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Evidence of an Epistatic Effect Between Dysbindin-1 and Neuritin-1 Genes on the Risk for Schizophrenia Spectrum Disorders

Published online by Cambridge University Press:  14 November 2016

C. Prats ,
B. Arias ,
J. Moya-Higueras ,
E. Pomarol-Clotet ,
M. Parellada ,
A. González-Pinto ,
V. Peralta ,
M.I. Ibáñez ,
M. Martín  and
L. Fañanás
...Show all authors
C. Prats
Affiliation:
Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals. Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
B. Arias
Affiliation:
Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals. Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
J. Moya-Higueras
Affiliation:
Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain Department of Psychology, Faculty of Education, Psychology and Social Work, University of Lleida, Spain
E. Pomarol-Clotet
Affiliation:
Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain
M. Parellada
Affiliation:
Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain Servicio de Psiquiatría del Niño y del Adolescente, Hospital General Universitario Gregorio Marañón, Madrid, Spain Instituto de Investigación Sanitaria del Hospital Gregorio Marañón (IiSGM), Madrid, Spain Departamento de Psiquiatría, Facultad de Medicina, Universidad Complutense, Madrid, Spain
A. González-Pinto
Affiliation:
Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain BIOARABA Health Research Institute, OSI Araba, University Hospital, Psychiatry Service, University of the Basque Country (EHU/UPV), Vitoria, Spain
V. Peralta
Affiliation:
Servicio de Psiquiatría, Complejo Hospitalario de Navarra, Pamplona, Spain Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
M.I. Ibáñez
Affiliation:
Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain Department of Basic and Clinical Psychology and Psychobiology, Universitat Jaume I, Castelló, Spain
M. Martín
Affiliation:
Adolescent Unit, CASM Benito Menni, Sant Boi de Llobregat, Spain
L. Fañanás
Affiliation:
Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals. Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
M. Fatjó-Vilas*
Affiliation:
Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals. Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain
*
* Corresponding author. at: Secció Zoologia i Antropologia Biológica, Facultat de Biologia, Universitat de Barcelona, Av Diagonal 643, 08028 Barcelona, Spain; FIDMAG Germanes Hospitaláries Research Foundation, Av Jordá 8, 08035 Barcelona, Spain. Tel.: +34 936 529 999x1490. E-mail address:[email protected], [email protected] (M. Fatjó-Vilas).
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Abstract

Background

The interest in studying gene–gene interactions is increasing for psychiatric diseases such as schizophrenia-spectrum disorders (SSD), where multiple genes are involved. Dysbindin-1 (DTNBP1) and Neuritin-1 (NRN1) genes have been previously associated with SSD and both are involved in synaptic plasticity. We aimed to study whether these genes show an epistatic effect on the risk for SSD.

Methods

The sample comprised 388 SSD patients and 397 healthy subjects. Interaction was tested between: (i) three DTNBP1 SNPs (rs2619537, rs2743864, rs1047631) related to changes in gene expression; and (ii) an haplotype in NRN1 previously associated with the risk for SSD (rs645649-rs582262: HAP-risk C-C).

Results

An interaction between DTNBP1 rs2743864 and NRN1 HAP-risk was detected by using the model based multifactor dimensionality reduction (MB-MDR) approach (P = 0.0049, after permutation procedure), meaning that the risk for SSD is significantly higher in those subjects carrying both the A allele of rs2743864 and the HAP-risk C-C. This interaction was confirmed by using a logistic regression model (P = 0.033, OR (95%CI) = 2.699 (1.08–6.71), R2 = 0.162).

Discussion

Our results suggest that DTNBP1 and NRN1 genes show a joint effect on the risk for SSD. Although the precise mechanism underlying this effect is unclear, the fact that these genes have been involved in synaptic maturation, connectivity and glutamate signalling suggests that our findings could be of value as a link to the schizophrenia aetiology.

