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Schizophrenia Exome Studies Delineate Role of De Novo Mutations

NEW YORK – A pair of papers published online yesterday in Nature Neuroscience has offered a more refined look at de novo variants contributing to schizophrenia, as well as the proportion of risk for the disease that may stem from those variants.

For the first of these studies, a team from the US and Taiwan sequenced the exomes of 1,695 children with schizophrenia and their unaffected parents, including 1,033 male and 662 female individuals with the disease. More than 90 percent of the schizophrenia cases were classified as sporadic, the group noted, while a family history of mental illness was reported in the remaining individuals.

When the researchers analyzed these trios in conjunction with almost 1,100 more d parent-patient trios and around 104,000 control exomes from the Genome Aggregation Database, they did see some enrichment for de novo mutations in the individuals with schizophrenia. But those de novo changes typically centered on highly conserved or neurodevelopmental disease-related genes, particularly those expressed in the brain or contributing to synaptic pathways.

The team highlighted more than a dozen genes affected by recurrent de novo mutations that are predicted to truncate the resulting proteins, though none of those candidates reached exome-wide significant ties to schizophrenia. More generally, the study authors stressed that de novo mutations appeared to have fairly modest enrichment in the schizophrenia cases.

"These findings suggest that coding [de novo mutations] do not explain a large fraction of [schizophrenia] diagnoses, and larger samples are needed to robustly identify genes that putatively contribute to [schizophrenia] risk," senior and co-corresponding author Benjamin Neale, a researcher affiliated with Massachusetts General Hospital and the Broad Institute, and his colleagues wrote.

For their own analysis in Nature Neuroscience, investigators at Cardiff University and other centers in the UK, Germany, Russia, Spain, and beyond searched for de novo mutations in 613 newly-sequenced schizophrenia parent-patient trios, alongside available data for thousands more families assessed genetically for past studies.

That search, which included more than 3,400 parent-child trios, pointed to a schizophrenia-related overrepresentation of loss-of-function (LOF) de novo mutations in almost 3,500 genes that are classified as LOF-intolerant, including 159 neurodevelopmental disorder-related genes. Among them were the gamma-aminobutyric acid transporter-coding gene SLC6A1, which was recurrently affected by missense de novo mutations in the schizophrenia-affected group.

"We highlight strong evidence that mutations in SLC6A1, a gene known to be associated with [autism spectrum disorder], developmental disorders, and epilepsy, confer a high risk for schizophrenia," co-corresponding authors Michael Owen and Michael O'Donovan, neuropsychiatric genetics and genomics researchers at Cardiff University, and their co-authors wrote.

When they tapped into genome-wide SNP data for more than 1,100 parent-child trios, meanwhile, the researchers noted that common variants implicated in schizophrenia and bipolar disorder were also overrepresented in individuals with schizophrenia, though the schizophrenia cases marked by suspicious de novo variants were usually far less prone to having high polygenic risk scores (PRS) for schizophrenia.

This, they wrote, "provides statistically independent evidence that a substantial proportion of this class of [de novo variants] contributes to schizophrenia pathogenesis."

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