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The genetic architecture of schizophrenia: review of large-scale genetic studies

Abstract

Schizophrenia is a complex and often chronic psychiatric disorder with high heritability. Diagnosis of schizophrenia is still made clinically based on psychiatric symptoms; no diagnostic tests or biomarkers are available. Pathophysiology-based diagnostic scheme and treatments are also not available. Elucidation of the pathogenesis is needed for development of pathology-based diagnostics and treatments. In the past few decades, genetic research has made substantial advances in our understanding of the genetic architecture of schizophrenia. Rare copy number variations (CNVs) and rare single-nucleotide variants (SNVs) detected by whole-genome CNV analysis and whole-genome/-exome sequencing analysis have provided the great advances. Common single-nucleotide polymorphisms (SNPs) detected by large-scale genome-wide association studies have also provided important information. Large-scale genetic studies have been revealed that both rare and common genetic variants play crucial roles in this disorder. In this review, we focused on CNVs, SNVs, and SNPs, and discuss the latest research findings on the pathogenesis of schizophrenia based on these genetic variants. Rare variants with large effect sizes can provide mechanistic hypotheses. CRISPR-based genetics approaches and induced pluripotent stem cell technology can facilitate the functional analysis of these variants detected in patients with schizophrenia. Recent advances in long-read sequence technology are expected to detect variants that cannot be detected by short-read sequence technology. Various studies that bring together data from common variant and transcriptomic datasets provide biological insight. These new approaches will provide additional insight into the pathophysiology of schizophrenia and facilitate the development of pathology-based therapeutics.

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References

  1. Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016;388:86–97.

    PubMed  PubMed Central  Article  Google Scholar 

  2. Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382:1575–86.

    PubMed  Article  Google Scholar 

  3. Charlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E, Scott JG, et al. Global epidemiology and burden of schizophrenia: findings from the global burden of disease study 2016. Schizophr Bull. 2018;44:1195–203.

    PubMed  PubMed Central  Article  Google Scholar 

  4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders 5th ed. (DSM-5). Arlington: American Psychiatric Publishing; 2013.

  5. Zhuo C, Hou W, Li G, Mao F, Li S, Lin X, et al. The genomics of schizophrenia: shortcomings and solutions. Prog Neuropsychopharmacol Biol Psychiatry. 2019;93:71–76.

    CAS  PubMed  Article  Google Scholar 

  6. Kimura H, Mori D, Aleksic B, Ozaki N. Elucidation of molecular pathogenesis and drug development for psychiatric disorders from rare disease-susceptibility variants. Neurosci Res. 2021;170:24–31.

    CAS  PubMed  Article  Google Scholar 

  7. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait. Arch Gen Psychiatry. 2003;60:1187.

    PubMed  Article  Google Scholar 

  8. Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, et al. Heritability of schizophrenia and schizophrenia spectrum based on the nationwide danish twin register. Biol Psychiatry. 2018;83:492–98.

    PubMed  Article  Google Scholar 

  9. Stessman HA, Bernier R, Eichler EE. A genotype-first approach to defining the subtypes of a complex disease. Cell. 2014;156:872–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Nakatochi M, Kushima I, Ozaki N. Implications of germline copy-number variations in psychiatric disorders: review of large-scale genetic studies. J Hum Genet. 2021;66:25–37.

    PubMed  Article  Google Scholar 

  11. Zarrei M, MacDonald JR, Merico D, Scherer SW. A copy number variation map of the human genome. Nat Rev Genet. 2015;16:172–83.

    CAS  PubMed  Article  Google Scholar 

  12. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437–55.

    CAS  PubMed  Article  Google Scholar 

  13. Rees E, Walters JTR, Georgieva L, Isles AR, Chambert KD, Richards AL, et al. Analysis of copy number variations at 15 schizophrenia-associated loci. Brit J Psychiat. 2014;204:108–14.

    PubMed  Article  Google Scholar 

  14. Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017;49:27–35.