Keywords

Schizophrenia-spectrum disorders (SSD)Epistatic effectDTNBP1NRN1
Type
Original article
Information
European Psychiatry , Volume 40 , February 2017 , pp. 60 - 64
Copyright
Copyright © Elsevier Masson SAS 2017

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References

Cordell, H.J.Detecting gene–gene interactions that underlie human diseases. Nat Rev Genet 2009; 10: 392–404http://dx.doi.org/10.1038/nrg2579CrossRefGoogle ScholarPubMed
Hall, J.Trent, S.Thomas, K.L.O’Donovan, M.C.Owen, M.J.Genetic risk for schizophrenia: convergence on synaptic pathways involved in plasticity. Biol Psychiatry 2015; 77: 52–58http://dx.doi.org/10.1016/j.biopsych.2014.07.011CrossRefGoogle ScholarPubMed
Dickman, D.K.Davis, G.W.The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis. Science 2009; 326: 1127–1130http://dx.doi.org/10.1126/science.1179685CrossRefGoogle ScholarPubMed
Chen, X.W.Feng, Y.Q.Hao, C.J.Guo, X.L.He, X.Zhou, Z.Y.et al.DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release. J Cell Biol 2008; 181: 791–801http://dx.doi.org/10.1083/jcb.200711021CrossRefGoogle ScholarPubMed
Numakawa, T.Yagasaki, Y.Ishimoto, T.Okada, T.Suzuki, T.Iwata, N.et al.Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 2004; 13: 2699–2708http://dx.doi.org/10.1093/hmg/ddh280CrossRefGoogle Scholar
Talbot, K.Eidem, W.L.Tinsley, C.L.Benson, M.A.Thompson, E.W.Smith, R.J.et al.Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 2004; 113: 1353–1363http://dx.doi.org/10.1172/JCI20425CrossRefGoogle Scholar
Weickert, C.S.Straub, R.E.McClintock, B.W.Matsumoto, M.Hashimoto, R.Hyde, T.M.et al.Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 2004; 61: 544–555http://dx.doi.org/10.1001/archpsyc.61.6.544CrossRefGoogle ScholarPubMed
Kumamoto, N.Matsuzaki, S.Inoue, K.Hattori, T.Shimizu, S.Hashimoto, R.et al.Hyperactivation of midbrain dopaminergic system in schizophrenia could be attributed to the down-regulation of dysbindin. Biochem Biophys Res Commun 2006; 345: 904–909http://dx.doi.org/10.1016/j.bbrc.2006.04.163CrossRefGoogle ScholarPubMed
Weickert, C.S.Straub, R.E.McClintock, B.W.Matsumoto, M.Hashimoto, R.Hyde, T.M.et al.Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 2004; 61: 544–555http://dx.doi.org/10.1016/S0084-3970(08)70270-6CrossRefGoogle ScholarPubMed
Bray, N.J.Preece, A.Williams, N.M.Moskvina, V.Buckland, P.R.Owen, M.J.et al.Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 2005; 14: 1947–1954http://dx.doi.org/10.1093/hmg/ddi199CrossRefGoogle ScholarPubMed
Straub, R.E.Jiang, Y.MacLean, C.J.Ma, Y.Webb, B.T.Myakishev, M.V.et al.Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002; 71: 337–348http://dx.doi.org/10.1086/341750CrossRefGoogle ScholarPubMed
Fatjó-Vilas, M.Papiol, S.Estrada, G.Bombín, I.Peralta, V.Rosa, A.et al.Dysbindin-1 gene contributes differentially to early- and adult-onset forms of functional psychosis. Am J Med Genet B: Neuropsychiatr Genet 2011; 156: 322–333http://dx.doi.org/10.1002/ajmg.b.31166CrossRefGoogle Scholar
