Schizophrenia and bipolar disorder run in families with an 81 percent heritability rate in twin studies, yet standard genome-wide surveys have only uncovered about a quarter of that genetic risk.
Researchers in Pune, India, propose that short, stuttering stretches of DNA largely overlooked by standard methods account for the missing inheritance, News-Medical reported. These repetitive sequences consist of CAG codes for the amino acid glutamine, which expand in genes across the brain.
Mahabaleshwar V. Hegde, director of the Center for Innovation in Nutrition Health and Disease at the Interactive Research School for Health Affairs, leads the team examining these repeat genes. “What if many modest repeat containing genes, scattered across the brain, could add up to cause highly debilitating chronic mental health condition,” Hegde asked regarding the hypothesis published in Genomic Psychiatry.
First floated in 2011 under the title “Unstable Genes Unstable Mind; Beyond the central Dogma of Molecular Biology,” the hypothesis now incorporates 45 candidate genes from a published catalogue. Ten of these genes can expand into classic neurodegenerative diseases, three feature repeats outside coding regions, and 32 involve moderately expanding repeats.
Genome-wide association studies identified hundreds of risk loci by examining unique sequences while missing these repeats. “We propose that cumulative variation across these 45 CAG-repeat genes may be a substantial component of the missing heritability,” Hegde stated, adding that the exact magnitude remains unknown until measured with repeat-aware genomic approaches.
The proposed biological mechanism runs through astrocytes, the support cells that supply neurons with glutamine as a raw material for neurotransmitters. If numerous proteins feature enlarged glutamine stretches, astrocytes face an outsized metabolic demand and shift toward a side route to manufacture extra alpha-ketoglutarate.
This metabolic shift involves scavenging ammonia from D-serine, glycine, and adenosine while retaining glutamine rather than exporting it to neurons. Glutamine accumulation inside astrocytes swells the cells and turns them reactive, releasing inflammatory signals that eliminate synapses and disrupt neural circuits.
Magnetic resonance spectroscopy at 7 tesla can now separate overlapping glutamate and glutamine signals that lower-powered scanners missed. A meta-analysis of 28 studies comprising 647 patients and 608 controls concluded that glutamine rises while glutamate falls in the medial frontal region in schizophrenia.
“These measurements are the most encouraging fit for our model, but they carry a real limitation,” Hegde noted regarding the whole-region totals reported by spectroscopy. Assigning higher glutamine to astrocytes and lower glutamate to neurons remains a model-based inference consistent with data rather than a direct scan proof.
Men develop schizophrenia three to four years earlier than women, and the authors speculate that highly unstable repeats in the androgen receptor gene on the X chromosome could account for the difference.
Computational tools for profiling tandem repeats and single-cell transcriptomics could map where each candidate gene expresses itself across brain tissue.
The mechanism involves glutamate deficits rather than excitotoxicity, meaning it does not predict neuronal death and fits a neurodevelopmental course.
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