Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Evaluating historical candidate genes for schizophrenia

Subjects

Abstract

Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2

References

  1. Sullivan PF, Kendler KS, Neale MC . Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60: 1187–1192.

    Article  PubMed  Google Scholar 

  2. Allen NC, Bagade S, McQueen MB, Ioannidis JPA, Kavvoura FK, Khoury MJ et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 2008; 40: 827–834.

    Article  CAS  PubMed  Google Scholar 

  3. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860–921.

    Article  CAS  PubMed  Google Scholar 

  4. International HapMap Consortium. A haplotype map of the human genome. Nature 2005; 437: 1299–1320.

    Article  CAS  Google Scholar 

  5. Zou Z, Liu C, Che C, Huang H . Clinical genetics of Alzheimer's disease. Biomed Res Int 2014; 2014: 291862.

    PubMed  PubMed Central  Google Scholar 

  6. Reich T, Hinrichs A, Culverhouse R, Bierut L . Genetic studies of alcoholism and substance dependence. Am J Hum Genet 1999; 65: 599–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sullivan PF . Spurious genetic associations. Biol Psychiatry 2007; 61: 1121–1126.

    Article  CAS  PubMed  Google Scholar 

  8. Ioannidis JP . Commentary: grading the credibility of molecular evidence for complex diseases. Int J Epidemiol 2006; 35: 572–578.

    Article  PubMed  Google Scholar 

  9. Neale BM, Sham PC . The future of association studies: gene-based analysis and replication. Am J Hum Genet 2004; 75: 353–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421–427.

    Article  CAS  PubMed Central  Google Scholar 

  12. Owen MJ, Craddock N, O'Donovan MC . Schizophrenia: genes at last? Trends Genet 2005; 21: 518–525.

    Article  CAS  PubMed  Google Scholar 

  13. Sullivan PF . The genetics of schizophrenia. PLoS Med 2005; 2: 614–618.

    Article  CAS  Google Scholar 

  14. Harrison PJ, Weinberger DR . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2004.

  15. Pe'er I, Yelensky R, Altshuler D, Daly MJ . Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol 2008; 32: 381–385.

    Article  PubMed  Google Scholar 

  16. Collins AL, Kim Y, Sklar P, O'Donovan MC, Sullivan PF . Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. Psychol Med 2012; 42: 607–616.

    Article  CAS  PubMed  Google Scholar 

  17. Sullivan PF, Daly MJ, O'Donovan M . Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012; 13: 537–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014; 506: 185–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014; 506: 179–184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Crocq MA, Mant R, Asherson P, Williams J, Hode Y, Mayerova A et al. Association between schizophrenia and homozygosity at the dopamine D3 receptor gene. J Med Genet 1992; 29: 858–860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Marti SB, Cichon S, Propping P, Nothen M . Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population. Am J Med Genet 2002; 114: 46–50.

    Article  PubMed  Google Scholar 

  22. Gauderman WJ . Sample size requirements for matched case-control studies of gene-environment interaction. Stat Med 2002; 21: 35–50.

    Article  PubMed  Google Scholar 

  23. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N . Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 2004; 96: 434–442.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci 2013; 14: 365–376.

    Article  CAS  PubMed  Google Scholar 

  25. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE . Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 2007; 39: 17–23.

    Article  CAS  PubMed  Google Scholar 

  26. Watanabe Y, Nunokawa A, Someya T . Association of the BDNF C270T polymorphism with schizophrenia: updated meta-analysis. Psychiatry Clin Neurosci 2013; 67: 123–125.

    Article  CAS  PubMed  Google Scholar 

  27. Lee KY, Joo EJ, Jeong SH, Kang UG, Roh MS, Kim SH et al. No association between AKT1 polymorphism and schizophrenia: a case-control study in a Korean population and a meta-analysis. Neurosci Res 2010; 66: 238–245.

