Research Highlights Rare Genetic Variants Linked to Severe Schizophrenia

Schizophrenia
Schizophrenia and split personality disorder and mental health psychiatric disease concept in a 3d illustration style.

Research led by Columbia University Irving Medical Center and Baylor College of Medicine has uncovered new genetic variants linked with severe schizophrenia and treatment resistance.

The research team focused on a small group of patients with severe symptoms and showed they were significantly more likely to be carriers of rare, damaging variants than controls or those with less severe disease.

“The hypothesis is that these patients might have a greater prevalence of disease-causing mutations because they have such a severe form of the illness, and that’s what we ended up seeing,” said Anthony Zoghbi, corresponding author of the study published in PNAS and Beth K. And Stuart C. Yudofsky Scholar at Baylor, in a press statement.

Schizophrenia only affects around 1% of the population, but has a heritability of around 80%, suggesting genetics plays a strong role in the pathology of this debilitating mental illness. However, it has been difficult to pin down disease-causing variants to date.

The Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) consortium recently carried out the largest sequencing study ever of schizophrenia, including more than 24,000 individuals with the condition and identifying variants in 10 genes as causative for the condition. While this study is a big advance on previous knowledge, there is still relatively little genetic information available about patients with this neuropsychiatric condition.

Zoghbi and colleagues carried out sequencing of 112 patients at the most extreme end of the schizophrenia scale with severe, extremely treatment-resistant schizophrenia who had required continuous hospitalization for at least 5 years, 218 patients with typical schizophrenia and almost 5000 controls without the condition.

Of the severe schizophrenia group, 48.2% had at least one rare, damaging missense or loss-of-function variant in genes thought to be linked to schizophrenia, compared with 29.8% of typical schizophrenia cases and 25.4% of controls.

When the analysis was restricted to only genes known to be linked to the condition from previous research, 8.9% of those in the severe group carried a damaging variant compared with 2.3% of the typical schizophrenia group.

“We think that this method of study could be a new paradigm for trying to understand how to enrich a genetic signal in a psychiatric disorder by focusing on individuals who are very severely affected by the disease,” said Zoghbi.

“We hope that this research brings light and attention to these patients who are often left out of cutting-edge research because of the severity of their condition.”

The team hopes the new knowledge could improve prognosis predictions in individuals with schizophrenia and also help to predict who might develop a more severe case of the condition, as well as providing new targets for future drug development.

“The high rate of identifiable rare variants (many in druggable genes) in severe, extremely treatment-resistant schizophrenia provides an opportunity to functionally characterize these variants in model systems, paving the way for the development of mechanistically targeted therapeutics for patients in dire need of novel treatments,” conclude the authors.

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