Abstract
BACKGROUND: Cognitive impairments constitute a core feature of schizophrenia, and a genetic overlap between schizophrenia and cognitive functioning in healthy individuals has been identified. However, due to the high polygenicity and complex genetic architecture of both traits, overlapping biological pathways have not yet been identified between schizophrenia and normal cognitive ability. Network medicine offers a framework to study biologically meaningful gene networks through protein-protein interactions among risk genes. Here, established network-based methods were used to further reveal the biological relatedness of schizophrenia and cognition. METHODS: The protein interactome was used to examine the genetic link between schizophrenia risk genes and genes associated with cognitive performance in healthy individuals. First, we used a method called network separation to examine if there is an overlap between schizophrenia and cognition in the interactome network space. Then, we used network propagation analyses to identify schizophrenia risk genes that are close to cognition-associated genes in the interactome network space. Gene ontology and pathway enrichment analysis was performed to describe the function of this gene set. RESULTS: Network separation analyses showed a profound interactome overlap between schizophrenia risk genes and genes associated with cognitive performance (SAB = -0.22, z-score = -6.80, p = 5.38e-12). We identified 140 schizophrenia risk genes that are close to cognition-associated genes in the interactome. Risk genes close to cognition were enriched for pathways including long-term potentiation and Alzheimer’s disease, and included genes with a role in neurotransmitter systems implemented in cognition, such as glutamate and dopamine, that were not part of the direct genetic overlap. Moreover, schizophrenia risk genes close to cognition included 45 druggable genes not yet used as drug targets. DISCUSSION: These results pinpoint schizophrenia risk genes of particular interest for further examination in schizophrenia patient groups to reveal the genetic architecture of cognitive impairments in schizophrenia, of which some are druggable genes with potential as candidate targets for cognitive enhancing drugs.