Psychosis susceptibility gene ZNF804A and cognitive performance in schizophrenia

Context: The Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia susceptibility by several genome-wide association studies. ZNF804A is brain expressed but of unknown function. Objective: To investigate whether the identified risk allele at the disease-associated single nucleotide polymorphism rs1344706 is associated with variation in neuropsychological performance in patients and controls. Design: Comparison of cases and controls grouped according to ZNF804A genotype (AA vs AC vs CC) on selected measures of cognition in 2 independent samples. Setting: Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy participants from the general population were ascertained. Participants: Patients with DSM-IV–diagnosed schizophrenia and healthy participants from independent samples of Irish (297 cases and 165 controls) and German (251 cases and 1472 controls) nationality. Main Outcome Measures: In this 2-stage study, we tested for an association between ZNF804A rs1344706 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attention) in an Irish discovery sample. We then tested significant results in a German replication sample. Results: In the Irish samples, the ZNF804A genotype was associated with differences in episodic and working memory in patients but not in controls. These findings replicated in the same direction in the German samples. Furthermore, in both samples, when patients with a lower IQ were excluded, the association between ZNF804A and schizophrenia strengthened. Conclusions: In a disorder characterized by heterogeneity, a risk variant at ZNF804A seems to delineate a patient subgroup characterized by relatively spared cognitive ability. Further work is required to establish whether this represents a discrete molecular pathogenesis that differs from that of other patient groups and whether this also has consequences for nosologic classification, illness course, or treatment