Skip to main content
SpringerLink
Log in

Schizophrenia Genetics: Putting All the Pieces Together

  • Genetics (V Bonifati, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Schizophrenia is a major mental disorder characterized by a deep disruption of the thinking process and of emotional response. For many decades, genetics studies have yielded little success in identifying genetic factors responsible for the disease. However, with the recent breakthroughs in genome analysis technologies, the field of the genetics of schizophrenia has progressed a lot in the last years. Both common and rare variants have been successfully associated with the disease and a particular emphasis has been made on rare copy number variations. Recently, a new paradigm linking de novo mutations to the genetic mechanism of schizophrenia has been unravelled. The aim of this review is to discuss the most important genetic studies made in the field to give a general perspective of where to go in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. van Os J, Kapur S. Schizophrenia. Lancet. 2009;374(9690):635–45.

    Article  PubMed  Google Scholar 

  2. Tienari P. Schizophrenia in Finnish male twins. In: Lader MH, editor. Studies of schizophrenia. 1975. pp. 29–35.

  3. Fischer M, Harvald B, Hauge M. A Danish twin study of schizophrenia. Br J Psychiatry. 1969;115(526):981–90.

    Article  PubMed  CAS  Google Scholar 

  4. Kendler KS, Robinette CD. Schizophrenia in the National Academy of Sciences-National Research Council Twin Registry: a 16-year update. Am J Psychiatry. 1983;140(12):1551–63.

    PubMed  CAS  Google Scholar 

  5. Onstad S, Skre I, Torgersen S, Kringlen E. Twin concordance for DSM-III-R schizophrenia. Acta Psychiatr Scand. 1991;83(5):395–401.

    Article  PubMed  CAS  Google Scholar 

  6. Cannon TD, Kaprio J, Lönnqvist J, Huttunen M, Koskenvuo M. The genetic epidemiology of schizophrenia in a Finnish twin cohort. A population-based modeling study. Arch Gen Psychiatry. 1998;55(1):67–74.

    Article  PubMed  CAS  Google Scholar 

  7. Cardno AG, Marshall EJ, Coid B, et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry. 1999;56(2):162–8.

    Article  PubMed  CAS  Google Scholar 

  8. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187–92.

    Article  PubMed  Google Scholar 

  9. Riley B. Linkage studies of schizophrenia. Neurotox Res. 2004;6(1):17–34.

    Article  PubMed  Google Scholar 

  10. Pulver AE, Karayiorgou M, Wolyniec PS, et al. Sequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: part 1. Am J Med Genet. 1994;54(1):36–43.

    Article  PubMed  CAS  Google Scholar 

  11. Stefansson H, Sigurdsson E, Steinthorsdottir V, et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 2002;71(4):877–92.

    Article  PubMed  Google Scholar 

  12. Petryshen TL, Middleton FA, Kirby A, et al. Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol Psychiatry. 2005;10(4):366–74. 328.

    Article  PubMed  CAS  Google Scholar 

  13. Seshadri S, Kamiya A, Yokota Y, et al. Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. Proc Natl Acad Sci U S A. 2010;107(12):5622–7.

    Article  PubMed  CAS  Google Scholar 

  14. Bray NJ, Preece A, Williams NM, et al. Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet. 2005;14(14):1947–54.

    Article  PubMed  CAS  Google Scholar 

  15. Blackwood DH, Fordyce A, Walker MT, et al. Schizophrenia and affective disorders–cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 2001;69(2):428–33.

    Article  PubMed  CAS  Google Scholar 

  16. Millar JK, Wilson-Annan JC, Anderson S, et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000;9(9):1415–23.

    Article  PubMed  CAS  Google Scholar 

  17. Brandon NJ, Millar JK, Korth C, et al. Understanding the role of DISC1 in psychiatric disease and during normal development. J Neurosci. 2009;29(41):12768–75.

