Psychosis Susceptibility Gene ZNF804A and Cognitive Performance in Schizophrenia

Abstract

Background: The Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia (SZ) susceptibility by several genome-wide association studies (GWAS). ZNF804A is brain-expressed, but of unknown function. Objective: To investigate whether the identified risk allele at the disease associated single nucleotide polymorphism (SNP) rs1344706 is associated with variation in neuropsychological performance in patients and controls. Design: A comparison of both cases and controls grouped according to ZNF804A genotype (AA v AC v CC) on selected measures of cognition in two independent samples. Setting: Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy volunteers from the general population were ascertained. Participants: 65 Patients with DSM-IV diagnosed schizophrenia and healthy controls from independent samples of Irish (n=297 cases and n=165 controls) and German (n=251 cases and n=1472 controls) nationality. Method: A two-stage study. We tested for association between ZNF804A rs1344706 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attentional control) in an Irish discovery sample. We then tested significant results in a German replication sample. Result: An interaction effect between ZNF804A genotype and diagnosis was observed for measures of episodic and working memory in the Irish patient sample but not controls. These findings replicated in the same direction in the German sample. Furthermore, in both samples the association between ZNF804A and schizophrenia strengthened when patients with lower general cognitive function were excluded. Discussion: In a disorder characterized by heterogeneity, a risk variant at ZNF804A appears to delineate a patient subgroup characterized by relatively spared cognitive ability. Further work is required to establish if this represents a discrete molecular pathogenesis that differs from other patient groups and whether this also has consequences for nosology, illness course or treatment.