title: Evidence of an epistatic effect between Dysbindin-1 and Neuritin-1 genes on the risk for schizophrenia spectrum disorders.
abstract: 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.
  
  
  
  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).
  
  
  
  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).
  
  
  
  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.
authors.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.
authors.forename: C
authors.initials: C
authors.lastname: Prats
authors.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.
authors.forename: B
authors.initials: B
authors.lastname: Arias
authors.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.
authors.forename: J
authors.initials: J
authors.lastname: Moya-Higueras
authors.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.
authors.forename: E
authors.initials: E
authors.lastname: Pomarol-Clotet
authors.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.
authors.forename: M
authors.initials: M
authors.lastname: Parellada
authors.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.
authors.forename: A
authors.initials: A
authors.lastname: González-Pinto
authors.affiliation: Servicio de Psiquiatría, Complejo Hospitalario de Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Peralta
authors.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.
authors.forename: M I
authors.initials: MI
authors.lastname: Ibáñez
authors.affiliation: Adolescent Unit, CASM Benito Menni, Sant Boi de Llobregat, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Martín
authors.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.
authors.forename: L
authors.initials: L
authors.lastname: Fañanás
authors.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. Electronic address: mar.fatjovilas@ub.edu.
authors.forename: M
authors.initials: M
authors.lastname: Fatjó-Vilas
mesh_terms: D000328:Adult; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics; D000074765:Dysbindin / Q000235:genetics*; D049029:Dystrophin-Associated Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020890:Neuregulin-1 / Q000235:genetics*; D009473:Neuronal Plasticity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; C094131:NRG1 protein, human; D020890:Neuregulin-1
keywords: DTNBP1; Epistatic effect; NRN1; Schizophrenia-spectrum disorders (SSD)