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Meta-analyses of genetic studies on major depressive disorder

Abstract

The genetic basis of major depressive disorder (MDD) has been investigated extensively, but the identification of MDD genes has been hampered by conflicting results from underpowered studies. We review all MDD case–control genetic association studies published before June 2007 and perform meta-analyses for polymorphisms that had been investigated in at least three studies. The study selection and data extraction were performed in duplicate by two independent investigators. The 183 papers that met our criteria studied 393 polymorphisms in 102 genes. Twenty-two polymorphisms (6%) were investigated in at least three studies. Seven polymorphisms had been evaluated in previous meta-analyses, 5 of these had new data available. Hence, we performed meta-analyses for 20 polymorphisms in 18 genes. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistically significant associations were found for the APOE ɛ2 (OR, 0.51), GNB3 825T (OR, 1.38), MTHFR 677T (OR, 1.20), SLC6A4 44 bp Ins/Del S (OR, 1.11) alleles and the SLC6A3 40 bpVNTR 9/10 genotype (OR, 2.06). To date, there is statistically significant evidence for six MDD susceptibility genes (APOE, DRD4, GNB3, MTHFR, SLC6A3 and SLC6A4).

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References

  1. Murray CJ, Lopez AD . Evidence-based health policy—lessons from the Global Burden of Disease Study. Science 1996; 274: 740–743.

    Article  CAS  PubMed  Google Scholar 

  2. Ebmeier KP, Donaghey C, Steele JD . Recent developments and current controversies in depression. Lancet 2006; 367: 153–167.

    Article  PubMed  Google Scholar 

  3. Sullivan PF, Neale MC, Kendler KS . Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000; 157: 1552–1562.

    Article  CAS  PubMed  Google Scholar 

  4. Levinson DF . The genetics of depression: a review. Biol Psychiatry 2006; 60: 84–92.

    Article  CAS  PubMed  Google Scholar 

  5. Beckman G, Beckman L, Cedergren B, Perris C, Strandman E . Serum protein and red cell enzyme polymorphisms in affective disorders. Hum Hered 1978; 28: 41–47.

    Article  CAS  PubMed  Google Scholar 

  6. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN . Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33: 177–182.

    Article  CAS  PubMed  Google Scholar 

  7. Levinson DF . Meta-analysis in psychiatric genetics. Curr Psychiatry Rep 2005; 7: 143–151.

    Article  PubMed  Google Scholar 

  8. Anguelova M, Benkelfat C, Turecki G . A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 2003; 8: 574–591.

    Article  CAS  PubMed  Google Scholar 

  9. Zintzaras E . C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: a meta-analysis of genetic association studies. Psychiatr Genet 2006; 16: 105–115.

    Article  PubMed  Google Scholar 

  10. Furlong RA, Rubinsztein JS, Ho L, Walsh C, Coleman TA, Muir WJ et al. Analysis and metaanalysis of two polymorphisms within the tyrosine hydroxylase gene in bipolar and unipolar affective disorders. Am J Med Genet 1999; 88: 88–94.

    Article  CAS  PubMed  Google Scholar 

  11. Lopez Leon S, Croes EA, Sayed-Tabatabaei FA, Claes S, Van Broeckhoven C, van Duijn CM . The dopamine D4 receptor gene 48-base-pair-repeat polymorphism and mood disorders: a meta-analysis. Biol Psychiatry 2005; 57: 999–1003.

    Article  CAS  PubMed  Google Scholar 

  12. Lasky-Su JA, Faraone SV, Glatt SJ, Tsuang MT . Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B Neuropsychiatr Genet 2005; 133: 110–115.

    Article  Google Scholar 

  13. Furlong RA, Ho L, Walsh C, Rubinsztein JS, Jain S, Paykel ES et al. Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders. Am J Med Genet 1998; 81: 58–63.

    Article  CAS  PubMed  Google Scholar 

  14. Lopez-Leon S, Janssens AC, Hofman A, Claes S, Breteler MM, Tiemeier H et al. No association between the angiotensin-converting enzyme gene and major depression: a case–control study and meta-analysis. Psychiatr Genet 2006; 16: 225–226.

    Article  PubMed  Google Scholar 

  15. Lewis SJ, Lawlor DA, Davey Smith G, Araya R, Timpson N, Day IN et al. The thermolabile variant of MTHFR is associated with depression in the British women's heart and health study and a meta-analysis. Mol Psychiatry 2006; 11: 352–360.

    Article  CAS  PubMed  Google Scholar 

  16. DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

    Article  CAS  PubMed  Google Scholar 

  17. Higgins JP, Thompson SG, Deeks JJ, Altman DG . Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Higgins JP, Thompson SG . Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558.

    Article  PubMed  Google Scholar 

  19. Egger M, Davey Smith G, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM . Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry 2003; 60: 618–626.

    Article  CAS  PubMed  Google Scholar 

  21. Exton MS, Artz M, Siffert W, Schedlowski M . G protein beta3 subunit 825T allele is associated with depression in young, healthy subjects. NeuroReport 2003; 14: 531–533.

    Article  CAS  PubMed  Google Scholar 

  22. Schmand B, Hooijer C, Jonker C, Lindeboom J, Havekes LM . Apolipoprotein E phenotype is not related to late-life depression in a population-based sample. Soc Psychiatry Psychiatr Epidemiol 1998; 33: 21–26.

    Article  CAS  PubMed  Google Scholar 

  23. Kravitz HM, Janssen I, Lotrich FE, Kado DM, Bromberger JT . Sex steroid hormone gene polymorphisms and depressive symptoms in women at midlife. Am J Med 2006; 119(9 Suppl 1): S87–S93.

    Article  CAS  PubMed  Google Scholar 

  24. Almeida OP, Flicker L, Lautenschlager NT, Leedman P, Vasikaran S, van Bockxmeer FM . Contribution of the MTHFR gene to the causal pathway for depression, anxiety and cognitive impairment in later life. Neurobiol Aging 2005; 26: 251–257.

    Article  CAS  PubMed  Google Scholar 

  25. Bailer U, Wiesegger G, Leisch F, Fuchs K, Leitner I, Letmaier M et al. No association of clock gene T3111C polymorphism and affective disorders. Eur Neuropsychopharmacol 2005; 15: 51–55.

    Article  CAS  PubMed  Google Scholar 

  26. Khait VD, Huang YY, Zalsman G, Oquendo MA, Brent DA, Harkavy-Friedman JM et al. Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects. Neuropsychopharmacology 2005; 30: 166–172.

    Article  CAS  PubMed  Google Scholar 

  27. Bellivier F, Szoke A, Henry C, Lacoste J, Bottos C, Nosten-Bertrand M et al. Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders. Biol Psychiatry 2000; 48: 319–322.

    Article  CAS  PubMed  Google Scholar 

  28. Kessing LV, Jorgensen OS . Apolipoprotein E-epsilon 4 frequency in affective disorder. Biol Psychiatry 1999; 45: 430–434.

    Article  CAS  PubMed  Google Scholar 

  29. Tanna VL, Winokur G . A study of association and linkage of ABO blood types and primary affective disorder. Br J Psychiatry 1968; 114: 1175–1181.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  PubMed  Google Scholar 

  31. Lin S, Jiang S, Jiang K . [Genetic association between mood disorder and monoamine oxidase gene]. Zhonghua Yi Xue Za Zhi 1999; 79: 897–899.