    Article  CAS  PubMed  Google Scholar 

  28. Loh HC, Chow TJ, Tang PY, Yong HS . No association between AKT1 gene variants and schizophrenia: a Malaysian case-control study and meta-analysis. Psychiatry Res 2013; 209: 732–733.

    Article  CAS  PubMed  Google Scholar 

  29. Shi J, Gershon ES, Liu C . Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. Schizophr Res 2008; 104: 96–107.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Okochi T, Ikeda M, Kishi T, Kawashima K, Kinoshita Y, Kitajima T et al. Meta-analysis of association between genetic variants in COMT and schizophrenia: an update. Schizophr Res 2009; 110: 140–148.

    Article  PubMed  Google Scholar 

  31. Costas J, Sanjuan J, Ramos-Rios R, Paz E, Agra S, Ivorra JL et al. Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis. J Psychiatr Res 2011; 45: 7–14.

    Article  PubMed  Google Scholar 

  32. Muller DJ, Zai CC, Shinkai T, Strauss J, Kennedy JL . Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia. Bipolar Disord 2011; 13: 198–207.

    Article  CAS  PubMed  Google Scholar 

  33. Tan J, Lin Y, Su L, Yan Y, Chen Q, Jiang H et al. Association between DAOA gene polymorphisms and the risk of schizophrenia, bipolar disorder and depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2014; 51: 89–98.

    Article  CAS  PubMed  Google Scholar 

  34. Mathieson I, Munafo MR, Flint J . Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Mol Psychiatry 2012; 17: 634–641.

    Article  CAS  PubMed  Google Scholar 

  35. Ni J, Lu W, Wu Z, Chen J, Yi Z, Zhang C . T102C polymorphism of serotonin 2A type receptor gene confers susceptibility to (early onset) schizophrenia in Han Chinese: an association study and meta-analysis. Asia Pac Psychiatry 2013; 5: 24–30.

    Article  PubMed  Google Scholar 

  36. Gu L, Long J, Yan Y, Chen Q, Pan R, Xie X et al. HTR2A-1438A/G polymorphism influences the risk of schizophrenia but not bipolar disorder or major depressive disorder: a meta-analysis. J Neurosci Res 2013; 91: 623–633.

    Article  CAS  PubMed  Google Scholar 

  37. Peerbooms OL, van Os J, Drukker M, Kenis G, Hoogveld L, de Hert et al. Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun 2011; 25: 1530–1543.

    Article  CAS  PubMed  Google Scholar 

  38. Nishi A, Numata S, Tajima A, Kinoshita M, Kikuchi K, Shimodera S et al. Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia. Schizophr Bull 2014; 40: 1154–1163.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hu CY, Qian ZZ, Gong FF, Lu SS, Feng F, Wu YL et al. Methylenetetrahydrofolate reductase (MTHFR) polymorphism susceptibility to schizophrenia and bipolar disorder: an updated meta-analysis. J Neural Transm 2014; 122: 307–320.

    Article  CAS  PubMed  Google Scholar 

  40. Gong YG, Wu CN, Xing QH, Zhao XZ, Zhu J, He L . A two-method meta-analysis of Neuregulin 1(NRG1) association and heterogeneity in schizophrenia. Schizophr Res 2009; 111: 109–114.

    Article  CAS  PubMed  Google Scholar 

  41. Xu M St, Clair D, He L . Testing for genetic association between the ZDHHC8 gene locus and susceptibility to schizophrenia: an integrated analysis of multiple datasets. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 1266–1275.

