Effects of Shared and Nonshared Schizophrenia and Bipolar Disorder Alleles on Cognition and Educational Attainment in the UK Biobank.

Background: Cognitive impairment is typically more severe in schizophrenia (SZ) than bipolar disorder (BD). We explored the underlying genetics and biology of this difference and its relationship to educational attainment (EA) using genomic structural equation modeling. Methods: Shared and differentiating fractions of liability for SZ and BD were derived and tested for their association with general intelligence (n = 93,541), fluid intelligence (n = 160,465), and EA (n = 354,609) in the UK Biobank. Liabilities were tested for enrichment in genes with high expression specificity (HES) for developmental stages, cell types, and functional categories. Results: Shared liability was associated with poorer cognition but higher EA. The SZ differentiating fraction (SZdiff) was associated with poorer cognition and lower EA. When we adjusted for cognition, the effects of SZdiff on EA were attenuated but still significant. The differentiating fraction was enriched for HES genes for young adulthood (20-30 years), mid-adulthood (30-60 years), and the dentate gyrus. Conclusions: Shared liability for SZ and BD is enriched for alleles that confer risk for poorer cognitive function in the general population but is associated with noncognitive traits that enhance EA. In contrast, SZdiff is enriched for alleles that confer risk for poorer EA through both cognitive and noncognitive mechanisms, which has implications for interventions. The enrichment of the differentiating fraction for HES genes in early and mid-adulthood and in the dentate gyrus highlights developmental stages and cell types important for future research.