Influence of DAOA and RGS4 genes on the risk for psychotic disorders and their associated executive dysfunctions: A family-based study

Eur Psychiatry. 2016 Feb;32:42-7. doi: 10.1016/j.eurpsy.2015.11.002. Epub 2016 Jan 21.

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.

Keywords: Bipolar disorder; DAOA; Executive function; RGS4; Schizophrenia; Schizophrenia-spectrum disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Carrier Proteins / genetics*
  • Cognition / physiology
  • Family Health
  • Female
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Linkage Disequilibrium
  • Male
  • Neuropsychological Tests
  • Polymorphism, Single Nucleotide
  • Psychotic Disorders* / diagnosis
  • Psychotic Disorders* / genetics
  • RGS Proteins / genetics*
  • Synaptic Transmission / genetics*

Substances

  • Carrier Proteins
  • DAOA protein, human
  • Intracellular Signaling Peptides and Proteins
  • RGS Proteins
  • RGS4 protein
  • Calcium-Calmodulin-Dependent Protein Kinases