H.
        Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants.
        J Neurochem. 1995; 65: 1157-1165
        • Barbini B.
        • Scherillo P.
        • Benedetti F.
        • Crespi G.
        • Colombo C.
        • Smeraldi E.
        Response to clozapine in acute mania is more rapid than that of chlorpromazine.
        Int Clin Psychopharmacol. 1997; 12: 109-112
        • Bocchetta A.
        • Piccardi M.P.
        • Palmas M.A.
        • Chillotti C.
        • Oi A.
        • Del Zompo M.
        Family-based association study between bipolar disorder and DRD2, DRD4, DAT, and SERT in Sardinia.
        Am J Med Genet. 1999; 88: 522-526
        • Bowden C.
        • Theodorou A.E.
        • Cheetham S.C.
        • Lowther S.
        • Katona C.L.
        • Crompton M.R.
        • et al.
        Dopamine D1 and D2 receptor binding sites in brain samples from depressed suicides and controls.
        Brain Res. 1997; 752: 227-233
        • Calabrese J.R.
        • Kimmel S.E.
        • Woyshville M.J.
        • Rapport D.J.
        • Faust C.J.
        • Thompson P.A.
        • et al.
        Clozapine for treatment-refractory mania.
        Am J Psychiatry. 1996; 153: 759-764
        • Chotai J.
        • Serretti A.
        • Lattuada E.
        • Lorenzi C.
        • Lilli R.
        Gene-environment interaction in psychiatric disorders as indicated by season of birth variations in tryptophan hydroxylase (TPH), serotonin transporter (5-HTTLPR) and dopamine receptor (DRD4) gene polymorphisms.
        Psychiatry Res. 2003; 119: 99-111
        • Cohen A.I.
        • Todd R.D.
        • Harmon S.
        • O’Malley K.L.
        Photoreceptors of mouse retinas possess D4 receptors coupled to adenylate cyclase.
        Proc Natl Acad Sci U S A. 1992; 89: 12093-12097
        • Collu M.
        • Poggiu A.S.
        • Devoto P.
        • Serra G.
        Behavioural sensitization of mesolimbic dopamine D2 receptors in chronic fluoxetine-treated rats.
        Eur J Pharmacol. 1997; 322: 123-127
        • Cusin C.
        • Serretti A.
        • Lattuada E.
        • Lilli R.
        • Lorenzi C.
        • Smeraldi E.
        Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders.
        Am J Med Genet. 2002; 114: 380-390
        • D’Aquila P.S.
        • Collu M.
        • Gessa G.L.
        • Serra G.
        Role of alpha 1 receptors in the behavioural supersensitivity to D2 agonists induced by chronic treatment with imipramine.
        Pharmacol Res. 1992; 25: 95-101
        • D’Aquila P.S.
        • Collu M.
        • Gessa G.L.
        • Serra G.
        The role of dopamine in the mechanism of action of antidepressant drugs.
        Eur J Pharmacol. 2000; 405: 365-373
        • De Bruyn A.
        • Mendelbaum K.
        • Sandkuijl L.A.
        • Delvenne V.
        • Hirsch D.
        • Staner L.
        • et al.
        Nonlinkage of bipolar illness to tyrosine hydroxylase, tyrosinase, and D2 and D4 dopamine receptor genes on chromosome 11.
        Am J Psychiatry. 1994; 151: 102-106
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Diehl D.J.
        • Gershon S.
        The role of dopamine in mood disorders.
        Compr Psychiatry. 1992; 33: 115-120
        • Drevets W.C.
        • Gautier C.
        • Price J.C.
        • Kupfer D.J.
        • Kinahan P.E.
        • Grace A.A.
        • et al.
        Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria.
        Biol Psychiatry. 2001; 49: 81-96
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Emilien G.
        • Maloteaux J.M.
        • Geurts M.
        • Hoogenberg K.
        • Cragg S.
        Dopamine receptors-physiological understanding to therapeutic intervention potential.
        Pharmacol Ther. 1999; 84: 133-156
        • Endicott J.
