Genetic Influences on Cognitive Dysfunction in Schizophrenia

Schizophrenia is a severe and debilitating psychotic disorder that is highly heritable and relatively common in the population. The clinical heterogeneity associated with schizophrenia is substantial, with patients exhibiting a broad range of deficits and symptom severity. Large-scale genomic studies employing a case-control design have begun to provide some biological insight. However, this strategy combines individuals with clinically diverse symptoms and ignores the genetic risk that is carried by many clinically unaffected individuals. Consequently, the majority of the genetic architecture underlying schizophrenia remains unexplained, and the pathways by which the implicated variants contribute to the clinically observable signs and symptoms are still largely unknown. Parsing the complex, clinical phenotype of schizophrenia into biologically relevant components may have utility in research aimed at understanding the genetic basis of liability. Cognitive dysfunction is a hallmark symptom of schizophrenia that is associated with impaired quality of life and poor functional outcome. Here, we examine the value of quantitative measures of cognitive dysfunction to objectively target the underlying neurobiological pathways and identify genetic variants and gene networks contributing to schizophrenia risk. For a complex disorder, quantitative measures are also more efficient than diagnosis, allowing for the identification of associated genetic variants with fewer subjects. Such a strategy supplements traditional analyses of schizophrenia diagnosis, providing the necessary biological insight to help translate genetic findings into actionable treatment targets. Understanding the genetic basis of cognitive dysfunction in schizophrenia may thus facilitate the development of novel pharmacological and procognitive interventions to improve real-world functioning.