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Role for SETD1A Mutations in Schizophrenia

Rare loss-of-function mutations in SETD1A increase schizophrenia risk by some 35-fold, Reuters reports.

Researchers from the Wellcome Trust Sanger Institute and elsewhere examined the whole exomes of 4,264 people with schizophrenia, 9,343 controls, and 1,077 trios to find an enrichment of loss-of-function mutations in SETD1A among the cases, as they report in Nature Neuroscience. The controls, meanwhile, largely lacked any such mutations.

Though these loss-of-function mutations only explain a small portion of schizophrenia cases, Cardiff University's Mike Owen says they could point researchers toward pathways involved in the disease.

Seven of the 10 schizophrenia cases with a loss-of-function mutation in SETD1A also had developmental disorders, and the researchers further found four SETD1A loss-of-function carriers among nearly 4,300 children with severe developmental disorders and two more carriers — both with neuropsychiatric phenotypes — in a separate sample of 5,720 Finns. This, the Sanger-led team says, indicates that loss-of-function mutations in SETD1A may influence a variety of neuropsychiatric disorders and may share common biological pathways.

As SETD1A encodes a methyltransferase that catalyze the methylation of lysine residues in histone H3, this suggested to the researchers that epigenetic dysregulation might be an important aspect of disease pathogenesis.

"Our implication of SETD1A therefore contributes to the growing body of evidence that chromatin modification, specifically histone H3 methylation, is an important mechanism in the pathogenesis of schizophrenia," the researchers write in their paper.