        • Spitzer R.L.
        A diagnostic interview.
        Arch Gen Psychiatry. 1978; 35: 837-844
        • Faraone S.V.
        • Biederman J.
        • Weiffenbach B.
        • Keith T.
        • Chu M.P.
        • Weaver A.
        • et al.
        Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder.
        Am J Psychiatry. 1999; 156: 768-770
        • Frisch A.
        • Postilnick D.
        • Rockah R.
        • Michaelovsky E.
        • Postilnick S.
        • Birman E.
        • et al.
        Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways.
        Mol Psychiatry. 1999; 4: 389-392
        • Glatt S.J.
        • Faraone S.V.
        • Tsuang M.T.
        Schizophrenia is not associated with DRD4 48-base-pair-repeat length or individual alleles.
        Biol Psychiatry. 2003; 54: 629-635
        • Ioannidis J.P.
        • Ntzani E.E.
        • Trikalinos T.A.
        • Contopoulos-Ioannidis D.G.
        Replication validity of genetic association studies.
        Nat Genet. 2001; 29: 306-309
        • Kaplitz S.E.
        Withdrawn, apathetic geriatric patients responsive to methylphenidate.
        J Am Geriatr Soc. 1975; 23: 271-276
        • Katon W.
        • Raskind M.
        Treatment of depression in the medically ill elderly with methylphenidate.
        Am J Psychiatry. 1980; 137: 963-965
        • Kaufmann M.W.
        • Murray G.B.
        • Cassem N.H.
        Use of psychostimulants in medically ill depressed patients.
        Psychosomatics. 1982; 23: 817-819
        • Laruelle M.
        • Abi-Dargham A.
        • van Dyck C.H.
        • Rosenblatt W.
        • Zea-Ponce Y.
        • Zoghbi S.S.
        • et al.
        SPECT imaging of striatal dopamine release after amphetamine challenge.
        J Nucl Med. 1995; 36: 1182-1190
        • Li T.
        • Liu X.
        • Sham P.C.
        • Aitchison K.J.
        • Cai G.
        • Arranz M.J.
        • et al.
        Association analysis between dopamine receptor genes and bipolar affective disorder.
        Psychiatry Res. 1999; 86: 193-201
        • Lim L.C.
        • Nothen M.M.
        • Korner J.
        • Rietschel M.
        • Castle D.
        • Hunt N.
        • et al.
        No evidence of association between dopamine D4 receptor variants and bipolar affective disorder.
        Am J Med Genet. 1994; 54: 259-263
        • Lohmueller K.E.
        • Pearce C.L.
        • Pike M.
        • Lander E.S.
        • Hirschhorn J.N.
        Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.
        Nat Genet. 2003; 33: 177-182
        • Manki H.
        • Kanba S.
        • Muramatsu T.
        • Higuchi S.
        • Suzuki E.
        • Matsushita S.
        • et al.
        Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders.
        J Affect Disord. 1996; 40: 7-13
        • Masand P.
        • Pickett P.
        • Murray G.B.
        Psychostimulants for secondary depression in medical illness.
        Psychosomatics. 1991; 32: 203-208
        • Muglia P.
        • Petronis A.
        • Mundo E.
        • Lander S.
        • Cate T.
        • Kennedy J.L.
        Dopamine D4 receptor and tyrosine hydroxylase genes in bipolar disorder.
        Mol Psychiatry. 2002; 7: 860-866
        • Nordin C.
        • Siwers B.
        • Bertilsson L.
        Bromocriptine treatment of depressive disorders. Clinical and biochemical effects.
        Acta Psychiatr Scand. 1981; 64: 25-33
        • Oak J.N.
        • Oldenhof J.
        • Van Tol H.H.
        The dopamine D(4) receptor.
        Eur J Pharmacol. 2000; 405: 303-327
        • Obadiah J.
        • Avidor-Reiss T.
        • Fishburn C.S.
        • Carmon S.
        • Bayewitch M.
        • Vogel Z.
        • et al.
