Epistatic and independent effects on schizophrenia-related phenotypes following co-disruption of the risk factors neuregulin-1 × DISC1
Open accessAbstract
Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1.
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Ngr1 HET / Disc1 HOM mutant mice exhibited decreased sociability and increased self-grooming behaviour, accompanied by increased expression of OXT in the hypothalamus.
“The Nrg1 heterozygous/ Disc1 homozygous ( Ngr1 HET / Disc1 HOM ) mutant mice exhibited decreased sociability and increased self-grooming behaviour, accompanied by increased expression of OXT in the hypo thalamus.”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as O'Tuathaigh et al., 2017
The Social Interaction section reports disrupted sociability in NRG1 HET/DISC1 HOM mice, but increased self-grooming specifically in males. The Hypothalamic Expression section reports that NRG1 co-disruption reversed a reduction in oxytocin mRNA in male DISC1 HOM mice; it does not establish increased expression relative to wild-type mice. The claim omits these sex and comparison qualifiers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNo significant changes were found in the levels of DA and its associated metabolites in the PFC and hippocampus.
“However, no significant changes were found in the levels of DA and its associated metabolites (i.e., 3,4-dihydroxyphenylacetic acid and homovanillic acid) in the PFC and hippocampus.”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as O'Tuathaigh et al., 2017
Ngr1 HET / Disc1 HOM mice showed lower striatal D2R expression, an essential component of DA signalling.
“In addition, Ngr1 HET / Disc1 HOM mice showed lower striatal D2R expression, an essential component of DA signalling.”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as O'Tuathaigh et al., 2017
The phenotypes of Nrg1 and Disc1 mutant mice were characterised.
“The phenotypes of Neuregulin-1 ( Nrg1 ) and Disrupted-in-schizophrenia 1 ( Disc1 ) mutant mice -both genes associ ated with schizophrenia- were characterised (O ' Tuathaigh et al., 2017).”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as O'Tuathaigh et al., 2017
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Cites
Fabbri, M., Garzon, R., Cimmino, A., Liu, Z., Zanesi, N. A. O., Callegari, E., Liu, S., Alder, H., Costinean, S., Fernandez-Cymering, C., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707628104 · Cited by 1,676 · see citing works
Neuregulin 1 and Susceptibility to Schizophrenia
Stefánsson, H., Pétursson, H., Sigurðsson, E., Steinthórsdóttir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/342734 · Cited by 1,671 · see citing works
Self-citationDe novo mutations in schizophrenia implicate synaptic networks
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., et al. (2014) · Nature · doi:10.1038/nature12929 · Cited by 1,617 · see citing works
Genome-wide association analysis identifies 13 new risk loci for schizophrenia
Multicenter Genetic Studies of Schizophrenia Consortium, Ripke, S., Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, O'Dushlaine, C., Chambert, K., Moran, J. L., Kähler, A. K., Akterin, S., Bergen, S. E., et al. (2013) · Nature Genetics · doi:10.1038/ng.2742 · Cited by 1,496 · see citing works
Genetic architectures of psychiatric disorders: the emerging picture and its implications
Sullivan, P. F., Daly, M. J., & O'Donovan, M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3240 · Cited by 1,177 · see citing works
Neuregulin 1 in neural development, synaptic plasticity and schizophrenia