    Article  PubMed  CAS  Google Scholar 

  18. Betcheva ET, Mushiroda T, Takahashi A, et al. Case–control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population. J Hum Genet. 2009;54(2):98–107.

    Article  PubMed  CAS  Google Scholar 

  19. Shifman S, Johannesson M, Bronstein M, et al. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. 2008;4(2):e28.

    Article  PubMed  Google Scholar 

  20. Kirov G, Zaharieva I, Georgieva L, et al. A genome-wide association study in 574 schizophrenia trios using DNA pooling. Mol Psychiatry. 2009;14(8):796–803.

    Article  PubMed  CAS  Google Scholar 

  21. Sullivan PF, Lin D, Tzeng JY, et al. Genomewide association for schizophrenia in the CATIE study: results of stage 1. Mol Psychiatry. 2008;13(6):570–84.

    Article  PubMed  CAS  Google Scholar 

  22. O’Donovan MC, Craddock N, Norton N, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet. 2008;40(9):1053–5.

    Article  PubMed  Google Scholar 

  23. Steinberg S, Mors O, Borglum AD, et al. Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry. 2010;16(1):59–66.

    Google Scholar 

  24. Riley B, Thiselton D, Maher BS, et al. Replication of association between schizophrenia and ZNF804A in the Irish Case–control Study of Schizophrenia sample. Mol Psychiatry. 2010;15(1):29–37.

    Article  PubMed  CAS  Google Scholar 

  25. Hill MJ, Jeffries AR, Dobson RJB, Price J, Bray NJ. Knockdown of the psychosis susceptibility gene ZNF804A alters expression of genes involved in cell adhesion. Hum Mol Genet. 2011;21(5):1018–24.

    Google Scholar 

  26. • Stefansson H, Ophoff RA, Steinberg S, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460(7256):744–7. This is one of the first GWAS that identified the MHC as an associated region.

    PubMed  CAS  Google Scholar 

  27. • Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748–52. This is one of the first GWAS that identified the MHC as an associated region.

    PubMed  CAS  Google Scholar 

  28. Handel AE, Ramagopalan SV. The potential role of major histocompatibility complex class I in schizophrenia. Biol Psychiatry. 2010;68(7):e29–30. author reply e31.

    Article  PubMed  CAS  Google Scholar 

  29. Shi Y, Li Z, Xu Q, et al. Common variants on 8p12 and 1q24.2 confer risk of schizophrenia. Nat Genet. 2011;43(12):1224–7.

    Article  PubMed  CAS  Google Scholar 

  30. Yue W-H, Wang H-F, Sun L-D, et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nat Genet. 2011;43(12):1228–31.

    Article  PubMed  CAS  Google Scholar 

  31. •• Ripke S, Sanders AR, Kendler KS, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43(10):969–76. This is the largest GWAS made on a SCZ cohort. It identifies MIR137 as an associated locus.

    Article  PubMed  CAS  Google Scholar 

  32. Balaguer F, Link A, Lozano JJ, et al. Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis. Cancer Res. 2010;70(16):6609–18.

    Article  PubMed  CAS  Google Scholar 

  33. Liu M, Lang N, Qiu M, et al. miR-137 targets Cdc42 expression, induces cell cycle G1 arrest and inhibits invasion in colorectal cancer cells. Int J Cancer. 2011;128(6):1269–79.

    Article  PubMed  CAS  Google Scholar 

  34. Silber J, Lim DA, Petritsch C, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;6:14.

    Article  PubMed  Google Scholar 

  35. Tarantino C, Paolella G, Cozzuto L, et al. miRNA 34a, 100, and 137 modulate differentiation of mouse embryonic stem cells. FASEB J. 2010;24(9):3255–63.

    Article  PubMed  CAS  Google Scholar 

  36. • Walsh T, McClellan JM, McCarthy SE, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008;320(5875):539–43. This is one of the most important genome-wide CNV studies made in the field of SCZ.