    CAS  PubMed  Article  Google Scholar 

  15. Kushima I, Aleksic B, Nakatochi M, Shimamura T, Shiino T, Yoshimi A, et al. High-resolution copy number variation analysis of schizophrenia in Japan. Mol Psychiatry. 2017;22:430–40.

    CAS  PubMed  Article  Google Scholar 

  16. McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JA, et al. 22q11.2 deletion syndrome. Nat Rev Dis Prim. 2015;1:15071.

    PubMed  Article  Google Scholar 

  17. Fiksinski AM, Schneider M, Murphy CM, Armando M, Vicari S, Canyelles JM, et al. Understanding the pediatric psychiatric phenotype of 22q11.2 deletion syndrome. Am J Med Genet A. 2018;176:2182–91.

    PubMed  PubMed Central  Article  Google Scholar 

  18. Schneider M, Debbane M, Bassett AS, Chow EW, Fung WL, van den Bree M, et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry. 2014;171:627–39.

    PubMed  PubMed Central  Article  Google Scholar 

  19. Jonas RK, Montojo CA, Bearden CE. The 22q11.2 deletion syndrome as a window into complex neuropsychiatric disorders over the lifespan. Biol Psychiatry. 2014;75:351–60.

    CAS  PubMed  Article  Google Scholar 

  20. Mok KY, Sheerin U, Simon-Sanchez J, Salaka A, Chester L, Escott-Price V, et al. Deletions at 22q11.2 in idiopathic Parkinson’s disease: a combined analysis of genome-wide association data. Lancet Neurol. 2016;15:585–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Kushima I, Aleksic B, Nakatochi M, Shimamura T, Okada T, Uno Y, et al. Comparative analyses of copy-number variation in autism spectrum disorder and schizophrenia reveal etiological overlap and biological insights. Cell Rep. 2018;24:2838–56.

    CAS  PubMed  Article  Google Scholar 

  22. Hayashi Y, Kushima I, Aleksic B, Senaha T, Ozaki N. Variable psychiatric manifestations in patients with 16p11.2 duplication: a case series of 4 patients. Psychiatry Clin Neurosci. 2021;76:86–8.

    Article  CAS  Google Scholar 

  23. Kato H, Kushima I, Mori D, Yoshimi A, Aleksic B, Nawa Y, et al. Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder. Transl Psychiatry. 2020;10:421.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Kimura H, Kushima I, Yohimi A, Aleksic B, Ozaki N. Copy number variant in the region of adenosine kinase (ADK) and its possible contribution to schizophrenia susceptibility. Int J Neuropsychopharmacol. 2018;21:405–09.

    CAS  PubMed  Article  Google Scholar 

  25. Sobue A, Kushima I, Nagai T, Shan W, Kohno T, Aleksic B, et al. Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia. Sci Rep. 2018;8:13046.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Saito R, Koebis M, Nagai T, Shimizu K, Liao J, Wulaer B, et al. Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus. Transl Psychiatry. 2020;10:35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Arioka Y, Shishido E, Kushima I, Suzuki T, Saito R, Aiba A, et al. Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons. EBioMedicine. 2021;63:103138.

    CAS  PubMed  Article  Google Scholar 

  28. Sekiguchi M, Sobue A, Kushima I, Wang C, Arioka Y, Kato H, et al. ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk. Transl Psychiatry. 2020;10:247.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Sanders SJ, Neale BM, Huang H, Werling DM, An JY, Dong S, et al. Whole genome sequencing in psychiatric disorders: the WGSPD consortium. Nat Neurosci. 2017;20:1661–68.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Kimura H, Fujita Y, Kawabata T, Ishizuka K, Wang C, Iwayama Y, et al. A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility. Transl Psychiatry. 2017;7:e1214.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Kimura H, Tsuboi D, Wang C, Kushima I, Koide T, Ikeda M, et al. Identification of rare, single-nucleotide mutations in NDE1 and their contributions to schizophrenia susceptibility. Schizophr Bull. 2015;41:744–53.

