Gene deletions tied to poor cognition in schizophrenia patients

Several copy number variants (CNVs) contribute to severe phenotypes in schizophrenia spectrum disorders (SSDs), and disruptions in foetal brain development are associated with poor cognition, suggests a study.

A total of 617 individuals with SSDs were included in the study, which explored the relationships of two severe phenotypes—childhood-onset psychosis and borderline intellectual functioning (IQ)—with known risk CNVs, genome-wide deletion burden scores, and novel scores capturing deletion burden in 18 previously validated and mutually exclusive gene sets, representing aspects of neurodevelopment.

The authors assessed associations with borderline IQ for replicability in 233 relatives of SSD patients, 581 control participants, and 9,930 youths from the Adolescent Brain Cognitive Development (ABCD) Study.

Both known SSD-risk CNVs (odds ratio [OR], 7.07, 95 percent confidence interval [CI], 1.60‒31.32) and neurodevelopmental disorder (NDD)-risk CNVs (OR, 4.56, 95 percent CI, 1.48‒14.10) significantly correlated with borderline IQ in SSDs.

Beyond effects of known NDD-risk CNVs, deletion of genes involved in regulating gene expression during foetal brain development contributed to borderline IQ across SSD patients and controls (OR, 2.57, 95 percent CI, 1.44‒4.60) and in the ABCD cohort (OR, 1.33, 95 percent CI, 1.00‒1.76).

Foetal gene regulatory gene deletions were also associated with altered grey matter volume (b, 0.09, 95 percent CI, 0.004‒0.17) and cortical thickness (b, 0.14, 95 percent CI, 0.05‒0.24) across SSD patients and controls in exploratory structural MRI-based analyses.

These findings “confirm contributions of known risk CNVs to severe phenotypes in SSDs, implicate disrupted foetal brain development in poor cognition, and demonstrate the utility of a neurodevelopmental framework for identifying mechanisms underlying severe SSD-relevant phenotypes,” the authors said.