    Article  PubMed  CAS  Google Scholar 

  37. Xu B, Roos JL, Levy S, et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008;40(7):880–5.

    Article  PubMed  CAS  Google Scholar 

  38. Anon. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455(7210):237–41.

    Article  Google Scholar 

  39. • Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455(7210):232–6. This is one of the most important genome-wide CNV study made in the field of SCZ.

    Article  PubMed  CAS  Google Scholar 

  40. Mulle JG, Dodd AF, McGrath JA, et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet. 2010;87(2):229–36.

    Article  PubMed  CAS  Google Scholar 

  41. McCarthy SE, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009;41(11):1223–7.

    Article  PubMed  CAS  Google Scholar 

  42. Ingason A, Rujescu D, Cichon S, et al. Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol Psychiatry. 2009;16(1):17–25.

    Google Scholar 

  43. •• Craddock N, Hurles ME, Cardin N, et al. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010;464(7289):713–20. This study made by the WTCCC shows that the common CNVs are unlikely to contribute significantly to disease as they are already tagged by the SNPs.

    Article  PubMed  CAS  Google Scholar 

  44. Malhotra D, McCarthy S, Michaelson JJ, et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron. 2011;72(6):951–63.

    Article  PubMed  CAS  Google Scholar 

  45. • Gauthier J, Champagne N, Lafreniere RG, et al. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci U S A. 2010;107(17):7863–8. This is the first study to report a de novo mutation in a gene and to associate this gene with the disease.

    Article  PubMed  CAS  Google Scholar 

  46. Tarabeux J, Champagne N, Brustein E, et al. De novo truncating mutation in Kinesin 17 associated with schizophrenia. Biol Psychiatry. 2010;68(7):649–56.

    Article  PubMed  CAS  Google Scholar 

  47. Gauthier J, Siddiqui TJ, Huashan P, et al. Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum Genet. 2011;130(4):563–73.

    Google Scholar 

  48. • Awadalla P, Gauthier J, Myers RA, et al. Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Am J Hum Genet. 2010;87(3):316–24. This study has shown that the de novo mutation rate is higher than expected in SCZ.

    Article  PubMed  CAS  Google Scholar 

  49. •• Girard SL, Gauthier J, Noreau A, et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 2011;43(9):860–3. This study has shown a higher than expected rate of de novo mutation as well as identified a strong enrichment in de novo truncating mutations.

    Article  PubMed  CAS  Google Scholar 

  50. •• Xu B, Roos JL, Dexheimer P, et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet. 2011;43(9):864–8. This study has shown a higher than expected rate of de novo mutation as well as identified a strong enrichment in nonsynonymous mutations.

    Article  PubMed  CAS  Google Scholar 

  51. O’Roak BJ, Deriziotis P, Lee C, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43(6):585–9.

    Article  PubMed  Google Scholar 

  52. Vissers LE, de Ligt J, Gilissen C, et al. A de novo paradigm for mental retardation. Nat Genet. 2010;42(12):1109–12.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Conflicts of interest: S.L. Girard: none; P.A. Dion: none; G.A. Rouleau: none.

Author information

Authors and Affiliations

  1. Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l’Université de Montréal Research Center, Montréal, Québec, Canada

    Simon L. Girard, Patrick A. Dion & Guy A. Rouleau

  2. Department of Pathology and Cellular Biology, Université de Montréal, Montréal, Québec, Canada

    Patrick A. Dion

  3. Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, Québec, Canada

    Guy A. Rouleau

  4. Faculty of Medicine, Department of Medicine, Université de Montréal, Montréal, Québec, Canada

    Guy A. Rouleau

Authors
  1. Simon L. Girard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick A. Dion
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guy A. Rouleau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guy A. Rouleau.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Girard, S.L., Dion, P.A. & Rouleau, G.A. Schizophrenia Genetics: Putting All the Pieces Together. Curr Neurol Neurosci Rep 12, 261–266 (2012). https://doi.org/10.1007/s11910-012-0266-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-012-0266-7

Keywords

Search

Navigation