Mei, L., & Xiong, W.-C. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2392 · Cited by 1,030 · see citing works
Neumann, I. D., & Landgraf, R. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.08.004 · Cited by 954 · see citing works
Behavioral phenotypes of Disc1 missense mutations in mice
Clapcote, S. J., Lipina, T. V., Millar, J. K., Mackie, S., Christie, S., Ogawa, F., Lerch, J. P., Trimble, K., Uchiyama, M., Sakuraba, Y., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.04.015 · Cited by 526 · see citing works
Perkins, D. O., Jeffries, C. D., Jarskog, L. F., Thomson, J. M., Woods, K., Newman, M. A., Parker, J. S., Jin, J., & Hammond, S. M. (2007) · Genome Biology · doi:10.1186/gb-2007-8-2-r27 · Cited by 479 · see citing works
Linking neurodevelopmental and synaptic theories of mental illness through DISC1
Brandon, N. J., & Sawa, A. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3120 · Cited by 422 · see citing works
Swerdlow, N. R., Light, G. A., Cadenhead, K. S., Sprock, J., Hsieh, M. H., & Braff, D. L. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.12.1325 · Cited by 339 · see citing works
Brigman, J. L., Wright, T., Talani, G., Prasad-Mulcare, S., Jinde, S., Seabold, G. K., Mathur, P., Davis, M. I., Bock, R., Gustin, R. M., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.0640-10.2010 · Cited by 339 · see citing works
Central vasopressin and oxytocin release: regulation of complex social behaviours
VEENEMA, A., & NEUMANN, I. (2008) · Progress in Brain Research · doi:10.1016/s0079-6123(08)00422-6 · Cited by 338 · see citing works
Jaaro-Peled, H., Hayashi‐Takagi, A., Seshadri, S., Kamiya, A., Brandon, N. J., & Sawa, A. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.05.007 · Cited by 315 · see citing works
European Network of National Networks studying Gene-Environment Interactions in Schizophrenia (EU-GEI) (2014) · Schizophrenia Bulletin · doi:10.1093/schbul/sbu069 · Cited by 258 · see citing works
NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia
Snyder, M. A., & Gao, W. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00031 · Cited by 237 · see citing works
Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia
Weickert, C. S., Fung, S. J., Catts, V. S., Schofield, P. R., Allen, K. M., Moore, L., Newell, K. A., Pellen, D., Huang, X.-F., Catts, S. V., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.137 · Cited by 234 · see citing works
Are There Sex Differences in Neuropsychological Functions Among Patients With Schizophrenia?
Goldstein, J. M., Seidman, L. J., Goodman, J. M., Koren, D., Lee, H., Weıntraub, S., & Tsuang, M. T. (1998) · American Journal of Psychiatry · doi:10.1176/ajp.155.10.1358 · Cited by 227 · see citing works
Differential expression of ARIA isoforms in the rat brain
Corfas, G., Rosen, K. M., Aratake, H., Krauss, R., & Fischbach, G. D. (1995) · Neuron · doi:10.1016/0896-6273(95)90244-9 · Cited by 221 · see citing works
Schneider, M., Schömig, E., & Leweke, F. M. (2008) · Addiction Biology · doi:10.1111/j.1369-1600.2008.00117.x · Cited by 189 · see citing works
Prévot, V., Río, C., Cho, G. J., et al. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-01-00230.2003 · Cited by 177 · see citing works
Law, A. J., Wang, Y., Sei, Y., O’Donnell, P., Piantadosi, P., Papaleo, F., Straub, R. E., Huang, W., Thomas, C. J., Vakkalanka, R., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206118109 · Cited by 147 · see citing works
Gender differences in cognitive function of patients with chronic schizophrenia.