        Adenylyl cyclase interaction with the D2 dopamine receptor family; differential coupling to Gi, Gz, and Gs.
        Cell Mol Neurobiol. 1999; 19: 653-664
        • Oruc L.
        • Verheyen G.R.
        • Furac I.
        • Jakovljevic M.
        • Ivezic S.
        • Raeymaekers P.
        • et al.
        Analysis of the tyrosine hydroxylase and dopamine D4 receptor genes in a Croatian sample of bipolar I and unipolar patients.
        Am J Med Genet. 1997; 74: 176-178
        • Perez De Castro I.
        • Torres P.
        • Fernandez-Piqueras J.
        • Saiz-Ruiz J.
        • Llinares C.
        No association between dopamine D4 receptor polymorphism and manic depressive illness.
        J Med Genet. 1994; 31: 897-898
        • Petronis A.
        The genes for major psychosis.
        Neuropsychopharmacology. 2000; 23: 1-12
        • Post R.M.
        • Gerner R.H.
        • Carman J.S.
        • Gillin J.C.
        • Jimerson D.C.
        • Goodwin F.K.
        • et al.
        Effects of a dopamine agonist piribedil in depressed patients.
        Arch Gen Psychiatry. 1978; 35: 609-615
        • Reik W.
        • Walter J.
        Genomic imprinting.
        Nat Rev Genet. 2001; 2: 21-32
        • Risch N.J.
        Searching for genetic determinants in the new millennium.
        Nature. 2000; 405: 847-856
        • Rothman J.
        Modern Epidemiology. 2nd ed. Lippincott, Philadelphia1998
        • Rubinstein M.
        • Phillips T.J.
        • Bunzow J.R.
        • Falzone T.L.
        • Dziewczapolski G.
        • Zhang G.
        • et al.
        Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine.
        Cell. 1997; 90: 991-1001
        • Sanyal S.
        • Van Tol H.H.
        Dopamine D4 receptor-mediated inhibition of cyclic adenosine 3’,5’-monophosphate production does not affect prolactin regulation.
        Endocrinology. 1997; 138: 1871-1878
        • Schinka J.A.
        • Letsch E.A.
        • Crawford F.C.
        DRD4 and novelty seeking.
        Am J Med Genet. 2002; 114: 643-648
        • Serretti A.
        • Cristina S.
        • Lilli R.
        • Cusin C.
        • Lattuada E.
        • Lorenzi C.
        • et al.
        Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders.
        Am J Med Genet. 2002; 114: 361-369
        • Serretti A.
        • Cusin C.
        • Lattuada E.
        • Lilli R.
        • Lorenzi C.
        • Di Bella D.
        • et al.
        No interaction between serotonin transporter gene and dopamine receptor D4 gene in symptomatology of major psychoses.
        Am J Med Genet. 1999; 88: 481-485
        • Serretti A.
        • Lilli R.
        • Di Bella D.
        • Bertelli S.
        • Nobile M.
        • Novelli E.
        • et al.
        Dopamine receptor D4 gene is not associated with major psychoses.
        Am J Med Genet. 1999; 88: 486-491
        • Serretti A.
        • Lilli R.
        • Lorenzi C.
        • Lattuada E.
        • Smeraldi E.
        DRD4 exon 3 variants associated with delusional symptomatology in major psychoses.
        Am J Med Genet. 2001; 105: 283-290
        • Serretti A.
        • Macciardi F.
        • Catalano M.
        • Bellodi L.
        • Smeraldi E.
        Genetic variants of dopamine receptor D4 and psychopathology.
        Schizophr Bull. 1999; 25: 609-618
        • Serretti A.
        • Macciardi F.
        • Cusin C.
        • Lattuada E.
        • Lilli R.
        • Smeraldi E.
        Dopamine receptor D4 gene is associated with delusional symptomatology in mood disorders.
        Psychiatry Res. 1998; 80: 129-136
        • Silverstone T.
        Response to bromocriptine distinguishes bipolar from unipolar depression.
        Lancet. 1984; 1: 903-904
        • Spitzer R.L.
