Genetics of Schizophrenia

Current Psychiatry Reports

Volumn 16, Issue 11, 2014, Pages

  Escudero, Irene ^a   Johnstone, Mandy ^a  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

Common variants; Copy number variants; Genetics; Neurodevelopmental disorders; Rare variants; Schizophrenia; Single nucleotide polymorphisms

Indexed keywords

ATTENTION DEFICIT DISORDER; AUTISM; BIPOLAR DISORDER; COPY NUMBER VARIATION; GENE DELETION; GENE DUPLICATION; GENE LOCUS; GENE MUTATION; GENETIC ASSOCIATION; GENETIC RISK; GENETIC VARIABILITY; HEREDITY; HERITABILITY; HUMAN; MAJOR DEPRESSION; NERVE CELL PLASTICITY; NEUROTRANSMISSION; NONHUMAN; REVIEW; SCHIZOPHRENIA; SINGLE NUCLEOTIDE POLYMORPHISM; GENETICS; MULTIFACTORIAL INHERITANCE;

GENETIC VARIATION; HUMANS; MULTIFACTORIAL INHERITANCE; SCHIZOPHRENIA;

EID: 84920911766     PISSN: 15233812     EISSN: 15351645     Source Type: Journal    
DOI: 10.1007/s11920-014-0502-8     Document Type: Review

References (44)

1. Ayhan Y et al. Animal models of gene-environment interactions in schizophrenia. Behav Brain Res. 2009;204(2):274–81.
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.
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.
4. Owen MJ et al. Neurodevelopmental hypothesis of schizophrenia. Br J Psychiatry. 2011;198(3):173–5.
5. Rapoport JL, Giedd JN, Gogtay N. Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry. 2012;17(12):1228–38.
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.
7. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44(7):660–9.
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.
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.
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.
11. Purcell SM et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748–52.
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.
13. Schizophrenia Psychiatric Genome-Wide Association Study. C., Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43(10):969–76.
14. Ripke S et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45(10):1150–9.
15. McAllister AK. Major histocompatibility complex I in brain development and schizophrenia. Biol Psychiatry. 2014;75(4):262–8.
16. Patterson PH. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res. 2009;204(2):313–21.
17. Glynn MW et al. MHCI negatively regulates synapse density during the establishment of cortical connections. Nat Neurosci. 2011;14(4):442–51.
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.
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.
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.
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.
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.
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.
25. Szulwach KE et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol. 2010;189(1):127–41.
26. Mitchell KJ, Porteous DJ. Rethinking the genetic architecture of schizophrenia. Psychol Med. 2011;41(1):19–32.
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.
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.
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.
30. Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci. 2011;12(12):707–22.
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.
32. Johnstone M et al. DISC1 in schizophrenia: genetic mouse models and human genomic imaging. Schizophr Bull. 2011;37(1):14–20.
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.
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.
35. ISC. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455(7210):237–41.
36. Xu B et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008;40(7):880–5.
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).
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.
39. Doherty JL, O'Donovan MC, Owen MJ. Recent genomic advances in schizophrenia. Clin Genet. 2012;81(2):103–9.
40. Reardon S. Gene-hunt gain for mental health. Nature. 2014;511(7510):393.
41. Flint J, Munafo MR. The endophenotype concept in psychiatric genetics. Psychol Med. 2007;37(2):163–80.
42. Decoster J et al. Genetic association study of the P300 endophenotype in schizophrenia. Schizophr Res. 2012;141(1):54–9.
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.
44. Stefansson H et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature. 2014;505(7483):361–6.