    CAS  PubMed  Google Scholar 

  32. Kurumaji A, Nomoto H, Yamada K, Yoshikawa T, Toru M . No association of two missense variations of the benzodiazepine receptor (peripheral) gene and mood disorders in a Japanese sample. Am J Med Genet 2001; 105: 172–175.

    Article  CAS  PubMed  Google Scholar 

  33. Qian W, Homma M, Itagaki F, Tachikawa H, Kawanishi Y, Mizukami K et al. MDR1 gene polymorphism in Japanese patients with schizophrenia and mood disorders including depression. Biol Pharm Bull 2006; 29: 2446–2450.

    Article  CAS  PubMed  Google Scholar 

  34. Pae CU, Yoon SJ, Patkar A, Kim JJ, Jun TY, Lee C et al. Manganese superoxide dismutase (MnSOD: Ala-9Val) gene polymorphism and mood disorders: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1326–1329.

    Article  CAS  PubMed  Google Scholar 

  35. Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ . Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 2003; 48: 186–189.

    Article  CAS  PubMed  Google Scholar 

  36. Tsai SJ, Cheng CY, Yu YW, Chen TJ, Hong CJ . Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet 2003; 123: 19–22.

    Article  Google Scholar 

  37. Du L, Faludi G, Palkovits M, Bakish D, Hrdina PD . Serotonergic genes and suicidality. Crisis 2001; 22: 54–60.

    Article  CAS  PubMed  Google Scholar 

  38. Lin CN, Tsai SJ, Hong CJ . Association analysis of a functional G protein beta3 subunit gene polymorphism (C825T) in mood disorders. Neuropsychobiology 2001; 44: 118–121.

    Article  CAS  PubMed  Google Scholar 

  39. Du L, Bakish D, Hrdina PD . Tryptophan hydroxylase gene 218A/C polymorphism is associated with somatic anxiety in major depressive disorder. J Affect Disord 2001; 65: 37–44.

    Article  CAS  PubMed  Google Scholar 

  40. Tsai SJ, Hong CJ, Wang YC . Tryptophan hydroxylase gene polymorphism (A218C) and suicidal behaviors. NeuroReport 1999; 10: 3773–3775.

    Article  CAS  PubMed  Google Scholar 

  41. Bellivier F, Henry C, Szoke A, Schurhoff F, Nosten-Bertrand M, Feingold J et al. Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression. Neurosci Lett 1998; 255: 143–146.

    Article  CAS  PubMed  Google Scholar 

  42. Choi MJ, Kang RH, Ham BJ, Jeong HY, Lee MS . Serotonin receptor 2A gene polymorphism (−1438A/G) and short-term treatment response to citalopram. Neuropsychobiology 2005; 52: 155–162.

    Article  CAS  PubMed  Google Scholar 

  43. Jun TY, Pae CU, Chae JH, Bahk WM, Kim KS, Pyo CW et al. Tumor necrosis factor-beta gene polymorphism may not be associated with major depressive disorder in the Korean population. Psychiatry Clin Neurosci 2003; 57: 31–35.

    Article  CAS  PubMed  Google Scholar 

  44. Bondy B, Baghai TC, Zill P, Bottlender R, Jaeger M, Minov C et al. Combined action of the ACE D- and the G-protein beta3 T-allele in major depression: a possible link to cardiovascular disease? Mol Psychiatry 2002; 7: 1120–1126.

    Article  CAS  PubMed  Google Scholar 

  45. Arias B, Gasto C, Catalan R, Gutierrez B, Pintor L, Fananas L . The 5-HT(2A) receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients. Am J Med Genet 2001; 105: 801–804.

    Article  CAS  PubMed  Google Scholar 

  46. Bondy B, Kuznik J, Baghai T, Schule C, Zwanzger P, Minov C et al. Lack of association of serotonin-2A receptor gene polymorphism (T102C) with suicidal ideation and suicide. Am J Med Genet 2000; 96: 831–835.

    Article  CAS  PubMed  Google Scholar 

  47. Zill P, Baghai TC, Zwanzger P, Schule C, Minov C, Riedel M et al. Evidence for an association between a G-protein beta3-gene variant with depression and response to antidepressant treatment. NeuroReport 2000; 11: 1893–1897.

    Article  CAS  PubMed  Google Scholar 

  48. Huang YY, Grailhe R, Arango V, Hen R, Mann JJ . Relationship of psychopathology to the human serotonin1B genotype and receptor binding kinetics in postmortem brain tissue. Neuropsychopharmacology 1999; 21: 238–246.

    Article  CAS  PubMed  Google Scholar 

  49. Kunugi H, Tatsumi M, Sakai T, Hattori M, Nanko S . Serotonin transporter gene polymorphism and affective disorder. Lancet 1996; 347: 1340.

    Article  CAS  PubMed  Google Scholar 

  50. Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwim GM et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 1996; 347: 731–733.

    Article  CAS  PubMed  Google Scholar 

  51. Harmar AJ, Ogilvie AD, Battersby S, Smith CA, Blackwood DH, Muir WJ et al. The serotonin transporter gene and affective disorder. Cold Spring Harb Symp Quant Biol 1996; 61: 791–795.

    Article  CAS  PubMed  Google Scholar 

  52. Souery D, Van Gestel S, Massat I, Blairy S, Adolfsson R, Blackwood D et al. Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study. Biol Psychiatry 2001; 49: 405–409.

    Article  CAS  PubMed  Google Scholar 

  53. Ham BJ, Lee MS, Lee HJ, Kang RH, Han CS, Choi MJ et al. No association between the tryptophan hydroxylase gene polymorphism and major depressive disorders and antidepressant response in a Korean population. Psychiatr Genet 2005; 15: 299–301.

    Article  PubMed  Google Scholar 

  54. Gizatullin R, Zaboli G, Jonsson EG, Asberg M, Leopardi R . Haplotype analysis reveals tryptophan hydroxylase (TPH) 1 gene variants associated with major depression. Biol Psychiatry 2005; 59: 295–300.

    Article  PubMed  CAS  Google Scholar 

  55. Collier DA, Stober G, Li T, Heils A, Catalano M, Di Bella D et al. A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996; 1: 453–460.

    CAS  PubMed  Google Scholar 

  56. D'Aquila PS, Collu M, Gessa GL, Serra G . The role of dopamine in the mechanism of action of antidepressant drugs. Eur J Pharmacol 2000; 405: 365–373.

    Article  CAS  PubMed  Google Scholar 

  57. Tremblay LK, Naranjo CA, Cardenas L, Herrmann N, Busto UE . Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine. Arch Gen Psychiatry 2002; 59: 409–416.

    Article  PubMed  Google Scholar 

  58. Ainsworth K, Smith SE, 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.

    Article  CAS  PubMed  Google Scholar 

  59. Routledge C, Middlemiss DN . The 5-HT hypothesis of depression revisited. Mol Psychiatry 1996; 1: 437.

    CAS  PubMed  Google Scholar 

  60. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 2006; 78: 815–826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rasenick MM, Chaney KA, Chen J . G protein-mediated signal transduction as a target of antidepressant and antibipolar drug action: evidence from model systems. J Clin Psychiatry 1996; 57(Suppl 13): 49–55; discussion 56–48.

    CAS  PubMed  Google Scholar 

  62. Kunugi H, Ishida S, Kato T, Tatsumi M, Sakai T, Hattori M et al. A functional polymorphism in the promoter region of monoamine oxidase-A gene and mood disorders. Mol Psychiatry 1999; 4: 393–395.

    Article  CAS  PubMed  Google Scholar 

  63. Crellin R, Bottiglieri T, Reynolds EH . Folates and psychiatric disorders. Clinical potential. Drugs 1993; 45: 623–636.

