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Scientists may have found the "missing heritability" in schizophrenia and bipolar disorder — and it's hiding in repetitive DNA. A new hypothesis published in Genomic Psychiatry proposes that cumulative expansions across 45 CAG-repeat genes, largely ignored by standard genome-wide studies, could drive psychosis by disrupting glutamine metabolism in brain support cells. The idea is still a hypothesis, but researchers say it's built to be tested.
Twin studies peg the heritability of schizophrenia and bipolar disorder at around 81%, yet decades of large-scale genetic surveys have only accounted for roughly a quarter of that risk. A new Perspective published in Genomic Psychiatry by researchers at Bharati Vidyapeeth Deemed University in Pune, India, proposes that the gap may lie in CAG repeats — short, stuttering DNA sequences that standard genome-wide association studies (GWAS) have largely overlooked.
The team identifies 45 candidate CAG-repeat genes and argues that modest expansions across many of them could cumulatively trigger psychosis — not by killing neurons (as in Huntington's disease), but by overloading astrocytes with glutamine. In their model, glutamine-burdened astrocytes hoard the molecule rather than supplying it to neurons, starving them of glutamate, GABA, and the antioxidant glutathione. This metabolic disruption, they suggest, breaks neural circuits and produces the symptoms of schizophrenia or bipolar disorder depending on which brain regions are affected.
Key Takeaways:
Why it matters: If validated, this model could reshape how researchers search for schizophrenia and bipolar disorder genes — and open new therapeutic targets at the earliest metabolic steps of psychosis, potentially treating both disorders with a single approach.
