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The implications of the shared genetics of psychiatric disorders

Abstract

Recent genomic studies have revealed the highly polygenic nature of psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. Many of the individual genetic associations are shared across multiple disorders in a way that points to extensive biological pleiotropy and further challenges the biological validity of existing diagnostic approaches. Here we argue that the existence of risk alleles specific to a single diagnostic category is unlikely. We also highlight some of the important clinical repercussions of pleiotropy.

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Figure 1: Types of pleiotropy.
Figure 2: Relative CNV frequencies.
Figure 3: Genetic correlation between schizophrenia and selected psychiatric disorders.

References

  1. Whiteford, H.A. et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382, 1575–1586 (2013).

    Article  Google Scholar 

  2. Salomon, J.A. et al. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet 380, 2129–2143 (2012).

    Article  Google Scholar 

  3. Owen, M.J. New approaches to psychiatric diagnostic classification. Neuron 84, 564–571 (2014).

    Article  CAS  Google Scholar 

  4. Malaspina, D. et al. Schizoaffective disorder in the DSM-5. Schizophr. Res. 150, 21–25 (2013).

    Article  Google Scholar 

  5. van Os, J. & Kapur, S. Schizophrenia. Lancet 374, 635–645 (2009).

    Article  CAS  Google Scholar 

  6. Lichtenstein, P. et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234–239 (2009).

    Article  CAS  Google Scholar 

  7. Kapur, S., Phillips, A.G. & Insel, T.R. Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol. Psychiatry 17, 1174–1179 (2012).

    Article  CAS  Google Scholar 

  8. Linden, D.E. The challenges and promise of neuroimaging in psychiatry. Neuron 73, 8–22 (2012).

    Article  CAS  Google Scholar 

  9. Sanders, S.J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215–1233 (2015).

    Article  CAS  Google Scholar 

  10. Gaugler, T. et al. Most genetic risk for autism resides with common variation. Nat. Genet. 46, 881–885 (2014).

    Article  CAS  Google Scholar 

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

  12. Rees, E. et al. Analysis of copy number variations at 15 schizophrenia-associated loci. Br. J. Psychiatry 204, 108–114 (2014).

    Article  Google Scholar 

  13. Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014).

    Article  CAS  Google Scholar 

  14. Purcell, S.M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014).

    Article  CAS  Google Scholar 

  15. Singh, T. et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat. Neurosci. 19, 571–577 (2016).

    Article  CAS  Google Scholar 

  16. Green, E.K. et al. Copy number variation in bipolar disorder. Mol. Psychiatry 21, 89–93 (2016).

    Article  CAS  Google Scholar 

  17. Hyde, C.L. et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nat. Genet. 48, 1031–1036 (2016).

    Article  CAS  Google Scholar 

  18. Paaby, A.B. & Rockman, M.V. The many faces of pleiotropy. Trends Genet. 29, 66–73 (2013).

    Article  CAS  Google Scholar 

  19. Solovieff, N., Cotsapas, C., Lee, P.H., Purcell, S.M. & Smoller, J.W. Pleiotropy in complex traits: challenges and strategies. Nat. Rev. Genet. 14, 483–495 (2013).

    Article  CAS  Google Scholar 

  20. Kirov, G. et al. The penetrance of copy number variations for schizophrenia and developmental delay. Biol. Psychiatry 75, 378–385 (2014).

    Article  CAS  Google Scholar 

  21. Rees, E. et al. Analysis of intellectual disability copy number variants for association with schizophrenia. JAMA Psychiatry 73, 963–969 (2016).

    Article  Google Scholar 

  22. Rujescu, D. et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–996 (2009).

    Article  CAS  Google Scholar 

  23. Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223–228 (2015).

  24. The International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).

  25. Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984–994 (2013).

  26. Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).

    Article  CAS  Google Scholar 

  27. Hamshere, M.L. et al. Shared polygenic contribution between childhood attention-deficit hyperactivity disorder and adult schizophrenia. Br. J. Psychiatry 203, 107–111 (2013).

    Article  Google Scholar 

  28. Samocha, K.E. et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944–950 (2014).

    Article  CAS  Google Scholar 

  29. Kirov, G. et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17, 142–153 (2012).

    Article  CAS  Google Scholar 

  30. Niarchou, M. et al. Psychopathology and cognition in children with 22q11.2 deletion syndrome. Br. J. Psychiatry 204, 46–54 (2014).

    Article  Google Scholar 

  31. Stefansson, H. et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505, 361–366 (2014).

    Article  CAS  Google Scholar 

  32. Tansey, K.E. et al. Common alleles contribute to schizophrenia in CNV carriers. Mol. Psychiatr. 21, 1085–1089 (2015).

    Article  Google Scholar 

  33. Rees, E. et al. Evidence that duplications of 22q11.2 protect against schizophrenia. Mol. Psychiatry 19, 37–40 (2014).

    Article  CAS  Google Scholar 

  34. Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984–994 (2012).

  35. Costain, G. et al. Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays. Hum. Mol. Genet. 22, 4485–4501 (2013).

    Article  CAS  Google Scholar 

  36. Gershon, E.S. & Alliey-Rodriguez, N. New ethical issues for genetic counseling in common mental disorders. Am. J. Psychiatry 170, 968–976 (2013).

    Article  Google Scholar 

  37. Walters, J.T.R. & Owen, M.J. Endophenotypes in psychiatric genetics. Mol. Psychiatry 12, 886–890 (2007).

    Article  CAS  Google Scholar 

  38. Kendler, K.S. & Neale, M.C. Endophenotype: a conceptual analysis. Mol. Psychiatr 15, 789–797 (2010).

    Article  Google Scholar 

  39. Antilla, V. et al. Analysis of shared heritability in common disorders of the brain. Preprint at bioRxiv http://dx.doi.org/10.1101/048991 (2016).

  40. Ruderfer, D.M. et al. A family-based study of common polygenic variation and risk of schizophrenia. Mol. Psychiatry 16, 887–888 (2011).

    Article  CAS  Google Scholar 

  41. Hamshere, M.L. 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 18, 708–712 (2013).

    Article  CAS  Google Scholar 

  42. Flint, J., Timpson, N. & Munafò, M. Assessing the utility of intermediate phenotypes for genetic mapping of psychiatric disease. Trends Neurosci. 37, 733–741 (2014).

    Article  CAS  Google Scholar 

  43. Franke, B. et al. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nat. Neurosci. 19, 420–431 (2016).

    Article  CAS  Google Scholar 

  44. Cuthbert, B.N. The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology. World Psychiatry 13, 28–35 (2014).

    Article  Google Scholar 

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Acknowledgements

This work was funded by Medical Research Council (MRC) Centre grant MR/L010305/1 and program grant G0800509.

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Correspondence to Michael C O'Donovan.

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Michael C.O'Donovan has received a consultancy fee from Roche for participation in a discussion about using genetics to identify drug targets.

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O'Donovan, M., Owen, M. The implications of the shared genetics of psychiatric disorders. Nat Med 22, 1214–1219 (2016). https://doi.org/10.1038/nm.4196

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