Article | Published:

Genetic associations and expression of extra-short isoforms of disrupted-in-schizophrenia 1 in a neurocognitive subgroup of schizophrenia


Disrupted-in-schizophrenia 1 (DISC1) was reported to be associated with schizophrenia. In a previous study, we found significant association with schizophrenia patients with deficient sustained attention assessed by continuous performance test (CPT). This study aimed to identify risk polymorphisms in this specific neurocognitive subgroup and investigate the expression of different isoforms of DISC1. A total of 83 genetic variants were identified through direct sequencing in 50 controls and 100 schizophrenia patients. Fourteen variants were genotyped in 600 controls and 912 patients. Patients were subgrouped by familial loading (multiplex or simplex) and performance on CPT. The frequency of AA genotype of rs11122324 at the 3′-UTR of Es and Esv1 isoforms and of rs2793091 at intron 4 were significantly higher in multiplex schizophrenia patients than those in controls (corrected p < 0.05). In further subgrouping, the frequency of AA genotype of the two SNPs were significantly higher in multiplex schizophrenia patients with deficient sustained attention than those in controls (corrected p < 0.005). The mRNA expression levels of two extra-short isoforms (Es and Esv1) in the EBV-transformed lymphocytes of schizophrenia were significantly higher than those of controls. Luciferase reporter assays demonstrated that the A-allele of rs11122324 significantly upregulated DISC1 extra-short isoforms transcription compared with the G-allele. We found two SNPs (rs11122324 and rs2793091) of DISC1 may be specifically associated with multiplex schizophrenia patients with deficient sustained attention. The SNP rs11122324 may be a risk polymorphism, which may have functional influence on the transcription of Es and Esv1 through increasing their expression.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Lichtenstein P, Yip BH, Bjork C, Pawitan Y, Cannon TD, Sullivan PF, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009;373:234–9.

  2. 2.

    Hwu HG, Liu CM, Fann CS, Ou-Yang WC, Lee SF. Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatry. 2003;8:445–52.

  3. 3.

    Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R, et al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet. 2001;10:1611–7.

  4. 4.

    Millar JK, Christie S, Anderson S, Lawson D, Hsiao-Wei Loh D, Devon RS, et al. Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry. 2001;6:173–8.

  5. 5.

    Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry. 2008;13:36–64.

  6. 6.

    Mathieson I, Munafo MR, Flint J. Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Mol Psychiatry. 2012;17:634–41.

  7. 7.

    Kinoshita M, Numata S, Tajima A, Ohi K, Hashimoto R, Shimodera S, et al. Meta-analysis of association studies between DISC1 missense variants and schizophrenia in the Japanese population. Schizophr Res. 2012;141:271–3.

  8. 8.

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

  9. 9.

    Wang HY, Liu Y, Yan JW, Hu XL, Zhu DM, Xu XT, et al. Gene polymorphisms of DISC1 is associated with schizophrenia: evidence from a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:64–73.

  10. 10.

    Liu YL, Fann CS, Liu CM, Chen WJ, Wu JY, Hung SI, et al. A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1: association with impairment of sustained attention. Biol Psychiatry. 2006;60:554–62.

  11. 11.

    Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, Partonen T, et al. A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia. Mol Psychiatry. 2005;10:1097–103.

  12. 12.

    Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry. 2005;62:1205–13.

  13. 13.

    Shaikh M, Hall MH, Schulze K, Dutt A, Li K, Williams I, et al. Effect of DISC1 on the P300 waveform in psychosis. Schizophr Bull. 2011;39:161–7.

  14. 14.

    Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA. 2005;102:8627–32.

  15. 15.

    Carless MA, Glahn DC, Johnson MP, Curran JE, Bozaoglu K, Dyer TD, et al. Impact of DISC1 variation on neuroanatomical and neurocognitive phenotypes. Mol Psychiatry. 2011;16:1063.

  16. 16.

    Sprooten E, Sussmann JE, Moorhead TW, Whalley HC, Ffrench-Constant C, Blumberg HP, et al. Association of white matter integrity with genetic variation in an exonic DISC1 SNP. Mol Psychiatry. 2011;16:688–9.

