title: Influence of DAOA and RGS4 genes on the risk for psychotic disorders and their associated executive dysfunctions: A family-based study.
abstract: BACKGROUND
  Glutamatergic neurotransmission dysfunction has classically been related to the aetiology of psychotic disorders. A substantial polygenic component shared across these disorders has been reported and molecular genetics studies have associated glutamatergic-related genes, such as d-amino acid oxidase activator (DAOA) and regulator of G-protein signalling 4 (RGS4) with the risk for psychotic disorders. Our aims were to examine: (i) the relationship between DAOA and RGS4 and the risk for psychotic disorders using a family-based association approach, and (ii) whether variations in these genes are associated with differences in patients' cognitive performance.
  
  
  METHODS
  The sample comprised 753 subjects (222 patients with psychotic disorders and 531 first-degree relatives). Six SNPs in DAOA and 5 SNPs in RGS4 were genotyped. Executive cognitive performance was assessed with Trail Making Test B (TMT-B) and Wisconsin Card Sorting Test (WCST). Genetic association analyses were conducted with PLINK, using the transmission disequilibrium test (TDT) for the family-based study and linear regression for cognitive performance analyses.
  
  
  RESULTS
  The haplotype GAGACT at DAOA was under-transmitted to patients (P=0.0008), indicating its association with these disorders. With regards to cognitive performance, the DAOA haplotype GAGGCT was associated with worse scores in TMT-B (P=0.018) in SZ patients only. RGS4 analyses did not report significant results.
  
  
  CONCLUSIONS
  Our findings suggest that the DAOA gene may contribute to the risk for psychotic disorders and that this gene may play a role as a modulator of executive function, probably through the dysregulation of the glutamatergic signalling.
authors.affiliation: Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Soler
authors.affiliation: Servei de Salut Mental, Psiquiatria i Addicions, Hospital Universitari Santa Maria Lleida, Institut de Recerca Biomèdica (IRB), Lleida, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Miret
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Servei de Psiquiatria i Psicologia Infantil i Juvenil, Hospital Clínic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Departament de Psiquiatria i Psicobiologia Clínica, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Lázaro
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Servicio de Psiquiatría del Niño y del Adolescente, Departamento de Psiquiatría, Hospital General Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón (IISGM), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Parellada
authors.affiliation: Unitat de Recerca i Àrea d'Adolescents del Complex Assistencial en Salut Mental, Benito Menni, Sant Boi de Llobregat, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Martín
authors.affiliation: Servei de Psiquiatria i Psicologia Infantil i Juvenil, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Lera-Miguel
authors.affiliation: Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rosa
authors.affiliation: Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: de Castro-Catala
authors.affiliation: Servicio de Psiquiatría, Complejo Hospitalario de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Cuesta
authors.affiliation: Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Fañanás
authors.affiliation: Inserm, UMR 894, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, PRES Sorbonne Paris Cité, 75014 Paris, France; Service Hospitalo-Universitaire, Faculté de Médecine, Université Paris Descartes, Hôpital Sainte-Anne, 75014 Paris, France; GDR3557, Institut de Psychiatrie, 75014 Paris, France.
authors.forename: M O
authors.initials: MO
authors.lastname: Krebs
authors.affiliation: Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain. Electronic address: mar.fatjovilas@ub.edu.
authors.forename: M
authors.initials: M
authors.lastname: Fatjó-Vilas
mesh_terms: D000293:Adolescent; D000328:Adult; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000235:genetics*; D003071:Cognition / Q000502:physiology; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D008297:Male; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000175:diagnosis / Q000235:genetics; D020710:RGS Proteins / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C475071:DAOA protein, human; D047908:Intracellular Signaling Peptides and Proteins; D020710:RGS Proteins; C098799:RGS4 protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases
keywords: Bipolar disorder; DAOA; Executive function; RGS4; Schizophrenia; Schizophrenia-spectrum disorders