    Article  PubMed  Google Scholar 

  42. International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.

    PubMed Central  Google Scholar 

  43. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe'er I et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009; 460: 753–757.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744–747.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sullivan PF . Questions about DISC1 as a genetic risk factor for schizophrenia. Mol Psychiatry 2013; 18: 1050–1052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Porteous DJ, Thomson PA, Millar JK, Evans KL, Hennah W, Soares DC et al. DISC1 as a genetic risk factor for schizophrenia and related major mental illness: response to Sullivan. Mol Psychiatry 2014; 19: 141–143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Levinson DF, Duan J, Oh S, Wang K, Sanders AR, Shi J et al. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 2011; 168: 302–316.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Szatkiewicz J, O'Dushlaine C, Chen G, Chambert K, Moran J, Neale B et al. Copy number variation in schizophrenia in Sweden. Mol Psychiatry 2014; 19: 762–773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bertram L, Tanzi RE . Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 2008; 9: 768–778.

    Article  CAS  PubMed  Google Scholar 

  50. Kendler KS . Toward a scientific psychiatric nosology: strengths and limitations. Arch Gen Psychiatry 1990; 47: 969–973.

    Article  CAS  PubMed  Google Scholar 

  51. Attia J, Ioannidis JP, Thakkinstian A, McEvoy M, Scott RJ, Minelli C et al. How to use an article about genetic association: C: What are the results and will they help me in caring for my patients? JAMA 2009; 301: 304–308.

    Article  CAS  PubMed  Google Scholar 

  52. Attia J, Ioannidis JP, Thakkinstian A, McEvoy M, Scott RJ, Minelli C et al. How to use an article about genetic association: B: Are the results of the study valid? JAMA 2009; 301: 191–197.

    Article  CAS  PubMed  Google Scholar 

  53. Ioannidis JP, Thomas G, Daly MJ . Validating, augmenting and refining genome-wide association signals. Nat Rev Genet 2009; 10: 318–329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kraft P, Zeggini E, Ioannidis JP . Replication in genome-wide association studies. Stat Sci 2009; 24: 561–573.

    Article  PubMed  PubMed Central  Google Scholar 

  55. McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 2008; 9: 356–369.

    Article  CAS  PubMed  Google Scholar 

  56. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR et al. Guidelines for investigating causality of sequence variants in human disease. Nature 2014; 508: 469–476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Editorial. Framework for a fully powered risk engine. Nat Genet 2005; 37: 1153.

    Article  CAS  Google Scholar 

  58. Barsh GS, Copenhaver GP, Gibson G, Williams SM . Guidelines for genome-wide association studies. PLoS Genet 2012; 8: e1002812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA . Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 2004; 36: 131–137.

    Article  CAS  PubMed  Google Scholar 

  60. Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 2013; 381: 1371–1379.

    Article  CAS  PubMed Central  Google Scholar 

  61. Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF et al. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry 2000; 5: 142–149.

    Article  CAS  PubMed  Google Scholar 

  62. Sullivan PF, Daly MJ, O'Donovan M . Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012; 13: 537–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Betancur C . Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 2011; 1380: 42–77.

    Article  CAS  PubMed  Google Scholar 

  64. McKusick VA . Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet 2007; 80: 588–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chiurazzi P, Schwartz CE, Gecz J, Neri G . XLMR genes: update 2007. Eur J Hum Genet 2008; 16: 422–434.

    Article  CAS  PubMed  Google Scholar 

  66. Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, Chen W et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 2011; 478: 57–63.

    Article  CAS  PubMed  Google Scholar 

  67. Inlow JK, Restifo LL . Molecular and comparative genetics of mental retardation. Genetics 2004; 166: 835–881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 43: 838–846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lips ES, Cornelisse LN, Toonen RF, Min JL, Hultman CM, Holmans PA et al. Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. Mol Psychiatry 2012; 17: 996–1006.

    Article  CAS  PubMed  Google Scholar 

  70. Croning MD, Marshall MC, McLaren P, Armstrong JD, Grant SG . G2Cdb: the Genes to Cognition database. Nucleic Acids Res 2009; 37: D846–D851.

    Article  CAS  PubMed  Google Scholar 

  71. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 2011; 146: 247–261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 2009; 106: 9362–9367.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Blake JA, Bult CJ, Kadin JA, Richardson JE, Eppig JT . The Mouse Genome Database (MGD): premier model organism resource for mammalian genomics and genetics. Nucleic Acids Res 2011; 39: D842–D848.