    Article  CAS  PubMed  Google Scholar 

  64. Paul RT, McDonnell AP, Kelly CB . Folic acid: neurochemistry, metabolism and relationship to depression. Hum Psychopharmacol 2004; 19: 477–488.

    Article  CAS  PubMed  Google Scholar 

  65. Mahley RW, Rall Jr SC . Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 2000; 1: 507–537.

    Article  CAS  PubMed  Google Scholar 

  66. Ioannidis JP, Gwinn M, Little J, Higgins JP, Bernstein JL, Boffetta P et al. A road map for efficient and reliable human genome epidemiology. Nat Genet 2006; 38: 3–5.

    Article  CAS  PubMed  Google Scholar 

  67. Ohara K, Suzuki Y, Yoshida K, Terada H, Ohara K . Lack of association between alpha1-antichymotrypsin polymorphism and late-onset depressive disorder. Psychiatry Res 1999; 88: 221–226.

    Article  CAS  PubMed  Google Scholar 

  68. Comings DE, Wu S, Rostamkhani M, McGue M, Iacono WG, MacMurray JP . Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women. Am J Med Genet 2002; 114: 527–529.

    Article  PubMed  Google Scholar 

  69. Oruc L, Verheyen GR, Furac I, Ivezic S, Jakovljevic M, Raeymaekers P et al. Positive association between the GABRA5 gene and unipolar recurrent major depression. Neuropsychobiology 1997; 36: 62–64.

    Article  CAS  PubMed  Google Scholar 

  70. Yamada K, Hattori E, Iwayama Y, Ohnishi T, Ohba H, Toyota T et al. Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression. Biol Psychiatry 2006; 60: 192–201.

    Article  CAS  PubMed  Google Scholar 

  71. Reif A, Strobel A, Jacob CP, Herterich S, Freitag CM, Topner T et al. A NOS-III haplotype that includes functional polymorphisms is associated with bipolar disorder. Int J Neuropsychopharmacol 2006; 9: 13–20.

    Article  CAS  PubMed  Google Scholar 

  72. Wong ML, Whelan F, Deloukas P, Whittaker P, Delgado M, Cantor RM et al. Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response. Proc Natl Acad Sci USA 2006; 103: 15124–15129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mendlewicz J, Oswald P, Claes S, Massat I, Souery D, Van Broeckhoven C et al. Patient-control association study of substance P-related genes in unipolar and bipolar affective disorders. Int J Neuropsychopharmacol 2005; 8: 505–513.

    Article  CAS  PubMed  Google Scholar 

  74. Lai IC, Hong CJ, Tsai SJ . Association study of nicotinic-receptor variants and major depressive disorder. J Affect Disord 2001; 66: 79–82.

    Article  CAS  PubMed  Google Scholar 

  75. Furlong RA, Coleman TA, Ho L, Rubinsztein JS, Walsh C, Paykel ES et al. No association of a functional polymorphism in the dopamine D2 receptor promoter region with bipolar or unipolar affective disorders. Am J Med Genet 1998; 81: 385–387.

    Article  CAS  PubMed  Google Scholar 

  76. Yamada K, Watanabe A, Iwayama-Shigeno Y, Yoshikawa T . Evidence of association between gamma-aminobutyric acid type A receptor genes located on 5q34 and female patients with mood disorders. Neurosci Lett 2003; 349: 9–12.

    Article  CAS  PubMed  Google Scholar 

  77. Heilig M, Zachrisson O, Thorsell A, Ehnvall A, Mottagui-Tabar S, Sjogren M et al. Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar major depression: preliminary evidence for association with preproNPY gene polymorphism. J Psychiatr Res 2004; 38: 113–121.

    Article  PubMed  Google Scholar 

  78. Lindberg C, Koefoed P, Hansen ES, Bolwig TG, Rehfeld JF, Mellerup E et al. No association between the −399 C>T polymorphism of the neuropeptide Y gene and schizophrenia, unipolar depression or panic disorder in a Danish population. Acta Psychiatr Scand 2006; 113: 54–58.

    Article  CAS  PubMed  Google Scholar 

  79. Toyota T, Hattori E, Meerabux J, Yamada K, Saito K, Shibuya H et al. Molecular analysis, mutation screening, and association study of adenylate cyclase type 9 gene (ADCY9) in mood disorders. Am J Med Genet 2002; 114: 84–92.

    Article  PubMed  Google Scholar 

  80. Desan PH, Oren DA, Malison R, Price LH, Rosenbaum J, Smoller J et al. Genetic polymorphism at the CLOCK gene locus and major depression. Am J Med Genet 2000; 96: 418–421.

    Article  CAS  PubMed  Google Scholar 

  81. Lappalainen J, Sanacora G, Kranzler HR, Malison R, Hibbard ES, Price LH et al. Mutation screen of the glutamate decarboxylase-67 gene and haplotype association to unipolar depression. Am J Med Genet B Neuropsychiatr Genet 2004; 124: 81–86.

    Article  Google Scholar 

  82. Birkett JT, Arranz MJ, Munro J, Osbourn S, Kerwin RW, Collier DA . Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. NeuroReport 2000; 11: 2017–2020.

    Article  CAS  PubMed  Google Scholar 

  83. Arias B, Collier DA, Gasto C, Pintor L, Gutierrez B, Valles V et al. Genetic variation in the 5-HT5A receptor gene in patients with bipolar disorder and major depression. Neurosci Lett 2001; 303: 111–114.

    Article  CAS  PubMed  Google Scholar 

  84. Lucae S, Salyakina D, Barden N, Harvey M, Gagne B, Labbe M et al. P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder. Hum Mol Genet 2006; 15: 2438–2445.

    Article  CAS  PubMed  Google Scholar 

  85. Tsai SJ, Hong CJ, Hou SJ, Yen FC . Association study of adenosine A2a receptor (1976C>T) genetic polymorphism and mood disorders and age of onset. Psychiatr Genet 2006; 16: 185.

    Article  PubMed  Google Scholar 

  86. Tsai SJ, Wang YC, Hong CJ . Association study between cannabinoid receptor gene (CNR1) and pathogenesis and psychotic symptoms of mood disorders. Am J Med Genet 2001; 105: 219–221.

    Article  CAS  PubMed  Google Scholar 

  87. van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S et al. Polymorphisms of the glucocorticoid receptor gene and major depression. Biol Psychiatry 2006; 59: 681–688.

    Article  CAS  PubMed  Google Scholar 

  88. van West D, Van Den Eede F, Del-Favero J, Souery D, Norrback KF, Van Duijn C et al. Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression. Neuropsychopharmacology 2006; 31: 620–627.

    Article  CAS  PubMed  Google Scholar 

  89. Hong CJ, Tsai SJ, Cheng CY, Liao WY, Song HL, Lai HC . Association analysis of the 5-HT(6) receptor polymorphism (C267T) in mood disorders. Am J Med Genet 1999; 88: 601–602.

    Article  CAS  PubMed  Google Scholar 

  90. Papadimitriou GN, Dikeos DG, Souery D, Del-Favero J, Massat I, Avramopoulos D et al. Genetic association between the phospholipase A2 gene and unipolar affective disorder: a multicentre case–control study. Psychiatr Genet 2003; 13: 211–220.

    Article  PubMed  Google Scholar 

  91. Pae CU, Yu HS, Kim JJ, Lee CU, Lee SJ, Lee KU et al. BanI polymorphism of the cytosolic phospholipase A2 gene and mood disorders in the Korean population. Neuropsychobiology 2004; 49: 185–188.