Riley, B.Kuo, P.-H.Maher, B.S.Fanous, A.H.Sun, J.Wormley, B.et al.The dystrobrevin binding protein 1 (DTNBP1) gene is associated with schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample. Schizophr Res 2009; 115: 245–253http://dx.doi.org/10.1016/j.schres.2009.09.008CrossRefGoogle ScholarPubMed
Schwab, S.G.Albus, M.Hallmayer, J.Hönig, S.Borrmann, M.Lichtermann, D.et al.Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis. Nat Genet 1995; 11: 325–327http://dx.doi.org/10.1038/ng1195-325CrossRefGoogle ScholarPubMed
Straub, R.E.MacLean, C.J.O’Neill, F.A.Burke, J.Murphy, B.Duke, F.et al.A potential vulnerability locus for schizophrenia on chromosome 6p24-22: evidence for genetic heterogeneity. Nat Genet 1995; 11: 287–293http://dx.doi.org/10.1038/ng1195-287CrossRefGoogle ScholarPubMed
Posthuma, D.Luciano, M.Geus, E.J.C.deWright, M.J.Slagboom, P.E.Montgomery, G.W.et al.A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p. Am J Hum Genet 2005; 77: 318–326http://dx.doi.org/10.1086/432647CrossRefGoogle ScholarPubMed
Fujino, T.Lee, W.C.A.Nedivi, E.Regulation of cpg15 by signaling pathways that mediate synaptic plasticity. Mol Cell Neurosci 2003; 24: 538–554http://dx.doi.org/10.1016/S1044-7431(03)00230-6CrossRefGoogle ScholarPubMed
Naeve, G.S.Ramakrishnan, M.Kramer, R.Hevroni, D.Citri, Y.Theill, L.E.Neuritin: a gene induced by neural activity and neurotrophins that promotes neuritogenesis. Proc Natl Acad Sci U S A 1997; 94: 2648–2653http://dx.doi.org/10.1073/pnas.94.6.2648CrossRefGoogle ScholarPubMed
Zhou, S.Zhou, J.Neuritin, a neurotrophic factor in nervous system physiology. Curr Med Chem 2014; 21: 1212–1219http://dx.doi.org/_pii:CMC-EPUB-58119CrossRefGoogle ScholarPubMed
Loebrich, S.Nedivi, E.The function of activity-regulated genes in the nervous system. Physiol Rev 2009; 89: 1079–1103http://dx.doi.org/10.1152/physrev.00013.2009CrossRefGoogle ScholarPubMed
Chandler, D.Dragović, M.Cooper, M.Badcock, J.C.Mullin, B.H.Faulkner, D.et al.Impact of Neuritin 1 (NRN1) polymorphisms on fluid intelligence in schizophrenia. Am J Med Genet B: Neuropsychiatr Genet 153B 2010 428–437 10.1002/ajmg.b.30996CrossRefGoogle Scholar
Fatjó-Vilas, M.Prats, C.Pomarol-Clotet, E.Lázaro, L.Moreno, C.González-Ortega, I.et al.Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning. World J Biol Psychiatry 2016; 17: 129–139http://dx.doi.org/10.3109/15622975.2015.1093658CrossRefGoogle ScholarPubMed
Sodhi, M.Wood, K.H.Meador-Woodruff, J.Role of glutamate in schizophrenia: integrating excitatory avenues of research. Expert Rev Neurother 2008; 8: 1389–1406http://dx.doi.org/10.1586/14737175.8.9.1389CrossRefGoogle ScholarPubMed
Bernstein, B.E.Birney, E.Dunham, I.Green, E.D.Gunter, C.Snyder, M.An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57–74http://dx.doi.org/10.1038/nature11247Google Scholar
Calle, M.L.Urrea, V.Malats, N.van Steen, K.Mbmdr: an R package for exploring gene–gene interactions associated with binary or quantitative traits. Bioinformatics 2010; 26: 2198–2199http://dx.doi.org/10.1093/bioinformatics/btq352CrossRefGoogle ScholarPubMed
