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Studies Converge on SETD1A as Schizophrenia Gene

22 Mar 2016

March 23, 2016. Two studies have converged on the same gene, SETD1A, as a major risk factor for schizophrenia. One study surveyed DNA from over 60,000 people and found that disabling mutations in SETD1A escalated risk for schizophrenia 38-fold. The other study implicates a different type of mutation in schizophrenia, so-called "silent" mutations that alter "letters" in the DNA blueprint code without actually affecting the structure of a protein produced from that blueprint. One of these "silent" mutations also hit SETD1A.

The findings suggest that glitches in how genes are turned into proteins can boost risk for schizophrenia. SETD1A encodes an enzyme that helps control what genes are available to the cellular protein-producing machinery. Problems with SETD1A could result in genes transcribed at the wrong time, in the wrong place, or as the wrong version, thus disrupting the brain's intricate developmental program.

The SETD1A mutations are exceedingly rare, accounting for only a tiny fraction of cases of schizophrenia. But there is reason to believe that the gene's role may generalize to other cases, too: Researchers have found that more common genetic variants likely impact protein production in the same way as SETD1A.

"The fact that the same bit of biology is coming up in the relatively mild perturbations seen in GWAS and the really catastrophic perturbations in SETD1A in exome sequencing suggests that the gene might be relevant in thinking about new treatment avenues for everyone with schizophrenia," said Jeffrey Barrett of the Wellcome Trust Sanger Institute in Cambridge, UK, who led the large-scale exome sequencing project published on March 14 in Nature Neuroscience.

This sentiment was echoed by Bin Xu, who was involved in the silent mutation study published in Neuron on March 6, which was led by Maria Karayiorgou at Columbia University, New York City.

"These findings altogether suggest that abnormalities in epigenetic regulation could be important for [the] etiology of schizophrenia in general," he wrote in an email to SRF. (For more details, see the related news story.)—Michele Solis.