    PubMed  Article  Google Scholar 

  32. Ishizuka K, Fujita Y, Kawabata T, Kimura H, Iwayama Y, Inada T, et al. Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders. Transl Psychiatry. 2017;7:e1184.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Ishizuka K, Yoshida T, Kawabata T, Imai A, Mori H, Kimura H, et al. Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia. J Neurodev Disord. 2020;12:25.

    PubMed  PubMed Central  Article  Google Scholar 

  34. Girard SL, Gauthier J, Noreau A, Xiong L, Zhou S, Jouan L, et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 2011;43:860–3.

    CAS  PubMed  Article  Google Scholar 

  35. Xu B, Ionita-Laza I, Roos JL, Boone B, Woodrick S, Sun Y, et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet. 2012;44:1365–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506:179–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Uno Y, Coyle JT. Glutamate hypothesis in schizophrenia. Psychiatry Clin Neurosci. 2019;73:204–15.

    PubMed  Article  Google Scholar 

  38. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell. 2011;146:247–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Ascano M Jr, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature. 2012;492:382–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Singh T, Kurki MI, Curtis D, Purcell SM, Crooks L, McRae J, et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat Neurosci. 2016;19:571–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Takata A, Xu B, Ionita-Laza I, Roos JL, Gogos JA, Karayiorgou M. Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron. 2014;82:773–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Howrigan DP, Rose SA, Samocha KE, Fromer M, Cerrato F, Chen WJ, et al. Exome sequencing in schizophrenia-affected parent-offspring trios reveals risk conferred by protein-coding de novo mutations. Nat Neurosci. 2020;23:185–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 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;506:185–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 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;19:1433–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Singh T, Poterba T, Curtis D, Akil H, Eissa MA, Barchas JD, et al. Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature. 2022;604:509–16.

    CAS  PubMed  Article  Google Scholar 

  46. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018;378:840–51.

    PubMed  Article  Google Scholar 

  47. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148:1301–8.

    CAS  PubMed  Article  Google Scholar 

  48. Zeppillo T, Schulmann A, Macciardi F, Hjelm BE, Focking M, Sequeira PA, et al. Functional impairment of cortical AMPA receptors in schizophrenia. Schizophr Res. 2020. (In press).

  49. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An JY, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell. 2020;180:568–84.e23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Palmer DS, Howrigan DP, Chapman SAB, Adolfsson R, Bass N, Blackwood D, et al. Exome sequencing in bipolar disorder reveals shared risk gene AKAP11 with schizophrenia. medRxiv. 2021.

  51. International Schizophrenia C, Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.

    Article  CAS  Google Scholar 

  52. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460:753–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460:744–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  55. Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    Article  CAS  Google Scholar 

  56. Pardinas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50:381–89.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Consortium TSWGotPG, Ripke S, Walters JT, O’Donovan MC. Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia. medRxiv. 2020:2020.09.12.20192922.

  58. Lee SH, DeCandia TR, Ripke S, Yang J, Schizophrenia Psychiatric Genome-Wide Association Study C, International Schizophrenia C. et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet. 2012;44:247–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 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;530:177–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Yue WH, Wang HF, Sun LD, Tang FL, Liu ZH, Zhang HX, et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nat Genet. 2011;43:1228–31.

    CAS  PubMed  Article  Google Scholar 

  61. Li Z, Chen J, Yu H, He L, Xu Y, Zhang D, et al. Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia. Nat Genet. 2017;49:1576–83.

    CAS  PubMed  Article  Google Scholar 

  62. Lam M, Chen CY, Li Z, Martin AR, Bryois J, Ma X, et al. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat Genet. 2019;51:1670–78.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Periyasamy S, John S, Padmavati R, Rajendren P, Thirunavukkarasu P, Gratten J, et al. Association of schizophrenia risk with disordered niacin metabolism in an Indian genome-wide association study. JAMA Psychiatry. 2019;76:1026–34.

