Imputed expression of schizophrenia-associated genes and cognitive measures in patients with schizophrenia

Cognitive dysfunction is a core manifestation of schizophrenia and one of the best predictors of long-term disability. Genes increasing risk for schizophrenia may partly act through the modulation of cognition.

We imputed the expression of 130 genes recently prioritized for association with schizophrenia, using PsychENCODE variant weights and genotypes of patients with schizophrenia in CATIE. Processing speed, reasoning, verbal memory, working memory, vigilance, and a composite cognitive score were used as phenotypes. We performed linear regression models for each cognitive measure and gene expression score, adjusting for age, years of education, antipsychotic treatment, years since the first antipsychotic treatment and population principal components.

We included 425 patients and expression scores of 91 genes (others had no heritable expression; Bonferroni corrected alpha = 5.49e-4). No gene expression score was associated with cognitive measures, though ENOX1 expression was very close to the threshold for verbal memory (p = 6e-4) and processing speed (p = 7e-4). Other genes were nominally associated with multiple phenotypes (MAN2A1 and PCGF3).

A better understanding of the mechanisms mediating cognitive dysfunction in schizophrenia may help in the definition of disease prognosis and in the identification of new treatments, as the treatment of cognitive impairment remains an unmet therapeutic need.