State-Dependent Transcriptomic Collapse of the Brain's Lactate and Ketone Thermodynamic Sensors in Schizophrenia

Metabolic psychiatry has recently achieved unprecedented clinical rescue in treatment-resistant Schizophrenia (SCZ) utilizing targeted ketogenic interventions. However, the field has operated without a defined genomic anchor, leaving the biophysical mechanism of these therapies largely unexplained. Here, we report the discovery of the definitive metabolic sensor array driving this pathology. By integrating high-resolution topological mapping of SCZ GWAS summary statistics, 3D chromatin conformation (Hi-C), and multi-tissue transcriptomics, we identify massive, non-coding structural variances flanking the HCAR2/HCAR1 tandem locus--the brain's master thermodynamic governor. We demonstrate that