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Genetics of Schizophrenia

  • Genetic Disorders (W Berrettini, Section Editor)
  • Published:
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Abstract

The genetic basis of schizophrenia has been a hotly debated research topic for decades, yet recent studies, especially in the past year, have confirmed genetics as the major cause of this complex condition. Psychiatry has come of age: it is perhaps more difficult for the current generation of psychiatrists, to comprehend how the biological root of the condition could have been denied for so long. Here we review how highly collaborative global efforts to pool samples, utilise the very latest advances in genotyping and high throughput sequencing technologies, and application of robust statistical analysis have reaped phenomenal rewards. The major findings are that schizophrenia is a highly polygenic disorder with a complex array of risk loci, many include genes implicated also in intellectual disability, autism spectrum disorders, bipolar disorder and major depressive disorder. These candidate genes converge on key neuronal signalling pathways identifying novel targets for potential future therapeutic intervention.

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References

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

  1. Ayhan Y et al. Animal models of gene-environment interactions in schizophrenia. Behav Brain Res. 2009;204(2):274–81.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Lichtenstein P et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009;373(9659):234–9.

    Article  PubMed  CAS  Google Scholar 

  3. Rodriguez-Murillo L, Gogos JA, Karayiorgou M. The genetic architecture of schizophrenia: new mutations and emerging paradigms. Annu Rev Med. 2012;63:63–80.

    Article  PubMed  CAS  Google Scholar 

  4. Owen MJ et al. Neurodevelopmental hypothesis of schizophrenia. Br J Psychiatry. 2011;198(3):173–5.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Rapoport JL, Giedd JN, Gogtay N. Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry. 2012;17(12):1228–38.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Stone JM, Morrison PD, Pilowsky LS. Glutamate and dopamine dysregulation in schizophrenia–a synthesis and selective review. J Psychopharmacol. 2007;21(4):440–52.

    Article  PubMed  CAS  Google Scholar 

  7. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44(7):660–9.

    Article  PubMed  CAS  Google Scholar 

  8. Umbricht D et al. Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry. 2000;57(12):1139–47.

    Article  PubMed  CAS  Google Scholar 

  9. Gershon ES, Alliey-Rodriguez N, Liu C. After GWAS: searching for genetic risk for schizophrenia and bipolar disorder. Am J Psychiatry. 2011;168(3):253–6.

    Article  PubMed  Google Scholar 

  10. Bassett AS, Scherer SW, Brzustowicz LM. Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. Am J Psychiatry. 2010;167(8):899–914.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Purcell SM et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748–52.

    PubMed  CAS  Google Scholar 

  12. Bergen SE, Petryshen TL. Genome-wide association studies of schizophrenia: does bigger lead to better results? Curr Opin Psychiatry. 2012;25(2):76–82.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schizophrenia Psychiatric Genome-Wide Association Study. C., Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43(10):969–76.

    Article  Google Scholar 

  14. Ripke S et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45(10):1150–9.

    Article  PubMed  CAS  Google Scholar 

  15. McAllister AK. Major histocompatibility complex I in brain development and schizophrenia. Biol Psychiatry. 2014;75(4):262–8.

    Article  PubMed  CAS  Google Scholar 

  16. Patterson PH. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res. 2009;204(2):313–21.

    Article  PubMed  CAS  Google Scholar 

  17. Glynn MW et al. MHCI negatively regulates synapse density during the establishment of cortical connections. Nat Neurosci. 2011;14(4):442–51.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Chacon MA, Boulanger LM. MHC class I protein is expressed by neurons and neural progenitors in mid-gestation mouse brain. Mol Cell Neurosci. 2013;52:117–27.

    Article  PubMed  CAS  Google Scholar 

  19. Schizophrenia Working Group of the Psychiatric Genomics, C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7. This is a landmark multistage schizophrenia genome-wide association study of 36,989 cases and 113,075 controls. It identifies 128 independent associates spanning 108 conservatively defined loci that meet genome-wide significance of which 83 have never before been reported. Furthermore, these associates provide novel insight into the biological basis of schizophrenia.

  20. Bromet EJ et al. Diagnostic shifts during the decade following first admission for psychosis. Am J Psychiatry. 2011;168(11):1186–94.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cross-Disorder Group of the Psychiatric Genomics, C et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45(9):984–94.

    Article  Google Scholar 

  22. Cross-Disorder Group of the Psychiatric Genomics, C. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381(9875):1371–9.

    Article  Google Scholar 

  23. van Erp TG et al. Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation. Biol Psychiatry. 2014;75(5):398–405.