    PubMed  PubMed Central  Article  Google Scholar 

  64. Fiorica PN, Wheeler HE. Transcriptome association studies of neuropsychiatric traits in African Americans implicate PRMT7 in schizophrenia. PeerJ. 2019;7:e7778.

    PubMed  PubMed Central  Article  Google Scholar 

  65. Bigdeli TB, Genovese G, Georgakopoulos P, Meyers JL, Peterson RE, Iyegbe CO, et al. Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry. Mol Psychiatry. 2020;25:2455–67.

    CAS  PubMed  Article  Google Scholar 

  66. Ikeda M, Takahashi A, Kamatani Y, Momozawa Y, Saito T, Kondo K, et al. Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect. Schizophr Bull. 2019;45:824–34.

    PubMed  Article  Google Scholar 

  67. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990;264:2511–8.

    CAS  PubMed  Article  Google Scholar 

  68. Buckley PF, Miller BJ, Lehrer DS, Castle DJ. Psychiatric comorbidities and schizophrenia. Schizophr Bull. 2009;35:383–402.

    PubMed  Article  Google Scholar 

  69. Brainstorm C, Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, et al. Analysis of shared heritability in common disorders of the brain. Science. 2018;360:eaap8757.

    Article  CAS  Google Scholar 

  70. Dennison CA, Legge SE, Pardinas AF, Walters JTR. Genome-wide association studies in schizophrenia: recent advances, challenges and future perspective. Schizophr Res. 2020;217:4–12.

    PubMed  Article  Google Scholar 

  71. Lewis CM, Vassos E. Polygenic risk scores: from research tools to clinical instruments. Genome Med. 2020;12:44.

    PubMed  PubMed Central  Article  Google Scholar 

  72. Ikeda M, Saito T, Kanazawa T, Iwata N. Polygenic risk score as clinical utility in psychiatry: a clinical viewpoint. J Hum Genet. 2021;66:53–60.

    PubMed  Article  Google Scholar 

  73. Zheutlin AB, Dennis J, Karlsson Linner R, Moscati A, Restrepo N, Straub P, et al. Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four health care systems. Am J Psychiatry. 2019;176:846–55.

    PubMed  PubMed Central  Article  Google Scholar 

  74. Curtis D. Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia. Psychiatr Genet. 2018;28:85–89.

    PubMed  Article  Google Scholar 

  75. Martin AR, Kanai M, Kamatani Y, Okada Y, Neale BM, Daly MJ. Clinical use of current polygenic risk scores may exacerbate health disparities. Nat Genet. 2019;51:584–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Vassos E, Collier DA, Holden S, Patch C, Rujescu D, St Clair D, et al. Penetrance for copy number variants associated with schizophrenia. Hum Mol Genet. 2010;19:3477–81.

    CAS  PubMed  Article  Google Scholar 

  77. Bipolar D, Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address drve, Bipolar D, Schizophrenia Working Group of the Psychiatric Genomics C. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell. 2018;173:1705–15.e16

    Article  CAS  Google Scholar 

  78. Fanous AH, Zhou B, Aggen SH, Bergen SE, Amdur RL, Duan J, et al. Genome-wide association study of clinical dimensions of schizophrenia: polygenic effect on disorganized symptoms. Am J Psychiatry. 2012;169:1309–17.

    PubMed  PubMed Central  Article  Google Scholar 

  79. Jonas KG, Lencz T, Li K, Malhotra AK, Perlman G, Fochtmann LJ, et al. Schizophrenia polygenic risk score and 20-year course of illness in psychotic disorders. Transl Psychiatry. 2019;9:300.

    PubMed  PubMed Central  Article  Google Scholar 

  80. Meier SM, Agerbo E, Maier R, Pedersen CB, Lang M, Grove J, et al. High loading of polygenic risk in cases with chronic schizophrenia. Mol Psychiatry. 2016;21:969–74.