  17. 17.

    Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci. 2011;12:707–22.

  18. 18.

    Ishizuka K, Kamiya A, Oh EC, Kanki H, Seshadri S, Robinson JF, et al. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature. 2011;473:92–96.

  19. 19.

    Kubo K, Tomita K, Uto A, Kuroda K, Seshadri S, Cohen J, et al. Migration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi. Biochem Biophys Res Commun. 2010;400:631–7.

  20. 20.

    Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K, et al. Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA. 2003;100:289–94.

  21. 21.

    Tsuboi D, Kuroda K, Tanaka M, Namba T, Iizuka Y, Taya S, et al. Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. Nat Neurosci. 2015;18:698–707.

  22. 22.

    Seshadri S, Faust T, Ishizuka K, Delevich K, Chung Y, Kim SH, et al. Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. Nat Commun. 2015;6:10118.

  23. 23.

    Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science. 2005;310:1187–91.

  24. 24.

    Niwa M, Cash-Padgett T, Kubo KI, Saito A, Ishii K, Sumitomo A, et al. DISC1 a key molecular lead in psychiatry and neurodevelopment: no-more disrupted-in-schizophrenia 1. Mol Psychiatry. 2016;21:1488–9.

  25. 25.

    Teng S, Thomson PA, McCarthy S, Kramer M, Muller S, Lihm J, et al. Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia. Mol Psychiatry. 2018;23:1270–7.

  26. 26.

    Tomoda T, Sumitomo A, Jaaro-Peled H, Sawa A. Utility and validity of DISC1 mouse models in biological psychiatry. Neuroscience. 2016;321:99–107.

  27. 27.

    Nakata K, Lipska BK, Hyde TM, Ye T, Newburn EN, Morita Y, et al. DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms. Proc Natl Acad Sci USA. 2009;106:15873–8.

  28. 28.

    Rastogi A, Zai C, Likhodi O, Kennedy JL, Wong AH. Genetic association and post-mortem brain mRNA analysis of DISC1 and related genes in schizophrenia. Schizophr Res. 2009;114:39–49.

  29. 29.

    Kumarasinghe N, Beveridge NJ, Gardiner E, Scott RJ, Yasawardene S, Perera A, et al. Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication. Int J Neuropsychopharmacol. 2013;16:1483–503.

  30. 30.

    Rampino A, Walker RM, Torrance HS, Anderson SM, Fazio L, Di Giorgio A, et al. Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia. PLoS ONE. 2014;9:e99892.

  31. 31.

    Dahoun T, Trossbach SV, Brandon NJ, Korth C, Howes OD. The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review. Transl Psychiatry. 2017;7:e1015.

  32. 32.

    Hwu HG, Chen CH, Hwang TJ, Liu CM, Cheng JJ, Lin SK, et al. Symptom patterns and subgrouping of schizophrenic patients: significance of negative symptoms assessed on admission. Schizophr Res. 2002;56:105–19.

  33. 33.

    Hwu HG, Faraone SV, Liu CM, Chen WJ, Liu SK, Shieh MH, et al. Taiwan schizophrenia linkage study: the field study. Am J Med Genet B Neuropsychiatr Genet. 2005;134:30–36.

  34. 34.

    Hwu HG Psychiatric diagnostic assessment. 2nd ed. Taipei: Publication Committee, College of Medicine, National Taiwan University; 1999.

  35. 35.

    Chen WJ, Hsiao CK, Hsiao LL, Hwu HG. Performance of the continuous performance test among community samples. Schizophr Bull. 1998;24:163–74.

  36. 36.

    Chang SS, Liu CM, Lin SH, Hwu HG, Hwang TJ, Liu SK, et al. Impaired flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives: the effect of genetic loading. Schizophr Bull. 2009;35:213–21.

  37. 37.

    Pan WH, Fann CS, Wu JY, Hung YT, Ho MS, Tai TH, et al. Han Chinese cell and genome bank in Taiwan: purpose, design and ethical considerations. Hum Hered. 2006;61:27–30.