    Article  CAS  PubMed  Google Scholar 

  92. Ohara K, Nagai M, Tani K, Tsukamoto T, Suzuki Y . Polymorphism in the promoter region of the alpha 2A adrenergic receptor gene and mood disorders. NeuroReport 1998; 9: 1291–1294.

    Article  CAS  PubMed  Google Scholar 

  93. Gelernter J, Van Dyck C, van Kammen DP, Malison R, Price LH, Cubells JF et al. Ciliary neurotrophic factor null allele frequencies in schizophrenia, affective disorders, and Alzheimer's disease. Am J Med Genet 1997; 74: 497–500.

    Article  CAS  PubMed  Google Scholar 

  94. Grunblatt E, Hupp E, Bambula M, Zehetmayer S, Jungwirth S, Tragl KH et al. Association study of BDNF and CNTF polymorphism to depression in non-demented subjects of the ‘VITA’ study. J Affect Disord 2006; 96: 111–116.

    Article  CAS  PubMed  Google Scholar 

  95. Tadokoro K, Hashimoto R, Tatsumi M, Kosuga A, Kamijima K, Kunugi H . The Gem interacting protein (GMIP) gene is associated with major depressive disorder. Neurogenetics 2005; 6: 127–133.

    Article  CAS  PubMed  Google Scholar 

  96. Yu YW, Chen TJ, Hong CJ, Chen HM, Tsai SJ . Association study of the interleukin-1 beta (C-511T) genetic polymorphism with major depressive disorder, associated symptomatology, and antidepressant response. Neuropsychopharmacology 2003; 28: 1182–1185.

    Article  CAS  PubMed  Google Scholar 

  97. Owen D, Du L, Bakish D, Lapierre YD, Hrdina PD . Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression. Psychiatry Res 1999; 87: 1–5.

    Article  CAS  PubMed  Google Scholar 

  98. Zill P, Baghai TC, Engel R, Zwanzger P, Schule C, Minov C et al. Beta-1-adrenergic receptor gene in major depression: influence on antidepressant treatment response. Am J Med Genet B Neuropsychiatr Genet 2003; 120: 85–89.

    Article  Google Scholar 

  99. Zill P, Baghai TC, Engel R, Zwanzger P, Schule C, Eser D et al. The dysbindin gene in major depression: an association study. Am J Med Genet B Neuropsychiatr Genet 2004; 129: 55–58.

    Article  Google Scholar 

  100. Zill P, Engel R, Baghai TC, Zwanzger P, Schule C, Minov C et al. Analysis of polymorphisms in the olfactory G-protein Golf in major depression. Psychiatr Genet 2002; 12: 17–22.

    Article  PubMed  Google Scholar 

  101. Hong CJ, Yu YW, Chen TJ, Tsai SJ . Interleukin-6 genetic polymorphism and Chinese major depression. Neuropsychobiology 2005; 52: 202–205.

    Article  CAS  PubMed  Google Scholar 

  102. Baghai TC, Binder EB, Schule C, Salyakina D, Eser D, Lucae S et al. Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism. Mol Psychiatry 2006; 11: 1003–1015.

    Article  CAS  PubMed  Google Scholar 

  103. Furlong RA, Keramatipour M, Ho LW, Rubinsztein JS, Michael A, Walsh C et al. No association of an insertion/deletion polymorphism in the angiotensin I converting enzyme gene with bipolar or unipolar affective disorders. Am J Med Genet 2000; 96: 733–735.

    Article  CAS  PubMed  Google Scholar 

  104. Pauls J, Bandelow B, Ruther E, Kornhuber J . Polymorphism of the gene of angiotensin converting enzyme: lack of association with mood disorder. J Neural Transm 2000; 107: 1361–1366.

    Article  CAS  PubMed  Google Scholar 

  105. Segman RH, Shapira Y, Modai I, Hamdan A, Zislin J, Heresco-Levy U et al. Angiotensin converting enzyme gene insertion/deletion polymorphism: case–control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia. Am J Med Genet 2002; 114: 310–314.

    Article  PubMed  Google Scholar 

  106. Arinami T, Li L, Mitsushio H, Itokawa M, Hamaguchi H, Toru M . An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and affective disorders. Biol Psychiatry 1996; 40: 1122–1127.

    Article  CAS  PubMed  Google Scholar 

  107. Konuk N, Atik L, Simsekyilmaz O, Dursun A, Acikgoz S . Association of angiotensin converting enzyme gene polymorphism and affective disorders in Turkish patients. Aust N Z J Psychiatry 2006; 40: 717–718.

    Article  PubMed  Google Scholar 

  108. Fan PL, Chen CD, Kao WT, Shu BC, Lung FW . Protective effect of the apo epsilon2 allele in major depressive disorder in Taiwanese. Acta Psychiatr Scand 2006; 113: 48–53.

    Article  CAS  PubMed  Google Scholar 

  109. Butters MA, Sweet RA, Mulsant BH, Ilyas Kamboh M, Pollock BG, Begley AE et al. APOE is associated with age-of-onset, but not cognitive functioning, in late-life depression. Int J Geriatr Psychiatry 2003; 18: 1075–1081.

    Article  PubMed  Google Scholar 

  110. Forsell Y, Corder EH, Basun H, Lannfelt L, Viitanen M, Winblad B . Depression and dementia in relation to apolipoprotein E polymorphism in a population sample age 75+. Biol Psychiatry 1997; 42: 898–903.

    Article  CAS  PubMed  Google Scholar 

  111. Holmes C, Russ C, Kirov G, Aitchison KJ, Powell JF, Collier DA et al. Apolipoprotein E: depressive illness, depressive symptoms, and Alzheimer's disease. Biol Psychiatry 1998; 43: 159–164.

    Article  CAS  PubMed  Google Scholar 

  112. Zubenko GS, Henderson R, Stiffler JS, Stabler S, Rosen J, Kaplan BB . Association of the APOE epsilon 4 allele with clinical subtypes of late life depression. Biol Psychiatry 1996; 40: 1008–1016.

    Article  CAS  PubMed  Google Scholar 

  113. Papassotiropoulos A, Bagli M, Jessen F, Rao ML, Schwab SG, Heun R . Early-onset and late-onset depression are independent of the genetic polymorphism of apolipoprotein E. Dement Geriatr Cogn Disord 1999; 10: 258–261.

    Article  CAS  PubMed  Google Scholar 

  114. Ohara K, Nagai M, Suzuki Y, Yoshida K, Tsukamoto T . Apolipoprotein E epsilon 4 allele and Japanese late-onset depressive disorders. Biol Psychiatry 1999; 45: 308–312.

    Article  CAS  PubMed  Google Scholar 

  115. Schahab S, Heun R, Schmitz S, Maier W, Kolsch H . Association of polymorphism in the transcription factor LBP-1c/CP2/LSF gene with Alzheimer's disease and major depression. Dement Geriatr Cogn Disord 2006; 22: 95–98.

    Article  CAS  PubMed  Google Scholar 

  116. Oswald P, Del-Favero J, Massat I, Souery D, Claes S, Van Broeckhoven C et al. No implication of brain-derived neurotrophic factor (BDNF) gene in unipolar affective disorder: evidence from Belgian first and replication patient-control studies. Eur Neuropsychopharmacol 2005; 15: 491–495.

    Article  CAS  PubMed  Google Scholar 

  117. Hwang JP, Tsai SJ, Hong CJ, Yang CH, Lirng JF, Yang YM . The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging 2005; 27: 1834–1837.