Lee, S.-Y.Chen, S.-L.Wang, Y.-S.Chang, Y.-H.Huang, S.-Y.Tzeng, N.-S.et al.COMT and BDNF interacted in bipolar II disorder not comorbid with anxiety disorder. Behav Brain Res 2013; 237: 243–248http://dx.doi.org/10.1016/j.bbr.2012.09.039CrossRefGoogle Scholar
Edwards, T.L.Wang, X.Chen, Q.Wormly, B.Riley, B.O’Neill, F.A.et al.Interaction between interleukin 3 and dystrobrevin-binding protein 1 in schizophrenia. Schizophr Res 2008; 106: 208–217http://dx.doi.org/10.1016/j.schres.2008.07.022CrossRefGoogle Scholar
Vilella, E.Costas, J.Sanjuan, J.Guitart, M.De Diego, Y.Carracedo, A.et al.Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction. J Psychiatr Res 2008; 42: 278–288http://dx.doi.org/10.1016/j.jpsychires.2007.02.005CrossRefGoogle Scholar
Li, Z.Zhang, Y.Wang, Z.Chen, J.Fan, J.Guan, Y.et al.The role of BDNF, NTRK2 gene and their interaction in development of treatment-resistant depression: data from multicenter, prospective, longitudinal clinic practice. J Psychiatr Res 2013; 47: 8–14http://dx.doi.org/10.1016/j.jpsychires.2012.10.003CrossRefGoogle ScholarPubMed
Berg, T.Modulation of protein–protein interactions with small organic molecules. Angew Chem Int Ed Engl 2003; 42: 2462–2481http://dx.doi.org/10.1002/anie.200200558CrossRefGoogle ScholarPubMed
Nicodemus, K.K.Callicott, J.H.Higier, R.G.Luna, A.Nixon, D.C.Lipska, B.K.et al.Evidence of statistical epistasis between DISC1, CIT and NDEL1 impacting risk for schizophrenia: biological validation with functional neuroimaging. Hum Genet 2010; 127: 441–452http://dx.doi.org/10.1007/s00439-009-0782-yCrossRefGoogle ScholarPubMed
Tan, H.Y.Chen a, G.Chen, Q.Browne, L.B.Verchinski, B.Kolachana, B.et al.Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications. Mol Psychiatry 2012; 17: 1007–1016http://dx.doi.org/10.1038/mp.2011.91CrossRefGoogle ScholarPubMed
Moore, J.H.Williams, S.M.Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis. Bioessays 2005; 27: 637–646http://dx.doi.org/10.1002/bies.20236CrossRefGoogle Scholar
Williams, N.M.O’Donovan, M.C.Owen, M.J.Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia?. Schizophr Bull 2005; 31: 800–805http://dx.doi.org/10.1093/schbul/sbi061CrossRefGoogle Scholar
Wang, S.Zhao, H.Sample size needed to detect gene–gene interactions using association designs. Am J Epidemiol 2003; 158: 899–914http://dx.doi.org/10.1093/aje/kwg233CrossRefGoogle ScholarPubMed
Weickert, C.S.Rothmond, D.A.Hyde, T.M.Kleinman, J.E.Straub, R.E.Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr Res 2008; 98: 105–110http://dx.doi.org/10.1016/j.schres.2007.05.041CrossRefGoogle ScholarPubMed
McClelland, G.H.Judd, C.M.Statistical difficulties of detecting interactions and moderator effects. Psychol Bull 1993; 114: 376–390http://dx.doi.org/10.1037/0033-2909.114.2.376CrossRefGoogle ScholarPubMed
Ken-Dror, G.Humphries, S.E.Drenos, F.The use of haplotypes in the identification of interaction between SNPs. Hum Hered 2013; 75: 44–51http://dx.doi.org/10.1159/000350964CrossRefGoogle ScholarPubMed
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