  38. 38.

    Fu CL & Yang UC. ISVdb: Integrated splicing variants database. National Yang-Ming University, Taipei, Taiwan; 2004.

  39. 39.

    Chen WJ, Chang CH, Liu SK, Hwang TJ, Hwu HG. Sustained attention deficits in nonpsychotic relatives of schizophrenic patients: a recurrence risk ratio analysis. Biol Psychiatry. 2004;55:995–1000.

  40. 40.

    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.

  41. 41.

    Walker E, Shaye J. Familial schizophrenia. A predictor of neuromotor and attentional abnormalities in schizophrenia. Arch Gen Psychiatry. 1982;39:1153–6.

  42. 42.

    Sautter FJ, McDermott BE, Cornwell J, Black FW, Borges A, Johnson J, et al. Patterns of neuropsychological deficit in cases of schizophrenia spectrum disorder with and without a family history of psychosis. Psychiatry Res. 1994;54:37–49.

  43. 43.

    Lui S, Deng W, Huang X, Jiang L, Ouyang L, Borgwardt SJ, et al. Neuroanatomical differences between familial and sporadic schizophrenia and their parents: an optimized voxel-based morphometry study. Psychiatry Res. 2009;171:71–81.

  44. 44.

    Song W, Li W, Feng J, Heston LL, Scaringe WA, Sommer SS. Identification of high risk DISC1 structural variants with a 2% attributable risk for schizophrenia. Biochem Biophys Res Commun. 2008;367:700–6.

  45. 45.

    Green EK, Grozeva D, Sims R, Raybould R, Forty L, Gordon-Smith K, et al. DISC1 exon 11 rare variants found more commonly in schizoaffective spectrum cases than controls. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:490–2.

  46. 46.

    Thomson PA, Parla JS, McRae AF, Kramer M, Ramakrishnan K, Yao J, 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;19:668–75.

  47. 47.

    Kamiya A, Tomoda T, Chang J, Takaki M, Zhan C, Morita M, et al. DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Hum Mol Genet. 2006;15:3313–23.

  48. 48.

    Morris JA, Kandpal G, Ma L, Austin CP. DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet. 2003;12:1591–608.

  49. 49.

    Millar JK, James R, Christie S, Porteous DJ. Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Mol Cell Neurosci. 2005;30:477–84.

Download references


We gratefully acknowledge the sequencing performed by the National Sequencing Core Facility, National Yang-Ming University, and the SNP genotyping performed by the National Center for Genome Medicine (NCGM), Taiwan. We thank Translational Resource Center for Genomic Medicine (TRC) of National Research Program for Biopharmaceuticals (NRPB) for their service. We also thank Taiwan Han Chinese Cell and Genome Bank of Academic Sinica for their support. Assistance was provided by the Microarray and SNP Core Facility for Genomic Medicine and the Department of Medical Research, National Taiwan University Hospital, and by Branch Office of Research and Development, National Taiwan University College of Medicine.


This work was supported by the National Research Program for Genomic Medicine (NRPGM), National Science Council and Ministry of Science, Taiwan [grant number NSC 97-3112-B-002- 046-, NSC 97-2321-B-002-041-, NSC 98-and 2321-B-002-008- to HGH; NSC 97-2314-B- 400-001-MY3 and NSC 101-2325-B-400-018 to HGH and CML; MOST 103-2325-B-002-047- and MOST 104-2314-B-002-068- to CML], the National Health Research Institute, Taiwan [grant number NHRI-EX-91, 92, 93-9113PP, MD095PP14, MD096PP12, MD097PP02, MD096PP12, MD097PP14, MD096SP01, and MD097SP01 to HGH], the National Institutes of Health, USA [grant number IR01 MH 59624-01 to MTT], and National Taiwan University [grant number 97HM00271~7 to HGH and CML]. The funding sources played no role in the design of the study, the collection, analysis, or interpretation of data, or the decision to submit this manuscript for publication.

Author information

Correspondence to Chih-Min Liu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary data

Supplementary Table 2

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2