Genetics of Schizophrenia: Ready to Translate?
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Purpose of Review
This is an era where we have significantly advanced the understanding of the genetic architecture of schizophrenia. In this review, we consider how this knowledge may translate into advances that will improve patient care.
Large-scale genome-wide association studies (GWAS) have identified more than a hundred loci each making a small contribution to illness risk. Meta-analysis of copy number variants (CNVs) in the Psychiatric Genomics Consortium (PGC) dataset has confirmed that some variants have a moderate or large impact on risk, although these are rare in the population. Genome sequencing advances allow a much more comprehensive evaluation of genomic variation. We describe the key findings from whole exome studies to date. These studies are happening against a backdrop of growing understanding of the regulation and expression of genes and better functional tools to investigate molecular mechanisms in model systems.
We provide an overview of how recent approaches in schizophrenia genetics are converging and consider how they could impact on diagnostics, the development of personalized medicine, and drug discovery.
KeywordsSchizophrenia Genomics Translational medicine Polygene score Mutations
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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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- 5.Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry. 2012;17(12):1206–27. doi: 10.1038/mp.2012.47.CrossRefPubMedGoogle Scholar
- 9.• Nioi P, Sigurdsson A, Thorleifsson G, Helgason H, Agustsdottir AB, Norddahl GL, et al. Variant ASGR1 associated with a reduced risk of coronary artery disease. N Engl J Med. 2016;374(22):2131–41. doi: 10.1056/NEJMoa1508419. This whole-genome sequencing study identified a deletion leading to inactivation of ASGR1, associated with reduced levels of non-HDL cholesterol and a resultant reduced risk of coronary artery disease. CrossRefPubMedGoogle Scholar
- 10.Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42(Database issue):6.Google Scholar
- 11.• Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7. doi: 10.1038/nature13595. This paper reported on an extensive GWAS analysis on schizophrenia, including data on up to 36,989 cases and 113,075 controls. 108 independent genomic risk loci associated with schizophrenia were identified. http://www.nature.com/nature/journal/v511/n7510/abs/nature13595.html#supplementary-information CrossRefGoogle Scholar
- 12.Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci. 2015;18(2):199–209.Google Scholar
- 15.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(8):620–8. doi: 10.1016/j.biopsych.2012.05.035.
- 16.Genome-wide association study identifies five new schizophrenia loci. Nature genetics. 2011;43(10):969–76. doi: 10.1038/ng.940.
- 17.Morris DW, Pearson RD, Cormican P, Kenny EM, O'Dushlaine CT, Lemieux Perreault L-P, et al. An inherited duplication at the gene p21 protein-activated kinase 7 (PAK7) is a risk factor for psychosis. Hum Mol Genet. 2014; doi: 10.1093/hmg/ddu025.
- 18.• Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530(7589):177–83. doi: 10.1038/nature16549. This study examined the association of schizophrenia with variation in the MHC locus, identifying a key role of excessive complement component 4 activity, possibly resulting in the synapse loss observed in schizophrenia CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455(7210):237–41. doi:http://www.nature.com/nature/journal/v455/n7210/suppinfo/nature07239_S1.html.
- 30.• Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017;49(1):27–35. doi: 10.1038/ng.3725. This study found genome-wide significant evidence for eight CNV loci contributing to schizophrenia risk with suggestive support for a further eight candidate susceptibility and protective loci
- 38.• Kirov G, Rees E, Walters JT, Escott-Price V, Georgieva L, Richards AL, et al. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 2014;75(5):378–85. doi: 10.1016/j.biopsych.2013.07.022. This study estimated total penetrance of thirteen schizophrenia-associated CNVs for neurodevelopmental disorders including SCZ, DD, ASD or a congenital malformation, to be high (ranging between 10.6%-100%), with significant implications for genetic counselling CrossRefPubMedGoogle Scholar
- 50.• 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(7487):185–90. doi: 10.1038/nature12975. This paper introduces the polygene score method and its application to schizophrenia CrossRefPubMedPubMedCentralGoogle Scholar
- 52.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(7487):179–84. doi: 10.1038/nature12929. http://www.nature.com/nature/journal/v506/n7487/abs/nature12929.html#supplementary-information CrossRefPubMedPubMedCentralGoogle Scholar
- 54.• Genovese G, Fromer M, Stahl EA, Ruderfer DM, Chambert K, Landen M, et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat Neurosci. 2016;19(11):1433–41. doi: 10.1038/nn.4402. This study explored the role of rare coding mutations in schizophrenia and identified that most dURVs contributing to the disorder appeared to be inherited and enriched in brain-specific genes. The findings provide evidence of a general synaptic dysfunction in the pathogenesis of schizophrenia CrossRefPubMedPubMedCentralGoogle Scholar
- 57.O'Byrne JJ, Lynch SA, Treacy EP, King MD, Betts DR, Mayne PD, et al. Unexplained developmental delay/learning disability: guidelines for best practice protocol for first line assessment and genetic/metabolic/radiological investigations. Ir J Med Sci. 2016;185(1):241–8. doi: 10.1007/s11845-015-1284-7.CrossRefPubMedGoogle Scholar
- 59.Kendall KM, Rees E, Escott-Price V, Einon M, Thomas R, Hewitt J, et al. Cognitive performance among carriers of pathogenic copy number variants: analysis of 152,000 UK biobank subjects. Biol Psychiatry. 2016; doi: 10.1016/j.biopsych.2016.08.014.
- 64.Han K, Jeng EE, Hess GT, Morgens DW, Li A, Bassik MC. Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nat Biotechnol. 2017; doi: 10.1038/nbt.3834.
- 66.Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014;515(7527):414–8. doi: 10.1038/nature13716. http://www.nature.com/nature/journal/v515/n7527/abs/nature13716.html#supplementary-information CrossRefPubMedPubMedCentralGoogle Scholar
- 68.Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; doi: 10.1038/nature16549.
- 72.• Krey JF, Pasca SP, Shcheglovitov A, Yazawa M, Schwemberger R, Rasmusson R, et al. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci. 2013;16(2):201–9. doi: 10.1038/nn.3307. This study examined the point mutation in the calcium channel CACNA1C causing Timothy syndrome (a neurodevelopmental disorder) in iPSC-derived cortical neurons and identified activity-dependent dendritic retraction in neurons, providing insights into the cellular basis of Timothy syndrome and potentially other neurodevelopmental disorders CrossRefPubMedPubMedCentralGoogle Scholar