Importance: Further understanding how genetic liabilities to schizophrenia (SZ) and bipolar disorder (BD) are related to cognition and educational attainment (EA) indicates important differences between these conditions that are relevant to future research and interventions. Objective: To determine how fractions of genetic liability that are shared between, and differentiate, SZ and BD, are associated with cognition and EA and characterise their biology using gene-set enrichment analysis. Design, setting and participants: Fractions of liability were derived using Genomic Structural Equation Modelling (gSEM) on genome-wide association studies of SZ and BD. Polygenic risk scores (PRS) representing each fraction were tested for association with two measures of cognition - a general cognitive factor g (n=93451) and fluid intelligence (FI, n=160465) and a measure of EA (n=354609) in the UK Biobank, excluding individuals with SZ, BD or a psychotic disorder. MAGMA and partitioned LDSC were used to examine the shared and differentiating fractions for enrichment in genes with high expression specificity for cell types, functional categories and developmental stages. Main outcomes and measures: PRS representing the shared and differentiating fractions were tested for association with FI, g and EA. Mean -log10 p-value across both MAGMA and partitioned LDSC results was used as a metric of enrichment. Results: The shared fraction was associated with poorer cognition (FI beta -0.079 p=5.57e-85; g beta -0.079, p =7.51e-51) but higher EA (beta 0.016, p=5.08e-07). The SZ differentiating fraction (SZdiff) was associated with poorer cognition (FI beta -0.027, p=6.34e-24; g beta -0.009, p=3.74e-3) and lower EA (EA beta -0.049, p=1.84e-58). The BD differentiating fraction (BDdiff) was associated with better cognition and higher EA, the effects being of the same magnitude as SZdiff but of opposite sign. Adjusting for cognitive function, the effects of SZdiff PRS on EA were attenuated but remained significantly (adjusted for FI, beta -0.025, p = 1.28e-6; adjusted for g, beta -0.032, p = 8.87e-6). The differentiating fraction was enriched for genes specifically expressed in young adulthood (20-30 years) and mid adulthood (30-60 years), but not in earlier developmental stages. It was also enriched in murine pyramidal CA1 cells and striatal medium spiny neurones. Conclusions and relevance: Our findings partly explain the greater cognitive impairments and stronger negative genetic correlation with intelligence in SZ compared to BD. This may reflect neurodevelopmental processes indexed by cognitive function that are more prominent in SZ than BD, although the relatively modest effect of SZdiff on cognition is consistent with studies suggesting that inherited genetic variation is not the major determinant of cognitive impairment in SZ. Despite negative effects on cognition, the shared fraction is weakly associated with better EA, suggesting that this is the result of influences on noncognitive traits. In contrast, the SZdiff fraction is enriched for alleles that confer risk to poorer EA through both cognitive and non-cognitive mechanisms, which has implications for interventions. The differentiating fraction was enriched for genes with relatively high expression specificity in early and mid-adulthood, corresponding to the typical age at onset of psychotic symptoms, a clinical feature that has previously been associated with this fraction of liability.

The authors have declared no competing interest.

This study was funded by Innovate UK.

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PGC Schizophrenia and Bipolar GWAS : https://pgc.unc.edu/for-researchers/download-results/ Skene et al single cell mouse brain expression gene specificity scores: https://doi.org/10.1038/s41588-018-0129-5 Habib et al single nucleus human brain expression gene specificity scores: https://doi.org/10.1038/nmeth.4407 Cameron et al single nucleus human brain expression gene specificity scores: https://doi.org/10.1016/j.biopsych.2022.06.033 Herring single nucleus human brain expression gene specificity scores: https://doi.org/10.1016/j.cell.2022.09.039 Brainseq bulk human brain area expression gene developmental stage specificity scores: https://doi.org/10.1016/j.neuron.2019.05.013 ; https://doi.org/10.1016/j.biopsych.2021.03.009

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