    Article  PubMed  CAS  Google Scholar 

  118. Surtees PG, Wainwright NW, Willis-Owen SA, Sandhu MS, Luben R, Day NE et al. No association between the BDNF Val66Met polymorphism and mood status in a non-clinical community sample of 7389 older adults. J Psychiatr Res 2006; 41: 404–409.

    Article  PubMed  Google Scholar 

  119. Jiang X, Xu K, Hoberman J, Tian F, Marko AJ, Waheed JF et al. BDNF variation and mood disorders: a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects. Neuropsychopharmacology 2005; 30: 1353–1361.

    Article  CAS  PubMed  Google Scholar 

  120. Iga JI, Ueno SI, Yamauchi K, Numata S, Tayoshi-Shibuya S, Kinouchi S et al. The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with psychotic feature and suicidal behavior in Japanese major depressive patients. Am J Med Genet B Neuropsychiatr Genet 2007; e-pub ahead of print.

  121. 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.

    Article  CAS  PubMed  Google Scholar 

  122. Garriock HA, Delgado P, Kling MA, Carpenter LL, Burke M, Burke WJ et al. Number of risk genotypes is a risk factor for major depressive disorder: a case–control study. Behav Brain Funct 2006; 2: 24.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Funke B, Malhotra AK, Finn CT, Plocik AM, Lake SL, Lencz T et al. COMT genetic variation confers risk for psychotic and affective disorders: a case–control study. Behav Brain Funct 2005; 1: 19.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Kunugi H, Vallada HP, Hoda F, Kirov G, Gill M, Aitchison KJ et al. No evidence for an association of affective disorders with high- or low-activity allele of catechol-O-methyltransferase gene. Biol Psychiatry 1997; 42: 282–285.

    Article  CAS  PubMed  Google Scholar 

  125. Ohara K, Nagai M, Suzuki Y . Low activity allele of catechol-O-methyltransferase gene and Japanese unipolar depression. NeuroReport 1998; 9: 1305–1308.

    Article  CAS  PubMed  Google Scholar 

  126. Massat I, Souery D, Del-Favero J, Nothen M, Blackwood D, Muir W et al. Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study. Mol Psychiatry 2005; 10: 598–605.

    Article  CAS  PubMed  Google Scholar 

  127. Serretti A, Rotondo A, Lorenzi C, Smeraldi E, Cassano GB . Catechol-O-methyltransferase gene variants in mood disorders in the Italian population. Psychiatr Genet 2006; 16: 181–182.

    Article  PubMed  Google Scholar 

  128. 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.

    Article  CAS  PubMed  Google Scholar 

  129. Koks S, Nikopensius T, Koido K, Maron E, Altmae S, Heinaste E et al. Analysis of SNP profiles in patients with major depressive disorder. Int J Neuropsychopharmacol 2006; 9: 167–174.

    Article  CAS  PubMed  Google Scholar 

  130. Dikeos DG, Papadimitriou GN, Avramopoulos D, Karadima G, Daskalopoulou EG, Souery D et al. Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder. Psychiatr Genet 1999; 9: 189–195.

    Article  CAS  PubMed  Google Scholar 

  131. Henkel V, Baghai TC, Eser D, Zill P, Mergl R, Zwanzger P et al. The gamma amino butyric acid (GABA) receptor alpha-3 subunit gene polymorphism in unipolar depressive disorder: a genetic association study. Am J Med Genet B Neuropsychiatr Genet 2004; 126: 82–87.

    Article  Google Scholar 

  132. Massat I, Souery D, Del-Favero J, Oruc L, Jakovljevic M, Folnegovic V et al. Lack of association between GABRA3 and unipolar affective disorder: a multicentre study. Int J Neuropsychopharmacol 2001; 4: 273–278.

    Article  CAS  PubMed  Google Scholar 

  133. Kunugi H, Kato T, Fukuda R, Tatsumi M, Sakai T, Nanko S . Association study of C825T polymorphism of the G-protein b3 subunit gene with schizophrenia and mood disorders. J Neural Transm 2002; 109: 213–218.

    Article  CAS  PubMed  Google Scholar 

  134. Lee HJ, Cha JH, Ham BJ, Han CS, Kim YK, Lee SH et al. Association between a G-protein beta 3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders. Pharmacogenomics J 2004; 4: 29–33.

    Article  CAS  PubMed  Google Scholar 

  135. Arias B, Arranz MJ, Gasto C, Catalan R, Pintor L, Gutierrez B et al. Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT(1A) receptor gene as putative risk factors in major depression. Mol Psychiatry 2002; 7: 930–932.

    Article  CAS  PubMed  Google Scholar 

  136. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 2003; 23: 8788–8799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Parsey RV, Oquendo MA, Ogden RT, Olvet DM, Simpson N, Huang YY et al. Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatry 2006; 59: 106–113.

    Article  CAS  PubMed  Google Scholar 

  138. Fehr C, Grintschuk N, Szegedi A, Anghelescu I, Klawe C, Singer P et al. The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy. Psychiatry Res 2000; 97: 1–10.

    Article  CAS  PubMed  Google Scholar 

  139. Huang YY, Oquendo MA, Friedman JM, Greenhill LL, Brodsky B, Malone KM et al. Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism. Neuropsychopharmacology 2003; 28: 163–169.

    Article  CAS  PubMed  Google Scholar 

  140. Geng YG, Su QR, Su LY, Chen Q, Ren GY, Shen SQ et al. Comparison of the polymorphisms of androgen receptor gene and estrogen alpha and beta gene between adolescent females with first-onset major depressive disorder and controls. Int J Neurosci 2007; 117: 539–547.

    Article  CAS  PubMed  Google Scholar 

  141. Claes S, Villafuerte S, Forsgren T, Sluijs S, Del-Favero J, Adolfsson R et al. The corticotropin-releasing hormone binding protein is associated with major depression in a population from Northern Sweden. Biol Psychiatry 2003; 54: 867–872.

    Article  CAS  PubMed  Google Scholar 

  142. Toyota T, Watanabe A, Shibuya H, Nankai M, Hattori E, Yamada K et al. Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler. Mol Psychiatry 2000; 5: 461, 489–494.

    Article  CAS  PubMed  Google Scholar 

  143. Jun TY, Pae CU, Chae JH, Bahk WM, Kim KS, Han H . Report on IL-10 gene polymorphism at position −819 for major depression and schizophrenia in Korean population. Psychiatry Clin Neurosci 2002; 56: 177–180.

    Article  CAS  PubMed  Google Scholar 

  144. van West D, Del-Favero J, Aulchenko Y, Oswald P, Souery D, Forsgren T et al. A major SNP haplotype of the arginine vasopressin 1B receptor protects against recurrent major depression. Mol Psychiatry 2004; 9: 287–292.

    Article  CAS  PubMed  Google Scholar 

  145. Ohara K, Nagai M, Tsukamoto T, Tani K, Suzuki Y . 5-HT2A receptor gene promoter polymorphism—1438G/A and mood disorders. NeuroReport 1998; 9: 1139–1141.

    Article  CAS  PubMed  Google Scholar 

  146. Bonnier B, Gorwood P, Hamon M, Sarfati Y, Boni C, Hardy-Bayle MC . Association of 5-HT(2A) receptor gene polymorphism with major affective disorders: the case of a subgroup of bipolar disorder with low suicide risk. Biol Psychiatry 2002; 51: 762–765.

