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

Abstract/SummaryCognitive impairments in schizophrenia are associated with poor outcomes and are largely unimproved by current medications. It remains uncertain to what extent cognitive impairments arise from shared aetiology and biology with schizophrenia, or are a consequence of having the condition. We analysed exome-sequencing data from 76,783 UK Biobank participants without schizophrenia to test for association between generalised cognition (g) and rare (minor allele count[≤]5) variants in schizophrenia-associated genes. Protein-truncating and deleterious missense variants in loss-of-function intolerant genes were associated with lower g. Stronger effects on g were found for protein-truncating variants in genes implicated in schizophrenia by rare coding variation, and for deleterious missense variants in credible causal genes at schizophrenia common allele loci. These findings indicate that biological processes disrupted in schizophrenia by common and rare variants are associated with g in unaffected individuals, suggesting the relationship between impaired cognition and schizophrenia reflects, in part, a shared underlying biology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/23294074v2_fig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1f1740forg.highwire.dtl.DTLVardef@fa85c8org.highwire.dtl.DTLVardef@1651733org.highwire.dtl.DTLVardef@1d65595_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1C_FLOATNO Graphical abstract. RCVs = rare coding variants. QC = quality control. g = generalised cognition. C_FIG