Han, M., Huang, X.-F., Chen, D.-C., Xiu, M. H., Hui, L., Liu, H., Kosten, T., & Zhang, X.-Y. (2012) · Progress in Neuro-psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.07.010 · Cited by 145 · see citing works
The emerging role of microRNAs in schizophrenia and autism spectrum disorders
Mellios, N., & Sur, M. (2012) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2012.00039 · Cited by 120 · see citing works
Seshadri, S., Kamiya, A., Yokota, Y., Prikulis, I., Kano, S., Hayashi‐Takagi, A., Stanco, A., Eom, T.-Y., Rao, S., Ishizuka, K., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909284107 · Cited by 108 · see citing works
Mouse models of genetic effects on cognition: Relevance to schizophrenia
Papaleo, F., Lipska, B. K., & Weinberger, D. R. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.04.025 · Cited by 104 · see citing works
Murakami, G., Hunter, R. G., Fontaine, C., Ribeiro, A., & Pfaff, D. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07761.x · Cited by 99 · see citing works
Genetic and pharmacological evidence for schizophrenia‐related Disc1 interaction with GSK‐3
Lipina, T. V., Kaidanovich‐Beilin, O., Patel, S., Wang, M., Clapcote, S. J., Liu, F., Woodgett, J. R., & Roder, J. (2010) · Synapse · doi:10.1002/syn.20839 · Cited by 91 · see citing works
Perez, S., & Lodge, D. (2013) · Molecular Psychiatry · doi:10.1038/mp.2013.111 · Cited by 87 · see citing works
Cognition in Mouse Models of Schizophrenia Susceptibility Genes
Arguello, P. A., & Gogos, J. A. (2009) · Schizophrenia Bulletin · doi:10.1093/schbul/sbp153 · Cited by 84 · see citing works
Lee, M. R., Wehring, H. J., McMahon, R. P., Linthicum, J., Cascella, N., Liu, F., Bellack, A., Buchanan, R. W., Strauss, G. P., Contoreggi, C., et al. (2013) · Schizophrenia Research · doi:10.1016/j.schres.2013.01.001 · Cited by 80 · see citing works
Duncan, G. E., Moy, S. S., Lieberman, J. A., & Koller, B. H. (2005) · Psychopharmacology · doi:10.1007/s00213-005-0214-1 · Cited by 78 · see citing works
Porteous, D. J., Thomson, P. A., Millar, J. K., Evans, K. L., Hennah, W., Soares, D. C., McCarthy, S., McCombie, W. R., Clapcote, S. J., Korth, C., et al. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.160 · Cited by 66 · see citing works
Seshadri, S., Faust, T. E., Ishizuka, K., Delevich, K. M., Chung, Y., Kim, S.-H., Cowles, M. W., Niwa, M., Jaaro-Peled, H., Tomoda, T., et al. (2015) · Nature Communications · doi:10.1038/ncomms10118 · Cited by 66 · see citing works
Mata, I. F., Pérez‐Iglesias, R., Roiz‐Santiáñez, R., Tordesillas‐Gutiérrez, D., González‐Mandly, A., Berja, A., Vázquez‐Barquero, J. L., & Crespo‐Facorro, B. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.11.010 · Cited by 47 · see citing works
Nicodemus, K. K., Hargreaves, A., Morris, D. W., Anney, R., Gill, M., Corvin, A. P., & Donohoe, G. J. (2014) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2014.528 · Cited by 36 · see citing works
Kirby, B. P., Waddington, J. L., & O’Tuathaigh, C. M. P. (2009) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2009.09.010 · Cited by 35 · see citing works
Self-citationFrontal cortical synaptic communication is abnormal in Disc1 genetic mouse models of schizophrenia
Holley, S. M., Wang, E. A., Cepeda, C., Jentsch, J. D., Ross, C. A., Pletnikov, M. V., & Levine, M. S. (2013) · Schizophrenia Research · doi:10.1016/j.schres.2013.02.007 · Cited by 29 · see citing works
Sex-specific neuroendocrine and behavioral phenotypes in hypomorphic Type II Neuregulin 1 rats
Taylor, S. B., Markham, J. A., Taylor, A. R., Kanaskie, B. Z., & Koenig, J. I. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.05.008 · Cited by 25 · see citing works
MicroRNAs: A Novel Therapeutic Target for Schizophrenia
Bravo, J. A., & Dinan, T. G. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795049543 · Cited by 15 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 10
- Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia- associated genetic loci. Nature. 2014;511:421-427.
- Harrison PJ. Recent genetic findings in schizophrenia and their therapeutic relevance. J Psychopharmacol. 2015;29:85-96.