    Article  CAS  PubMed  Google Scholar 

  147. Choi MJ, Lee HJ, Ham BJ, Cha JH, Ryu SH, Lee MS . Association between major depressive disorder and the −1438A/G polymorphism of the serotonin 2A receptor gene. Neuropsychobiology 2004; 49: 38–41.

    Article  CAS  PubMed  Google Scholar 

  148. Zhang HY, Ishigaki T, Tani K, Chen K, Shih JC, Miyasato K et al. Serotonin2A receptor gene polymorphism in mood disorders. Biol Psychiatry 1997; 41: 768–773.

    Article  CAS  PubMed  Google Scholar 

  149. Tsai SJ, Hong CJ, Hsu CC, Cheng CY, Liao WY, Song HL et al. Serotonin-2A receptor polymorphism (102T/C) in mood disorders. Psychiatry Res 1999; 87: 233–237.

    Article  CAS  PubMed  Google Scholar 

  150. Arias B, Gutierrez B, Pintor L, Gasto C, Fananas L . Variability in the 5-HT(2A) receptor gene is associated with seasonal pattern in major depression. Mol Psychiatry 2001; 6: 239–242.

    Article  CAS  PubMed  Google Scholar 

  151. Minov C, Baghai TC, Schule C, Zwanzger P, Schwarz MJ, Zill P et al. Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression. Neurosci Lett 2001; 303: 119–122.

    Article  CAS  PubMed  Google Scholar 

  152. Liu Z, Zhu F, Wang G, Xiao Z, Wang H, Tang J et al. Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression. Neurosci Lett 2006; 404: 358–362.

    Article  CAS  PubMed  Google Scholar 

  153. Qian Y, Lin S, Jiang S, Jiang K, Wu X, Tang G et al. Studies of the DXS7 polymorphism at the MAO loci in unipolar depression. Am J Med Genet 1999; 88: 598–600.

    Article  CAS  PubMed  Google Scholar 

  154. Thomson PA, Wray NR, Thomson AM, Dunbar DR, Grassie MA, Condie A et al. Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor. Mol Psychiatry 2005; 10: 470–478.

    Article  CAS  PubMed  Google Scholar 

  155. Villafuerte SM, Del-Favero J, Adolfsson R, Souery D, Massat I, Mendlewicz J et al. Gene-based SNP genetic association study of the corticotropin-releasing hormone receptor-2 (CRHR2) in major depression. Am J Med Genet 2002; 114: 222–226.

    Article  PubMed  Google Scholar 

  156. Tsai SJ, Wang YC, Hong CJ, Chiu HJ . Association study of oestrogen receptor alpha gene polymorphism and suicidal behaviours in major depressive disorder. Psychiatr Genet 2003; 13: 19–22.

    Article  PubMed  Google Scholar 

  157. Yu YW, Tsai SJ, Hong CJ, Chen TJ, Chen MC, Yang CW . Association study of a monoamine oxidase a gene promoter polymorphism with major depressive disorder and antidepressant response. Neuropsychopharmacology 2005; 30: 1719–1723.

    Article  CAS  PubMed  Google Scholar 

  158. Alda M, Grof P, Grof E . MN blood groups and bipolar disorder: evidence of genotypic association and Hardy–Weinberg disequilibrium. Biol Psychiatry 1998; 44: 361–363.

    Article  CAS  PubMed  Google Scholar 

  159. Beckman L, Cedergren B, Perris C, Strandman E . Blood groups and affective disorders. Hum Hered 1978; 28: 48–55.

    Article  CAS  PubMed  Google Scholar 

  160. Jun TY, Pae CU, Chae JH, Bahk WM, Kim KS . Polymorphism of CTLA-4 gene for major depression in the Korean population. Psychiatry Clin Neurosci 2001; 55: 533–537.

    Article  CAS  PubMed  Google Scholar 

  161. Matsuyama SS, Joseph J . Haptoglobin types and unipolar depression. Hum Hered 1984; 34: 65–68.

    Article  CAS  PubMed  Google Scholar 

  162. Maes M, Delanghe J, Scharpe S, Meltzer HY, Cosyns P, Suy E et al. Haptoglobin phenotypes and gene frequencies in unipolar major depression. Am J Psychiatry 1994; 151: 112–116.

    Article  CAS  PubMed  Google Scholar 

  163. Kolsch H, Ptok U, Majores M, Schmitz S, Rao ML, Maier W et al. Putative association of polymorphism in the mannose 6-phosphate receptor gene with major depression and Alzheimer's disease. Psychiatr Genet 2004; 14: 97–100.

    Article  PubMed  Google Scholar 

  164. Hattori E, Yamada K, Ebihara M, Toyota T, Nankai M, Shibuya H et al. Association study of the short tandem repeat in the 5′ upstream region of the cholecystokinin gene with mood disorders in the Japanese population. Am J Med Genet 2002; 114: 523–526.

    Article  PubMed  Google Scholar 

  165. Oswald P, Souery D, Massat I, Del-Favero J, Linotte S, Papadimitriou G et al. Lack of association between the 5HT2A receptor polymorphism (T102C) and unipolar affective disorder in a multicentric European study. Eur Neuropsychopharmacol 2003; 13: 365–368.

    Article  CAS  PubMed  Google Scholar 

  166. Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, Blairy S et al. Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder. Mol Psychiatry 2001; 6: 579–585.

    Article  CAS  PubMed  Google Scholar 

  167. Lerena A, Berecz R, Dorado P, Gonzalez AP, Penas LEM, De La Rubia A . CYP2C9 gene and susceptibility to major depressive disorder. Pharmacogenomics J 2003; 3: 300–302.

    Article  CAS  Google Scholar 

  168. Covault J, Pettinati H, Moak D, Mueller T, Kranzler HR . Association of a long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with enhanced niacin-induced dermal erythema. Am J Med Genet B Neuropsychiatr Genet 2004; 127: 42–47.

    Article  Google Scholar 

  169. Muramatsu T, Matsushita S, Kanba S, Higuchi S, Manki H, Suzuki E et al. Monoamine oxidase genes polymorphisms and mood disorder. Am J Med Genet 1997; 74: 494–496.

    Article  CAS  PubMed  Google Scholar 

  170. Tadic A, Rujescu D, Szegedi A, Giegling I, Singer P, Moller HJ et al. Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression. Am J Med Genet B Neuropsychiatr Genet 2003; 117: 1–6.

    Article  Google Scholar 

  171. Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R et al. SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 2004; 9: 1030–1036.

    Article  CAS  PubMed  Google Scholar 

  172. Van Den Bogaert A, Sleegers K, De Zutter S, Heyrman L, Norrback KF, Adolfsson R et al. Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population. Arch Gen Psychiatry 2006; 63: 1103–1110.

    Article  CAS  PubMed  Google Scholar 

  173. Zhou Z, Roy A, Lipsky R, Kuchipudi K, Zhu G, Taubman J et al. Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry 2005; 62: 1109–1118.

    Article  CAS  PubMed  Google Scholar 

  174. Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB et al. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 2005; 45: 11–16.

    Article  CAS  PubMed  Google Scholar 

  175. Delorme R, Durand CM, Betancur C, Wagner M, Ruhrmann S, Grabe HJ et al. No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects. Biol Psychiatry 2006; 60: 202–203.

