Rare coding variants in schizophrenia-associated genes affect generalised cognition in the UK Biobank

Abstract

AbstractImpairments in cognitive function are a feature of schizophrenia that strongly predict functional outcome and are generally not improved by current medications. However, the nature of the relationship between cognitive impairment and schizophrenia risk, and particularly the extent to which this reflects shared underlying biology, remains uncertain. We analysed exome-sequencing data from the UK Biobank to test for association between generalised cognition and damaging rare coding variation in genes and loci associated with schizophrenia in 30,487 people without the disorder. Rare protein-truncating variants (PTVs) and damaging missense variants in loss-of-function intolerant (LoFi) genes were associated with lower generalised cognition. Moreover, we found significantly stronger effects for damaging missense variants in credible causal genes at schizophrenia GWAS loci and for rare PTVs affecting LoFi genes in regions defined by schizophrenia-enriched CNVs. This suggests shared underlying biology between schizophrenia risk and general cognitive function in the population, and that exploiting large population sequencing datasets to identify genes with shared effects on cognition and schizophrenia can provide a route towards determining biological processes underlying cognitive impairment in schizophrenia.