        • Endicott J.
        • Robins E.
        Research diagnostic criteria.
        Psychopharmacol Bull. 1975; 11: 22-25
        • Spyraki C.
        • Fibiger H.C.
        Behavioural evidence for supersensitivity of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine.
        Eur J Pharmacol. 1981; 74: 195-206
        • Tang A.H.
        • Franklin S.R.
        • Himes C.S.
        • Smith M.W.
        • Tenbrink R.E.
        PNU-96415E, a potential antipsychotic agent with clozapine-like pharmacological properties.
        J Pharmacol Exp Ther. 1997; 281: 440-447
        • Tang L.
        • Todd R.D.
        • Heller A.
        • O’Malley K.L.
        Pharmacological and functional characterization of D2, D3 and D4 dopamine receptors in fibroblast and dopaminergic cell lines.
        J Pharmacol Exp Ther. 1994; 268: 495-502
        • Tarazi F.I.
        • Campbell A.
        • Yeghiayan S.K.
        • Baldessarini R.J.
        Localization of dopamine receptor subtypes in corpus striatum and nucleus accumbens septi of rat brain.
        Neuroscience. 1998; 83: 169-176
        • Tremblay L.K.
        • Naranjo C.A.
        • Cardenas L.
        • Herrmann N.
        • Busto U.E.
        Probing brain reward system function in major depressive disorder.
        Arch Gen Psychiatry. 2002; 59: 409-416
        • Van Broeckhoven C.
        • Verheyen G.
        Report of the chromosome 18 workshop.
        Am J MedGenet. 1999; 88: 263-270
        • Van Tol H.H.
        • Bunzow J.R.
        • Guan H.C.
        • Sunahara R.K.
        • Seeman P.
        • Niznik H.B.
        • et al.
        Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine.
        Nature. 1991; 350: 610-614
        • Van Tol H.H.
        • Wu C.M.
        • Guan H.C.
        • Ohara K.
        • Bunzow J.R.
        • Civelli O.
        • et al.
        Multiple dopamine D4 receptor variants in the human population.
        Nature. 1992; 358: 149-152
        • Villar J.
        • Piaggio G.
        • Carroli G.
        • Donner A.
        Factors affecting the comparability of meta-analyses and largest trials results in perinatology.
        J Clin Epidemiol. 1997; 50: 997-1002
        • Wang E.
        • Ding Y.C.
        • Flodman P.
        • Kidd J.R.
        • Kidd K.K.
        • Grady D.L.
        • et al.
        The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus.
        Am J Hum Genet. 2004; 74: 931-944
        • Watts V.J.
        • Vu M.N.
        • Wiens B.L.
        • Jovanovic V.
        • Van Tol H.H.
        • Neve K.A.
        Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors.
        Psychopharmacology (Berl). 1999; 141: 83-92
        • Wedzony K.
        • Chocyk A.
        • Mackowiak M.
        • Fijal K.
        • Czyrak A.
        Cortical localization of dopamine D4 receptors in the rat brain-immunocytochemical study.
        J Physiol Pharmacol. 2000; 51: 205-221
        • Willner P.
        The mesolimbic dopamine system as a target for rapid antidepressant action.
        Int Clin Psychopharmacol. 1997; 12: S7-S14
        • Woods S.W.
        • Tesar G.E.
        • Murray G.B.
        • Cassem N.H.
        Psychostimulant treatment of depressive disorders secondary to medical illness.
        J Clin Psychiatry. 1986; 47: 12-15
        • Yamaguchi I.
        • Harmon S.K.
        • Todd R.D.
        • O’Malley K.L.
        The rat D4 dopamine receptor couples to cone transducin (Galphat2) to inhibit forskolin-stimulated cAMP accumulation.
        J Biol Chem. 1997; 272: 16599-16602
        • Zarate Jr, C.A.
        • Tohen M.
        • Banov M.D.
        • Weiss M.K.
        • Cole J.O.
        Is clozapine a mood stabilizer?.
        J Clin Psychiatry. 1995; 56: 108-112