Metabolic Gating and the Evolution of Human Cognitive Plasticity: A Comparative Genomic Analysis

The genetic basis of extreme cognitive plasticity in human innovators remains poorly characterized. Here, we demonstrate that the genomic architecture underlying scientific innovation significantly overlaps with the polygenic risks for neuropsychiatric phenotypes, such as schizophrenia. Utilizing a comparative genomic approach across psychiatric cohorts (PGC) and the UK Biobank (Scientific Creativity), we identify a coordinated “Vanguard Engine” consisting of hyper-tuned voltage-gated calcium channels ( CACNA1C, CACNB2 ), glutamatergic receptors ( GRIN2A ), synaptic plasticity regulators ( BDNF ), and the core linguistic-symbolic coordinator ( FOXP2 ). We posit that these variants establish a high-voltage neural environment optimized for associative divergence. Furthermore, we characterize the PDHB and HCAR2 loci as critical metabolic governors against thermal overload and identify structural variance in HDAC2 as the epigenetic clamp linking ancestral fuel availability (β-hydroxybutyrate) directly to the transcriptional control of this plasticity network. We conclude that psychiatric pathology is an emergent property of a fuel-mismatch, wherein a high-performance cognitive architecture is sustained by a carbohydrate-heavy diet, leading to systemic thermodynamic failure. This framework provides a unified, mechanistic explanation for the spectrum between extreme cognitive innovation and pathological collapse.