    Article  CAS  PubMed  Google Scholar 

  74. Konneker T, Barnes T, Furberg H, Losh M, Bulik CM, Sullivan PF . A searchable database of genetic evidence for psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet 2008; 147: 671–675.

    Article  Google Scholar 

  75. Harrington CR, Roth M, Xuereb JH, McKenna PJ, Wischik CM . Apolipoprotein E type epsilon 4 allele frequency is increased in patients with schizophrenia. Neurosci Lett 1995; 202: 101–104.

    Article  CAS  PubMed  Google Scholar 

  76. Sasaki T, Dai XY, Kuwata S, Fukuda R, Kunugi H, Hattori et al. Brain-derived neurotrophic factor gene and schizophrenia in Japanese subjects. Am J Med Genet 1997; 74: 443–444.

    Article  CAS  PubMed  Google Scholar 

  77. Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 1997; 94: 587–592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917–6922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 2002; 99: 13675–13680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415–1423.

    Article  CAS  PubMed  Google Scholar 

  81. Comings DE, Comings BG, Muhleman D, Dietz G, Shahbahrami B, Tast D et al. The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA 1991; 266: 1793–1800.

    Article  CAS  PubMed  Google Scholar 

  82. Sommer SS, Lind TJ, Heston LL, Sobell JL . Dopamine D4 receptor variants in unrelated schizophrenic cases and controls. Am J Med Genet 1993; 48: 90–93.

    Article  CAS  PubMed  Google Scholar 

  83. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002; 71: 337–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Inayama Y, Yoneda H, Sakai T, Ishida T, Nonomura Y, Kono Y et al. Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia. Am J Med Genet 1996; 67: 103–105.

    Article  CAS  PubMed  Google Scholar 

  85. Chandy KG, Fantino E, Wittekindt O, Kalman K, Tong LL, Ho TH et al. Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder? Mol Psychiatry 1998; 3: 32–37.

    Article  CAS  PubMed  Google Scholar 

  86. 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 

  87. Wei J, Hemmings GP . The NOTCH4 locus is associated with susceptibility to schizophrenia. Nat Genet 2000; 25: 376–377.

    Article  CAS  PubMed  Google Scholar 

  88. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou et al. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci USA 2003; 100: 8993–8998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML et al. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA 2002; 99: 3717–3722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chowdari KV, Mirnics K, Semwal P, Wood J, Lawrence E, Bhatia T et al. Association and linkage analyses of RGS4 polymorphisms in schizophrenia. Hum Mol Genet 2002; 11: 1373–1380.

    Article  CAS  PubMed  Google Scholar 

  92. Li T, Yang L, Wiese C, Xu CT, Zeng Z, Giros B et al. No association between alleles or genotypes at the dopamine transporter gene and schizophrenia. Psychiatry Res 1994; 52: 17–23.

    Article  CAS  PubMed  Google Scholar 

  93. 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 

  94. Boin F, Zanardini R, Pioli R, Altamura CA, Maes M, Gennarelli M . Association between -G308A tumor necrosis factor alpha gene polymorphism and schizophrenia. Mol Psychiatry 2001; 6: 79–82.

    Article  CAS  PubMed  Google Scholar 

  95. Liu H, Abecasis GR, Heath SC, Knowles A, Demars S, Chen YJ et al. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc Natl Acad Sci USA 2002; 99: 16859–16864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by NIMH R01 MH077139 and U01 MH085520.

Author Contributions

All authors reviewed and approved the final version of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P F Sullivan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Farrell, M., Werge, T., Sklar, P. et al. Evaluating historical candidate genes for schizophrenia. Mol Psychiatry 20, 555–562 (2015). https://doi.org/10.1038/mp.2015.16

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.16

This article is cited by

Search

Quick links