Multiscale Integration of Genetic, Transcriptomic, and Structural Data Identifies Calcium Homeostasis as a Core Mechanism Underlying Neuropsychiatric Disorders

Human genetics has identified many genes underlying polygenic neuropsychiatric disorders. However, owing to the complexities of linkage disequilibrium (LD) and brain biology, understanding how the implicated genes coalesce into neurobiological pathways remains elusive, with few robust mechanistic insights to date. Here, we use single-nucleus RNA-sequencing data from neurons from across the human brain to identify gene co-expression networks, then weight them by polygenic heritability to implicate more-specific biology in neuropsychiatric disorders. Using this framework, we highlight the dysregulation of Ca ²⁺ homeostasis as an etiological driver of neuropsychiatric disorders. Further supporting these results, we find that a critical component of this molecular system, the P-type calcium ATPase ATP2B2 , exhibits marked expression deficits in both nuclear transcriptomic and synaptic proteomic datasets derived from the dorsolateral prefrontal cortices of individuals with schizophrenia. We then developed a method that uses missense variants in case-control cohorts together with protein structures (inferred from AlphaFold3) to systematically prioritize mutational hotspots of biological significance for downstream mechanistic interrogation. This approach identified an enrichment of deleterious missense variants - implicated across multiple neuropsychiatric disorders - that changed protein residues in close spatial proximity to both the Ca ²⁺ permeation tunnel and the ATP:Mg ²⁺ coordination site of ATP2B2. Cellular and biochemical analyses of the canonical Ca ²⁺ binding site revealed clear loss-of-function effects, establishing a distinct molecular mechanism that converges on impaired calcium extrusion, likely perturbing pre- and post-synaptic Ca ²⁺ homeostatic equilibrium. Altogether, our study makes a significant contribution by linking genetic risk to neuronal dysfunction through a critical calcium signaling axis, offering mechanistic insight into the pathogenesis of neuropsychiatric disorders.