State-Dependent 3D Enhancer Architecture Resolves a Shared Schizophrenia and Multiple Sclerosis Ketone and Lactate...

Recent cross-disorder meta-analyses have revealed substantial pleiotropic genetic architectures shared between Schizophrenia (SCZ) and Multiple Sclerosis (MS). However, reliance on automated 1D positional mapping heuristics has historically misattributed the significant shared risk locus at 12q24.31 (123.60 Mb) to adjacent structural genes such as PITPNM2 , obscuring the true biophysical checkpoint driving neuroimmune pathology. By integrating 3D chromatin conformation (Hi-C), historical Linkage Disequilibrium modeling ( D' > 0.92), and state-dependent macrophage transcriptomics, we definitively reassign this 772 kb structural block. We demonstrate that the 123.60 Mb index variant is transcriptionally dormant regarding PITPNM2 in activated macrophages, but instead, the entire region functions as a distal pleiotropic enhancer hub that physically bypasses local gene bodies to directly govern the tandemly duplicated HCAR metabolic sensor array. Crucially, the shared SCZ/MS mutational burden corrupts this 3D architecture, triggering a pathogen-specific thermodynamic logic gate. Under acute viral or Gram-negative inflammatory stress, the mutated enhancer loop structurally mis-docks, driving a catastrophic dual-failure: the transcriptomic collapse of the HCAR2 ketone sensor and the simultaneous silencing of the HCAR1 lactate brake. This genetic "dual-blindness" uncouples the peripheral immune system from both local lactate and systemic β-hydroxybutyrate anti-inflammatory stand-down signals. We propose that the HCAR enhancer hub represents a highly conserved, evolved pathogen-hunting engine that is catastrophically mismatched with modern, low-ketone metabolic environments. Ultimately, this 3D genomic architecture mechanistically resolves the shared neuroimmune etiology of SCZ and MS while explaining the profound clinical efficacy of HCAR2 synthetic agonists, derived from the drug dimethyl fumarate (e.g, MMF), in halting demyelinating disease.

Psychiatric and autoimmune diseases are traditionally studied in isolation, obscuring shared mechanisms. We reveal that Schizophrenia and Multiple Sclerosis share a 3D distal enhancer hub governing the tandem HCAR metabolic sensors. Utilizing spatial and state-dependent transcriptomic mapping, we demonstrate this shared mutation structurally mis-docks during pathogenic stress. Consequently, activated macrophages suffer a thermodynamic logic failure. Unable to sense systemic anti-inflammatory signals, they drive unchecked neuroimmune invasion. By reframing pathogenesis through an evolutionary mismatch, this discovery resolves a critical biophysical checkpoint and explains the profound clinical efficacy of synthetic HCAR2 agonists, such as dimethyl fumarate, acting as a pharmacological ketone-surrogate to halt demyelinating disease.