    Article  CAS  PubMed  Google Scholar 

  176. Slow E . TPH2: an answer for unipolar depression? Clin Genet 2005; 67: 392–394.

    Article  CAS  PubMed  Google Scholar 

  177. Philibert R, Caspers K, Langbehn D, Troughton EP, Yucuis R, Sandhu HK et al. The association of the D2S2944 124 bp allele with recurrent early onset major depressive disorder in women. Am J Med Genet B Neuropsychiatr Genet 2003; 121: 39–43.

    Article  Google Scholar 

  178. Langbehn DR, Philibert R, Caspers KM, Yucuis R, Cadoret RJ . Association of a D2S2944 allele with depression specifically among those with substance abuse or antisocial personality. Drug Alcohol Depend 2006; 83: 33–41.

    Article  CAS  PubMed  Google Scholar 

  179. Zubenko GS, Hughes IH, Stiffler JS, Zubenko WN, Kaplan BB . D2S2944 identifies a likely susceptibility locus for recurrent, early-onset, major depression in women. Mol Psychiatry 2002; 7: 460–467.

    Article  CAS  PubMed  Google Scholar 

  180. Hashimoto R, Suzuki T, Iwata N, Yamanouchi Y, Kitajima T, Kosuga A et al. Association study of the frizzled-3 (FZD3) gene with schizophrenia and mood disorders. J Neural Transm 2005; 112: 303–307.

    Article  CAS  PubMed  Google Scholar 

  181. Jun TY, Pae CU, Hoon H, Chae JH, Bahk WM, Kim KS et al. Possible association between -G308A tumour necrosis factor-alpha gene polymorphism and major depressive disorder in the Korean population. Psychiatr Genet 2003; 13: 179–181.

    Article  PubMed  Google Scholar 

  182. Borglum AD, Bruun TG, Kjeldsen TE, Ewald H, Mors O, Kirov G et al. Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder. Mol Psychiatry 1999; 4: 545–551.

    Article  CAS  PubMed  Google Scholar 

  183. Jahnes E, Muller DJ, Schulze TG, Windemuth C, Cichon S, Ohlraun S et al. Association study between two variants in the DOPA decarboxylase gene in bipolar and unipolar affective disorder. Am J Med Genet 2002; 114: 519–522.

    Article  PubMed  Google Scholar 

  184. Hong W, Fang YR, Wang ZW, Qian YP, Zhang QT, Jiang SD et al. Association between depression and G72 gene polymorphism. Chinese Journal of Medical Genetics 2006; 23: 532–535.

    CAS  PubMed  Google Scholar 

  185. Kunugi H, Hashimoto R, Yoshida M, Tatsumi M, Kamijima K . A missense polymorphism (S205L) of the low-affinity neurotrophin receptor p75NTR gene is associated with depressive disorder and attempted suicide. Am J Med Genet B Neuropsychiatr Genet 2004; 129: 44–46.

    Article  Google Scholar 

  186. Ohtsuki T, Ishiguro H, Yoshikawa T, Arinami T . WFS1 gene mutation search in depressive patients: detection of five missense polymorphisms but no association with depression or bipolar affective disorder. J Affect Disord 2000; 58: 11–17.

    Article  CAS  PubMed  Google Scholar 

  187. Schulze TG, Muller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV et al. Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder. Am J Med Genet 2000; 96: 801–803.

    Article  CAS  PubMed  Google Scholar 

  188. Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB et al. Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry 2005; 58: 307–314.

    Article  CAS  PubMed  Google Scholar 

  189. Syagailo YV, Stober G, Grassle M, Reimer E, Knapp M, Jungkunz G et al. Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders. Am J Med Genet 2001; 105: 168–171.

    Article  CAS  PubMed  Google Scholar 

  190. Du L, Bakish D, Ravindran A, Hrdina PD . MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males. NeuroReport 2004; 15: 2097–2101.

    Article  CAS  PubMed  Google Scholar 

  191. Gutierrez B, Arias B, Gasto C, Catalan R, Papiol S, Pintor L et al. Association analysis between a functional polymorphism in the monoamine oxidase A gene promoter and severe mood disorders. Psychiatr Genet 2004; 14: 203–208.

    Article  PubMed  Google Scholar 

  192. Koido K, Koks S, Nikopensius T, Maron E, Altmae S, Heinaste E et al. Polymorphisms in wolframin (WFS1) gene are possibly related to increased risk for mood disorders. Int J Neuropsychopharmacol 2005; 8: 235–244.

    Article  CAS  PubMed  Google Scholar 

  193. Furlong RA, Ho LW, Rubinsztein JS, Michael A, Walsh C, Paykel ES et al. A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases. Neurosci Lett 1999; 277: 123–126.

    Article  CAS  PubMed  Google Scholar 

  194. Arinami T, Yamada N, Yamakawa-Kobayashi K, Hamaguchi H, Toru M . Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet 1997; 74: 526–528.

    Article  CAS  PubMed  Google Scholar 

  195. Kunugi H, Fukuda R, Hattori M, Kato T, Tatsumi M, Sakai T et al. C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry 1998; 3: 435–437.

    Article  CAS  PubMed  Google Scholar 

  196. Tan EC, Chong SA, Lim LC, Chan AO, Teo YY, Tan CH et al. Genetic analysis of the thermolabile methylenetetrahydrofolate reductase variant in schizophrenia and mood disorders. Psychiatr Genet 2004; 14: 227–231.

    Article  PubMed  Google Scholar 

  197. Chen CS, Tsai JC, Tsang HY, Kuo YT, Lin HF, Chiang IC et al. Homocysteine levels, MTHFR C677T genotype, and MRI Hyperintensities in late-onset major depressive disorder. Am J Geriatr Psychiatry 2005; 13: 869–875.

    Article  PubMed  Google Scholar 

  198. Kelly CB, McDonnell AP, Johnston TG, Mulholland C, Cooper SJ, McMaster D et al. The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol 2004; 18: 567–571.

    Article  CAS  PubMed  Google Scholar 

  199. Zill P, Engel R, Baghai TC, Juckel G, Frodl T, Muller-Siecheneder F et al. Identification of a naturally occurring polymorphism in the promoter region of the norepinephrine transporter and analysis in major depression. Neuropsychopharmacology 2002; 26: 489–493.

    Article  CAS  PubMed  Google Scholar 

  200. Inoue K, Itoh K, Yoshida K, Shimizu T, Suzuki T . Positive association between T-182C polymorphism in the norepinephrine transporter gene and susceptibility to major depressive disorder in a Japanese population. Neuropsychobiology 2004; 50: 301–304.

    Article  CAS  PubMed  Google Scholar 

  201. Ryu SH, Lee SH, Lee HJ, Cha JH, Ham BJ, Han CS et al. Association between norepinephrine transporter gene polymorphism and major depression. Neuropsychobiology 2004; 49: 174–177.

    Article  CAS  PubMed  Google Scholar 

  202. Battersby S, Ogilvie AD, Smith CA, Blackwood DH, Muir WJ, Quinn JP et al. Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder. Psychiatr Genet 1996; 6: 177–181.

    Article  CAS  PubMed  Google Scholar 

  203. Pae CU, Yu HS, Kim TS, Lee CU, Lee SJ, Jun TY et al. Monocyte chemoattractant protein-1 (MCP1) promoter −2518 polymorphism may confer a susceptibility to major depressive disorder in the Korean population. Psychiatry Res 2004; 127: 279–281.

    Article  CAS  PubMed  Google Scholar 

  204. Hashimoto R, Numakawa T, Ohnishi T, Kumamaru E, Yagasaki Y, Ishimoto T et al. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Hum Mol Genet 2006; 15: 3024–3033.

