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Schizophrenia Meta-Analysis Reveals Role for Rare, Damaging Variants

NEW YORK (GenomeWeb) – A new meta-analysis suggests that rare, damaging mutations may contribute to schizophrenia, both alongside and in the absence of intellectual disability.

As they reported in Nature Genetics today, researchers from the Wellcome Trust Sanger Institute, Cardiff University, the Royal Edinburgh Hospital, and elsewhere brought together exome sequences, de novo mutation profiles, and copy number variant patterns for thousands of cases and controls from three existing cohorts. Together, these data led them to nearly 3,500 genes that are typically intolerant to change, but prone to rare loss-of-function mutations in schizophrenia.

"While the identification of individual genes remains difficult at current sample sizes, we show that the burden of damaging de novo mutations and rare [single nucleotide variants] and CNVs in schizophrenia is not scattered across the genome but is primarily concentrated in 3,488 genes intolerant of loss-of-function variants," first author Tarjinder Singh and his co-authors wrote.

Singh was a graduate student in Jeffrey Barrett's lab at the Sanger Institute when the study was done and is currently a postdoctoral researcher with Mark Daly's group at the Broad Institute.

When the team looked at the types of rare variants identified in schizophrenia in relation to those described in autism spectrum disorder (ASD) and other neurodevelopmental conditions, it found that many of the same genes were affected by loss-of-function mutations across the conditions. In individuals affected by both schizophrenia and intellectual disability, the rare, damaging variants tended to cluster in genes with neurodevelopmental roles, though rare variants also marked other schizophrenia cases.

"Our study supports the observation that genetic risk factors for psychiatric and neurodevelopmental disorders do not follow clear diagnostic boundaries," the authors explained. "Coding variants disrupting the same genes and, quite possibly, the same biological processes increase risk for a range of phenotypic manifestations."

Prior research has uncovered some of the pathway changes associated with schizophrenia, the team noted, along with some of the genes that tend to be affected by mutations ranging from common to rare. But the contribution of rare variants across schizophrenia cases — and potential ties between these rare variants and those involved in other conditions — are less fully delineated.

For their analyses, the researchers focused on rare variants identified in exome sequences for 4,133 individuals with schizophrenia and almost 9,300 population-matched controls, along with de novo mutations detected in 1,077 trios of children with schizophrenia and their parents. To that, they added array-based CNV profiles for another 6,882 individuals with schizophrenia and 11,255 individuals without.

After identifying 3,488 genes that appeared to be intolerant to loss-of-function mutations in psychiatric disease-free cases in the ExAC database, the team found an over-representation of rare, damaging changes to this gene set in the schizophrenia cases.

"Although this result is consistent with observations in ASD and severe developmental disorders," the authors noted, "the absolute effect size is smaller."

In 279 schizophrenia cases that also involved intellectual disability — found from a subset of 2,971 individuals with schizophrenia who had documented cognitive phenotypes — the researchers saw an apparent uptick in rare, damaging mutations in the loss-of-function intolerant gene set. That was particularly true for rare, damaging variants falling in genes previously implicated in developmental conditions, they reported.

Nevertheless, rare, damaging variants in the genes that are normally adverse to loss-of-function alterations also turned up in individuals with schizophrenia who did not have intellectual disability or those with indeterminate cognitive status.

"Together, these results demonstrate that rare variants have different contributions to schizophrenia risk depending on the degree of cognitive impairment," the authors wrote. "Notably, these variants do not simply confer risk for a small subset of patients but contribute to disease pathogenesis more broadly."