- Lee SH, DeCandia TR, Ripke S, et al. Estimating the propor- tion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet. 2012;44:247-250. Downloaded from https://academic.oup.com/schizophreniabulletin/article-abstract/43/1/214/2503733/Epistatic-and-Independent-Effects-on-Schizophrenia by Università degli Studi di Milano -Dip. Storia arti, musica e spettacolo user on 07 September 2017
- C. M. P. O'Tuathaigh et al 8. Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability: Genetic interactions create phantom her- itability. Proc Natl Acad Sci U S A. 2012;109:1193-1198.
- Kannan G, Sawa A, Pletnikov MV. Mouse models of gene- environment interactions in schizophrenia. Neurobiol Dis. 2013;57:5-11.
- Sams-Dodd F. Distinct effects of d-amphetamine and phen- cyclidine on the social behaviour of rats. Behav Pharmacol. 1995;6:55-65.
- Deacon RM. Assessing nest building in mice. Nat Protoc. 2006;1:1117-1119.
- Shoji H, Toyama K, Takamiya Y, Wakana S, Gondo Y, Miyakawa T. Comprehensive behavioral analysis of ENU- induced Disc1-Q31L and -L100P mutant mice. BMC Res Notes. 2012;5:108.
- Hill RA. Sex differences in animal models of schizophre- nia shed light on the underlying pathophysiology. Neurosci Biobehav Rev. 2016;67:41-56.
- Owen MJ. New approaches to psychiatric classification. Neuron. 2014;84:564-571.
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Self-citationRappeneau, V., & Castillo Díaz, F. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105675 · Cited by 51 · see citing works
“The phenotypes of Neuregulin-1 ( Nrg1 ) and Disrupted-in-schizophrenia 1 ( Disc1 ) mutant mice -both genes associated with schizophrenia-were characterised (O ’ Tuathaigh et al., 2017).”
Background
- Authors
- O’Tuathaigh, C. M. P., Fumagalli, F., Desbonnet, L., Perez-Branguli, F., Moloney, G., Loftus, S., O’Leary, C., Petit, E., Cox, R., Tighe, O., Clarke, G., Lai, D., Harvey, R. P., Cryan, J. F., Mitchell, K. J., Dinan, T. G., Riva, M. A., & Waddington, J. L.
- Affiliations
- Royal College of Surgeons in Ireland (IE)
- University of Milan (IT)
- University College Cork (IE)
- Smurfit Institute of Genetics, Trinity College Dublin 5 , Dublin 2 , Ireland ;
- Victor Chang Cardiac Research Institute (AU)
- Trinity College Dublin (IE)
- ORCID
- Venue
- Schizophrenia Bulletin
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-09-09
- Volume
- 43
- Issue
- 1
- Pages
- 214-225
- ISSN
- 0586-7614 (ISSN-L)
- 1745-1701
- PMC
- PMC5216856
- OpenAlex
- W2513513402
- Cited by
- 22
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 4 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 2
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Schizophrenia Bulletin (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, cc-by-nc-sa)
- Funders
- Science Foundation Ireland (07/IN.1/B960, SFI/12/RC/2273, 02/CE/B124, 07/CE/B1368)
- Health Research Board of Ireland Postdoctoral Fellowship (PD/2007/20)
- The Alimentary Pharmabiotic Centre is a research centre
- Health Research Board (HRA_POR/2011/23, HRA_POR/2012/32, HRA-POR-2014–647)
- European Community’s Seventh Framework Programme (FP7/2007–2013, 201 714, KBBE.2013.2.2-02)
- Brain and Behavior Research Foundation (20771)
- University College Cork Translational Research Access Programme
- RIKEN BRC
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- schizophrenia, epistasis
- MeSH terms
- Amphetamines, Animals, Behavior, Animal, Brain, Disease Models, Animal, Epistasis, Genetic, Female, Grooming, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Nesting Behavior, Oxytocin, Psychomotor Agitation, Psychotic Disorders, Schizophrenia, Social Behavior, Vasopressins, Mice, Knockout, Neuregulin-1, Mice, Endophenotypes, Prepulse Inhibition
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