Polymorphic CAG repeats and missing heritability in schizophrenia and bipolar disorder: A poly-glutamine neurodevelopmental hypothesis
Year: 2026
Type: article
Abstract: We revisit, revise, and refine our hypothesis of 2011 and propose that schizophrenia and bipolar disorder are neurodevelopmental neuropsychiatric polyglutamine disorders. We identify 45 new polymorphic CAG repeat-containing genes, possibly representing “missing heritability,” and posit that the expanded polyglutamine produced by them cumulatively initiate thus far unknown upstream events in psychosis by a new mode of inheritance earlier referred to as “Beyond the Central Dogma of Molecular Biology.” To meet the very high demand of glutamine for poly-glutamine synthesis, astrocytes activate the anaplerotic TCA pathway, increasing carboxylase activity to produce more alpha-ketoglutarate. Glutamine is trapped inside astrocytes by inhibiting its export to neurons. Neurons can not transport ammonia to astrocytes. Therefore, ammonia is generated by activating adenosine deaminase, d-serine amino oxidase, and glycine deaminase. NMDAR hypofunction results from reduced glutamate and NMDAR agonists D-serine and glycine. Accumulated glutamine, acting like an osmolyte, a TROJAN HORSE, causes astrocytes to swell and convert to reactive astrocytes. Reactive Astrocytes release cytokines that activate the complement system, eliminate synapses by phagocytosis, causing circuit breakdown and psychosis. Proposed model connects many murky dots and can be experimentally validated and may pave the way for developing new biomarkers, more effective drugs acting on initial steps in psychosis.
Source: Genomic psychiatry :
DOI: 10.61373/gp026p.0060
Institution: Bharati Vidyapeeth (Deemed to be University)
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7225743781