    CAS  PubMed  Article  Google Scholar 

  81. Landi I, Kaji DA, Cotter L, Van Vleck T, Belbin G, Preuss M, et al. Prognostic value of polygenic risk scores for adults with psychosis. Nat Med. 2021;27:1576–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Frank J, Lang M, Witt SH, Strohmaier J, Rujescu D, Cichon S, et al. Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients. Mol Psychiatry. 2015;20:150–1.

    CAS  PubMed  Article  Google Scholar 

  83. Kowalec K, Lu Y, Sariaslan A, Song J, Ploner A, Dalman C, et al. Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish National Register and Genomic Study. Mol Psychiatry. 2021;26:4487–95.

    PubMed  Article  CAS  Google Scholar 

  84. Legge SE, Dennison CA, Pardinas AF, Rees E, Lynham AJ, Hopkins L, et al. Clinical indicators of treatment-resistant psychosis. Br J Psychiatry. 2020;216:259–66.

    PubMed  Article  Google Scholar 

  85. Dickinson D, Zaidman SR, Giangrande EJ, Eisenberg DP, Gregory MD, Berman KF. Distinct polygenic score profiles in schizophrenia subgroups with different trajectories of cognitive development. Am J Psychiatry. 2020;177:298–307.

    PubMed  Article  Google Scholar 

  86. Richards AL, Pardinas AF, Frizzati A, Tansey KE, Lynham AJ, Holmans P, et al. The relationship between polygenic risk scores and cognition in schizophrenia. Schizophr Bull. 2020;46:336–44.

    PubMed  Google Scholar 

  87. Ohi K, Nishizawa D, Sugiyama S, Takai K, Kuramitsu A, Hasegawa J, et al. Polygenic risk scores differentiating schizophrenia from bipolar disorder are associated with premorbid intelligence in schizophrenia patients and healthy subjects. Int J Neuropsychopharmacol. 2021;24:562–69.

    PubMed  PubMed Central  Article  Google Scholar 

  88. Pardinas AF, Smart SE, Willcocks IR, Holmans PA, Dennison CA, Lynham AJ, et al. Interaction testing and polygenic risk scoring to estimate the association of common genetic variants with treatment resistance in schizophrenia. JAMA Psychiatry. 2022;79:260–9.

    PubMed  Article  Google Scholar 

  89. Harrisberger F, Smieskova R, Vogler C, Egli T, Schmidt A, Lenz C, et al. Impact of polygenic schizophrenia-related risk and hippocampal volumes on the onset of psychosis. Transl Psychiatry. 2016;6:e868.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Cao H, Zhou H, Cannon TD. Functional connectome-wide associations of schizophrenia polygenic risk. Mol Psychiatry. 2021;26:2553–61.

    PubMed  Article  Google Scholar 

  91. Bergen SE, Ploner A, Howrigan D, O’Donovan MC, Smoller JW, Sullivan PF, et al. Joint contributions of rare copy number variants and common SNPs to risk for schizophrenia. Am J Psychiatry. 2019;176:29–35.

    PubMed  Article  Google Scholar 

  92. Taniguchi S, Ninomiya K, Kushima I, Saito T, Shimasaki A, Sakusabe T, et al. Polygenic risk scores in schizophrenia with clinically significant copy number variants. Psychiatry Clin Neurosci. 2020;74:35–39.

    CAS  PubMed  Article  Google Scholar 

  93. Logsdon GA, Vollger MR, Eichler EE. Long-read human genome sequencing and its applications. Nat Rev Genet. 2020;21:597–614.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Song JHT, Lowe CB, Kingsley DM. Characterization of a human-specific tandem repeat associated with bipolar disorder and schizophrenia. Am J Hum Genet. 2018;103:421–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Nakazawa T Modeling schizophrenia with iPS cell technology and disease mouse models. Neuroscience Research. 2021.

  96. Chiaradia I, Lancaster MA. Brain organoids for the study of human neurobiology at the interface of in vitro and in vivo. Nat Neurosci. 2020;23:1496–508.

