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Schizophrenia genetics: emerging themes for a complex disorder

Molecular Psychiatry volume 20, pages 7276 (2015) | Download Citation

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Abstract

After two decades of frustration, genetic studies of schizophrenia have entered an era of spectacular success. Advances in genotyping technologies and high throughput sequencing, increasing analytic rigour and collaborative efforts on a global scale have generated a profusion of new findings. The broad conclusions from these studies are threefold: (1) schizophrenia is a highly polygenic disorder with a complex array of contributing risk loci across the allelic frequency spectrum; (2) many psychiatric illnesses share risk genes and alleles, specifically, schizophrenia has substantial overlaps with bipolar disorder, intellectual disability, major depressive disorder and autism spectrum disorders; and (3) some convergent biological themes are emerging from studies of schizophrenia and related disorders. In this commentary, we focus on the very recent findings that have emerged in the past 12 months, and in particular, the areas of convergence that are beginning to emerge from multiple study designs.

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References

  1. 1.

    , , . Schizophrenia In Psychiatric Genetics and Genomics. OUP Oxford New Ed edition 2002 pp 247–266.

  2. 2.

    , , , , , et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.

  3. 3.

    , , , , , et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744–747.

  4. 4.

    , , , , , et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009; 460: 753–757.

  5. 5.

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

  6. 6.

    , , , , , et al. Genome-wide association study of schizophrenia in a Japanese population. Biol Psychiatry 2011; 69: 472–478.

  7. 7.

    , , , , , et al. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry 2012; 18: 708–712 10.1038/mp.2012.67.

  8. 8.

    Genome-wide association study implicates HLA-C*01. 02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biol Psychiatry 2012; 72: 620–628.

  9. 9.

    , , , , , et al. Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder. Nat Commun 2013; 4: 2739.

  10. 10.

    , , . Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012; 13: 537–551.

  11. 11.

    , , , , , et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 2013; 45: 1150–1159.

  12. 12.

    , , , , , et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry 2010; 15: 1016–1022.

  13. 13.

    et al. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 2013; 381: 1371–1379.

  14. 14.

    , , , , , , et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 2013; 45: 984–994.

  15. 15.

    , , , . GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 2011; 88: 76–82.

  16. 16.

    , , , , , et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci 1995; 92: 7612–7616.

  17. 17.

    , . CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 2012; 148: 1223–1241.

  18. 18.

    , , , , , et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 2008; 40: 880–885.

  19. 19.

    , , , , , et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry 2012; 17: 142–153.

  20. 20.

    , , , , , et al. Analysis of copy number variations at 15 schizophrenia-associated loci in a large, independent cohort. Br J Psychiatry 2013; 204: 108–114.

  21. 21.

    , , , , , et al. Copy number variation in schizophrenia in Sweden. Mol Psychiatry 2014; 19: 762–773.

  22. 22.

    , , , , , et al. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 2012; 44: 78–84.

  23. 23.

    , , , , , et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 43: 838–846.

  24. 24.

    , , , , , et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry 2012; 169: 195–204.

  25. 25.

    , . Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet 2010; 19: R176–R187.

  26. 26.

    , , , , , et al. Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Genet Med 2011; 13: 868–880.

  27. 27.

    , , , , , et al. The Penetrance of Copy Number Variations for Schizophrenia and Developmental Delay. Biol Psychiatry 2013; 75: 378–385.

  28. 28.

    , , , , , et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008; 320: 539–543.

  29. 29.

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

  30. 30.

    , , , , , et al. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry 2013; 18: 708–712.

  31. 31.

    , , . Validating therapeutic targets through human genetics. Nat Rev Drug Discov 2013; 12: 581–594.

  32. 32.

    ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57–74.

  33. 33.

    , , . Is there a flame in the brain in psychosis? Biol Psychiatry 2014; 75: 258–259.

  34. 34.

    , , , , , et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014; 506: 179–184.

  35. 35.

    , , , , , et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014; 506: 185–190.

  36. 36.

    , , , , , et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet 2012; 44: 1365–1369.

  37. 37.

    , , , , , et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet 2011; 43: 860–863.

  38. 38.

    , , , , , et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 2013; 154: 518–529.

  39. 39.

    , , , , , et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012; 485: 242–245.

  40. 40.

    , , , , , et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012; 485: 246–250.

  41. 41.

    , , , , , et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485: 237–241.

  42. 42.

    , , , , , et al. De Novo Gene Disruptions in Children on the Autistic Spectrum. Neuron 2012; 74: 285–299.

  43. 43.

    , , , , , et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 2012; 380: 1674–1682.

  44. 44.

    , , , , , et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012; 367: 1921–1929.

  45. 45.

    , , , , , et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 2012; 488: 471–475.

  46. 46.

    , , , , , et al. A comprehensive assessment of parental age and psychiatric disorders. JAMA Psychiatry 2014; 71: 301–309.

  47. 47.

    , , , , , et al. De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Mol Psychiatry 2014; 19: 652–658.

  48. 48.

    , . The Kraepelinian dichotomy – going, going... but still not gone. Br J Psychiatry 2010; 196: 92–95.

  49. 49.

    , . The Research Domain Criteria: moving the goalposts to change the game. Br J Psychiatry 2014; 204: 171–173.

  50. 50.

    , . Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice. Genome Med 2014; 6: 29.

  51. 51.

    , . Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology. Neuron 2013; 80: 578–587.

  52. 52.

    , , . ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 2013; 31: 397–405.

  53. 53.

    , , . CRISPR/Cas9 for genome editing: progress, implications and challenges. Hum Mol Genet 2014; 23: R40–R46.

  54. 54.

    . The challenges and promise of neuroimaging in psychiatry. Neuron 2012; 73: 8–22.

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Acknowledgements

This work on schizophrenia is supported by MRC Centre (G0800509) and MRC Programme (G0801418) Grants, the European Community's Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI)) and the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no 279227.

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Affiliations

  1. MRC centre for Neuropsychiatric Genetics and Genomics, and Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK

    • D H Kavanagh
    • , K E Tansey
    • , M C O'Donovan
    •  & M J Owen

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The author declare no conflicts of intrest.

Corresponding author

Correspondence to M J Owen.

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DOI

https://doi.org/10.1038/mp.2014.148

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