    Article  CAS  PubMed  Google Scholar 

  205. Horiuchi Y, Nakayama J, Ishiguro H, Ohtsuki T, Detera-Wadleigh SD, Toyota T et al. Possible association between a haplotype of the GABA-A receptor alpha 1 subunit gene (GABRA1) and mood disorders. Biol Psychiatry 2004; 55: 40–45.

    Article  CAS  PubMed  Google Scholar 

  206. Yu YW, Chen TJ, Wang YC, Liou YJ, Hong CJ, Tsai SJ . Association analysis for neuronal nitric oxide synthase gene polymorphism with major depression and fluoxetine response. Neuropsychobiology 2003; 47: 137–140.

    Article  CAS  PubMed  Google Scholar 

  207. Collier DA, Arranz MJ, Sham P, Battersby S, Vallada H, Gill P et al. The serotonin transporter is a potential susceptibility factor for bipolar affective disorder. NeuroReport 1996; 7: 1675–1679.

    Article  CAS  PubMed  Google Scholar 

  208. Rees M, Norton N, Jones I, McCandless F, Scourfield J, Holmans P et al. Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT). Mol Psychiatry 1997; 2: 398–402.

    Article  CAS  PubMed  Google Scholar 

  209. Hoehe MR, Wendel B, Grunewald I, Chiaroni P, Levy N, Morris-Rosendahl D et al. Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders. Am J Med Genet 1998; 81: 1–3.

    Article  CAS  PubMed  Google Scholar 

  210. Liu W, Gu N, Feng G, Li S, Bai S, Zhang J et al. Tentative association of the serotonin transporter with schizophrenia and unipolar depression but not with bipolar disorder in Han Chinese. Pharmacogenetics 1999; 9: 491–495.

    CAS  PubMed  Google Scholar 

  211. Mellerup E, Bennike B, Bolwig T, Dam H, Hasholt L, Jorgensen MB et al. Platelet serotonin transporters and the transporter gene in control subjects, unipolar patients and bipolar patients. Acta Psychiatr Scand 2001; 103: 229–233.

    Article  CAS  PubMed  Google Scholar 

  212. Yen FC, Hong CJ, Hou SJ, Wang JK, Tsai SJ . Association study of serotonin transporter gene VNTR polymorphism and mood disorders, onset age and suicide attempts in a Chinese sample. Neuropsychobiology 2003; 48: 5–9.

    Article  CAS  PubMed  Google Scholar 

  213. Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T et al. Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 1997; 2: 457–462.

    Article  CAS  PubMed  Google Scholar 

  214. Hauser J, Leszczynska A, Samochowiec J, Czerski PM, Ostapowicz A, Chlopocka M et al. Association analysis of the insertion/deletion polymorphism in serotonin transporter gene in patients with affective disorder. Eur Psychiatry 2003; 18: 129–132.

    Article  PubMed  Google Scholar 

  215. Hoefgen B, Schulze TG, Ohlraun S, von Widdern O, Hofels S, Gross M et al. The power of sample size and homogenous sampling: association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder. Biol Psychiatry 2005; 57: 247–251.

    Article  CAS  PubMed  Google Scholar 

  216. Cervilla JA, Rivera M, Molina E, Torres-Gonzalez F, Bellon JA, Moreno B et al. The 5-HTTLPR s/s genotype at the serotonin transporter gene (SLC6A4) increases the risk for depression in a large cohort of primary care attendees: the PREDICT-gene study. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 912–917.

    Article  CAS  PubMed  Google Scholar 

  217. Stober G, Heils A, Lesch KP . Serotonin transporter gene polymorphism and affective disorder. Lancet 1996; 347: 1340–1341.

    Article  CAS  PubMed  Google Scholar 

  218. Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC . No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder. Am J Med Genet 1998; 81: 245–247.

    Article  CAS  PubMed  Google Scholar 

  219. Tan EC, Chan AO, Tan CH, Mahendran R, Wang A, Chua HC . Case–control and linkage disequilibrium studies of the tryptophan hydroxylase gene polymorphisms and major depressive disorder. Psychiatr Genet 2003; 13: 151–154.

    Article  PubMed  Google Scholar 

  220. Kunugi H, Ishida S, Kato T, Sakai T, Tatsumi M, Hirose T et al. No evidence for an association of polymorphisms of the tryptophan hydroxylase gene with affective disorders or attempted suicide among Japanese patients. Am J Psychiatry 1999; 156: 774–776.

    CAS  PubMed  Google Scholar 

  221. Ohara K, Nagai M, Tsukamoto T, Tani K, Suzuki Y . Functional polymorphism in the serotonin transporter promoter at the SLC6A4 locus and mood disorders. Biol Psychiatry 1998; 44: 550–554.

    Article  CAS  PubMed  Google Scholar 

  222. Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000; 11: 215–219.

    Article  CAS  PubMed  Google Scholar 

  223. Oliveira JR, Carvalho DR, Pontual D, Gallindo RM, Sougey EB, Gentil V et al. Analysis of the serotonin transporter polymorphism (5-HTTLPR) in Brazilian patients affected by dysthymia, major depression and bipolar disorder. Mol Psychiatry 2000; 5: 348–349.

    Article  CAS  PubMed  Google Scholar 

  224. Steffens DC, Svenson I, Marchuk DA, Levy RM, Hays JC, Flint EP et al. Allelic differences in the serotonin transporter-linked polymorphic region in geriatric depression. Am J Geriatr Psychiatry 2002; 10: 185–191.

    Article  PubMed  Google Scholar 

  225. Serretti A, Lilli R, Lorenzi C, Smeraldi E . No association between serotonin-2A receptor gene polymorphism and psychotic symptomatology of mood disorders. Psychiatry Res 1999; 86: 203–209.

    Article  CAS  PubMed  Google Scholar 

  226. Mendlewicz J, Massat I, Souery D, Del-Favero J, Oruc L, Nothen MM et al. Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study. Eur J Hum Genet 2004; 12: 377–382.

    Article  CAS  PubMed  Google Scholar 

  227. Taylor WD, Steffens DC, Payne ME, MacFall JR, Marchuk DA, Svenson IK et al. Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression. Arch Gen Psychiatry 2005; 62: 537–544.

    CAS  PubMed  Google Scholar 

  228. Bozina N, Mihaljevic-Peles A, Sagud M, Jakovljevic M, Sertic J . Serotonin transporter polymorphism in Croatian patients with major depressive disorder. Psychiatr Danub 2006; 18: 83–89.

    CAS  PubMed  Google Scholar 

  229. Grunblatt E, Loffler C, Zehetmayer S, Jungwirth S, Tragl KH, Riederer P et al. Association study of the 5-HTTLPR polymorphism and depression in 75-Year-Old nondemented subjects from the Vienna Transdanube Aging (VITA) study. J Clin Psychiatry 2006; 67: 1373–1378.

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Center for Medical Systems Biology, Hersenstichting Nederland and the Interuniversity Attraction Poles (IUAP) Program P5/19 of the Belgian Federal Science Policy Office, Belgium. ACJWJ was supported by a fellowship grant of the Netherlands Genomics Initiative.

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Correspondence to C M van Duijn.

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López-León, S., Janssens, A., González-Zuloeta Ladd, A. et al. Meta-analyses of genetic studies on major depressive disorder. Mol Psychiatry 13, 772–785 (2008). https://doi.org/10.1038/sj.mp.4002088

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  • DOI: https://doi.org/10.1038/sj.mp.4002088

Keywords

  • meta-analysis
  • depression
  • genetics
  • epidemiology
  • polymorphism

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