Genetics-to-structure multiscale analysis identifies disrupted calcium homeostasis as a mechanism of psychiatric disease

Polygenic association studies implicate numerous genes in neuropsychiatric disorders, but linkage disequilibrium (LD) and cellular heterogeneity hinder mechanistic interpretation. Here, we integrate single-nucleus RNA-seq from human neurons with network inference and polygenic signal weighting to resolve pathway-level drivers. Neuron-resolved gene co-expression networks constructed across brain regions are reweighted by GWAS-derived polygenic signal (LD-aware heritability enrichment), prioritizing modules that disproportionately contribute to liability. Using this framework, we highlight the dysregulation of Ca2+ homeostasis as an etiological driver of neuropsychiatric disorders, and even relative to other neuronal gene sets, Ca2+ homeostasis exhibits the greatest concentration of rare variant signal. Furthermore, 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. To connect sequence variation to structure and mechanism, we developed a residue-centric three-dimensional neighborhood analysis that integrates case-control missense variation with AlphaFold3 structural models to localize 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 Ca2+ permeation tunnel and the ATP:Mg2+ coordination site of ATP2B2. Cellular and biochemical analyses of the canonical Ca2+ binding site revealed clear loss-of-function effects, corroborating the earlier functional genomics evidence, and establishing a distinct molecular mechanism that converges on impaired Ca2+ extrusion, likely perturbing pre-and post-synaptic Ca2+ homeostatic equilibrium in excitatory neurons. 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. In parallel, we develop a residue-centered 3D neighborhood framework that couples case-control genetics with structural models to discover pathogenic hotspots, generalizable across the proteome to any protein structure.