    CAS  PubMed  Article  Google Scholar 

  97. Sanchez-Roige S, Palmer AA. Emerging phenotyping strategies will advance our understanding of psychiatric genetics. Nat Neurosci. 2020;23:475–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Sullivan PF, Owen MJ. Increasing the clinical psychiatric knowledge base about pathogenic copy number variation. Am J Psychiatry. 2020;177:204–09.

    PubMed  PubMed Central  Article  Google Scholar 

  99. Hayashi Y, Kushima I, Aleksic B, Senaha T, Ozaki N. Variable psychiatric manifestations in patients with 16p11.2 duplication: a case series of 4 patients. Psychiatry Clin Neurosci. 2022;76:86–88.

    CAS  PubMed  Article  Google Scholar 

  100. Nawa Y, Kushima I, Aleksic B, Yamamoto M, Kimura H, Banno M, et al. Treatment-resistant schizophrenia in patients with 3q29 deletion: a case series of four patients. Psychiatry Clin Neurosci. 2022;76:338–9.

    PubMed  Article  Google Scholar 

  101. Kushima I, Uematsu M, Ishizuka K, Aleksic B, Ozaki N. Psychiatric patients with a de novo 17q12 deletion: Two case reports. Psychiatry Clin Neurosci. 2022;76:345–7.

    PubMed  Article  Google Scholar 

  102. Sullivan PF, Agrawal A, Bulik CM, Andreassen OA, Børglum AD, Breen G, et al. Psychiatric genomics: an update and an agenda. Am J Psychiatry. 2018;175:15–27.

    PubMed  Article  Google Scholar 

  103. Skene NG, Bryois J, Bakken TE, Breen G, Crowley JJ, Gaspar HA, et al. Genetic identification of brain cell types underlying schizophrenia. Nat Genet. 2018;50:825–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Li M, Santpere G, Imamura Kawasawa Y, Evgrafov OV, Gulden FO, Pochareddy S, et al. Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science. 2018;362:eaat7615.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Huckins LM, Dobbyn A, Ruderfer DM, Hoffman G, Wang W, Pardiñas AF, et al. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nat Genet. 2019;51:659–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Braff DL. The importance of endophenotypes in schizophrenia research. Schizophr Res. 2015;163:1–8.

    PubMed  Article  Google Scholar 

  107. Greenwood TA, Lazzeroni LC, Maihofer AX, Swerdlow NR, Calkins ME, Freedman R, et al. Genome-wide association of endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia (COGS) Study. JAMA Psychiatry. 2019;76:1274–84.

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Funding

This work was supported in part by research grants from the Japan Agency for Medical Research and Development (AMED) under grant numbers JP19km0405216, JP21wm0425007, JP21dm0207075, JP21dk0307103, JP21ak0101113, JP22dk0307113, and JP22tm0424222; and the Japan Society for the Promotion of Science (JSPS) KAKENHI under grant numbers 20K20602, 21H04815, 21H02848, 21K20866, and 22K15748.

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HK, HK, IK and NT wrote the article. BA and ON reviewed and edited the manuscript before submission.

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Correspondence to Branko Aleksic.

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HK, HK, IK, NT and BA declare no competing interest. NO has received research support or speakers’ honoraria from, or has served as a joint researcher with, or a consultant to, Sumitomo Dainippon, Eisai, Otsuka, KAITEKI, Mitsubishi Tanabe, Shionogi, Eli Lilly, Mochida, DAIICHI SANKYO, TSUMURA, Takeda, Meiji Seika Pharma, Kyowa, EA Pharma, Viatris, Kyowa Kirin, MSD, Janssen, Yoshitomi, Ricoh, Taisho, and Nippon Boehringer Ingelheim outside the submitted work.

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Kato, H., Kimura, H., Kushima, I. et al. The genetic architecture of schizophrenia: review of large-scale genetic studies. J Hum Genet (2022). https://doi.org/10.1038/s10038-022-01059-4

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