Cognitive pleiotropy reveals disorder-specific and shared biology for schizophrenia and bipolar disorder

Abstract

Schizophrenia (SCZ) and bipolar disorder (BIP) share substantial common-variant liability but differ in clinical course, cognition, and treatment response. We previously resolved this overlap into three cognitively divergent components, SCZcondBIP (negatively correlated with cognition and education), BIPcondSCZ (positively correlated with both), and PSY-shared (negative with cognition, positive with education), representing distinct neurocognitive axes. Here, we applied directional pleiotropic meta-analysis (PLEIO) to integrate these components with cognitive task performance and educational attainment, yielding 818 consensus loci of which 514 (63%) were shared across all three components and 220 were component-specific, including 99 novel loci absent from individual GWAS. Each component was partitioned into concordant (aligning with the expected cognitive direction, e.g., increased cognition with reduced SCZcondBIP risk) and discordant (reverse pattern, e.g., increased cognition with increased SCZcondBIP risk) locus sets. Pathway analyses revealed marked biological divergence: SCZcondBIP concordant loci were enriched for neurodevelopmental pathways and discordant loci for cellular-homeostasis pathways, suggesting two separable processes: an early developmental-regulatory branch linking cognitive disadvantage to increased risk, and a homeostatic/metabolic-stress branch enabling cognitive advantage despite increased risk. BIPcondSCZ concordant loci, where increased cognition co-occurs with increased bipolar risk, were enriched for synaptic pathways. Unlike neurodevelopmental pathways, which emerged as primary cognitive determinants in SCZcondBIP, synaptic pathways may principally mediate disease liability without substantially impacting cognition, explaining preserved or enhanced performance alongside increased bipolar risk. Discordant loci, where decreased cognition co-occurs with decreased bipolar risk; implicated cellular-homeostasis pathways through mitochondria mediated pathways, consistent with mitochondrial dysfunction and reduced cellular resilience contributing to bipolar pathophysiology and progressive cognitive decline. PSY-shared concordant loci showed nominal synaptic and cellular-homeostasis enrichment, while discordant loci implicated neuroimmune and vesicular processes, directionally consistent with disorder-specific partitions. Schizophrenia and bipolar disorder genetic risk comprises biologically coherent disorder-specific and shared dimensions; integrating these with cognition exposes directional pleiotropic architecture across divergent developmental, synaptic, and metabolic pathways, providing a mechanistic framework for understanding cognitive heterogeneity in severe psychiatric illness.