    Article  PubMed  Google Scholar 

  24. Hill MJ et al. Transcriptional consequences of schizophrenia candidate miR-137 manipulation in human neural progenitor cells. Schizophr Res. 2014;153(1–3):225–30.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Szulwach KE et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol. 2010;189(1):127–41.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Mitchell KJ, Porteous DJ. Rethinking the genetic architecture of schizophrenia. Psychol Med. 2011;41(1):19–32.

    Article  PubMed  CAS  Google Scholar 

  27. Blackwood DH 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  PubMed Central  Google Scholar 

  28. Millar JK 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 

  29. Thomson PA et al. 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits. Mol Psychiatry. 2014;19(6):668–75.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci. 2011;12(12):707–22.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Ogawa F et al. DISC1 complexes with TRAK1 and Miro1 to modulate anterograde axonal mitochondrial trafficking. Hum Mol Genet. 2014;23(4):906–19.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Johnstone M et al. DISC1 in schizophrenia: genetic mouse models and human genomic imaging. Schizophr Bull. 2011;37(1):14–20.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Purcell SM et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506(7487):185–90. This exome sequencing study of 2,536 schzophrenia cases and 2,543 controls demonstrated a polygenic burden from rare (less than 1 in 10,000) disruptive mutations across many genes but with enrichment in genes associated with voltage-gated calcium channels, ARC and FMRP complexes.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Fromer M et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506(7487):179–84. This study shows that de novo CNVs occur in a small fraction of schizophrenia cases and disproportionately disrupt genes encoding post-synaptic density proteins including ARC and NMDAR complexes suggesting disruption of synaptic networks. Furthermore, mutations found in schizophrenia overlap with those found in autism and intellectual disability suggesting a shared genetic basis to a range of neurodevelopmental disorders.

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  36. Xu B 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 

  37. Kirov G et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2012;17(2):142–53. This study of 662 schizophrenia proband-parent trios showed that rare de novo CNVs were significantly more frequent in cases compared to controls. Using a systems biology approach this study showed that de novo CNVs were significanly enriched for the post-synaptic density proteome (in partiular ARC and NMDAR complexes).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Power RA et al. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry. 2013;70(1):22–30.

    Article  PubMed  Google Scholar 

  39. Doherty JL, O'Donovan MC, Owen MJ. Recent genomic advances in schizophrenia. Clin Genet. 2012;81(2):103–9.

    Article  PubMed  CAS  Google Scholar 

  40. Reardon S. Gene-hunt gain for mental health. Nature. 2014;511(7510):393.

    Article  PubMed  CAS  Google Scholar 

  41. Flint J, Munafo MR. The endophenotype concept in psychiatric genetics. Psychol Med. 2007;37(2):163–80.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Decoster J et al. Genetic association study of the P300 endophenotype in schizophrenia. Schizophr Res. 2012;141(1):54–9.

    Article  PubMed  Google Scholar 

  43. Yoon KJ et al. Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity. Cell Stem Cell. 2014;15(1):79–91. This study elegantly demonstrated how iPSC technology can be used to investigate the molecular and cellular mechanisms in genetically tractable disease-relevant human cell types.

    Article  PubMed  CAS  Google Scholar 

  44. Stefansson H et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature. 2014;505(7483):361–6.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Irene Escudero is a Master’s student on exchange at the University of Edinburgh funded by a EUROlife Scholarship from the University of Barcelona, Spain. Mandy Johnstone is a PI at the CGEM and is supported by a Wellcome Trust Postdoctoral Clinical Fellowship. This work has also been funded by a starter grant from the Academy of Medical Sciences (to Mandy Johnstone) and a grant from the RS Macdonald Charitable Trust (to Mandy Johnstone).

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Conflict of Interest

Irene Escudero declares that she has no conflict of interest.

Mandy Johnstone has received grants from the Wellcome Trust, RS Macdonald Charitable Trust, and the Academy of Medical Sciences.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. The Centre for Genomic and Experimental Medicine, The Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom

    Irene Escudero & Mandy Johnstone

  2. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Morningside Terrace, Edinburgh, EH10 5HF, United Kingdom

    Mandy Johnstone

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  1. Irene Escudero
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  2. Mandy Johnstone
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Correspondence to Mandy Johnstone.

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This article is part of the Topical Collection on Genetic Disorders

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Escudero, I., Johnstone, M. Genetics of Schizophrenia. Curr Psychiatry Rep 16, 502 (2014). https://doi.org/10.1007/s11920-014-0502-8

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  • DOI: https://doi.org/10.1007/s11920-014-0502-8

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