Two studies in Nature show that rare disruptive and de novo mutations may contribute to the pathophysiology of schizophrenia.
Although no single mutation came close to having a significant impact, patients with schizophrenia had a high burden of these types of mutations, particularly in genes previously implicated in schizophrenia, such as those encoding glutamatergic postsynaptic proteins.
In one study, Michael Owen (Cardiff University, UK) and colleagues looked at small de novo (non-inherited) mutations by sequencing the DNA of 617 schizophrenia patients and their parents. In the other study, Shaun Purcell (Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA) and team looked for rare mutations in the DNA of 2536 schizophrenia patients and 2543 controls, focusing on 2546 genes (about 10% of the exome) previously linked to schizophrenia.
Although the studies were independent, the researchers shared data, revealing, for example, that genes with an increased rate of de novo mutations also had increased rates of rare disruptive mutations.
Both studies identified “particularly striking” elevations of loss-of-function mutation rates affecting proteins that interact with activity-regulated cytoskeleton-associated protein (ARC), “indicating that disruption of ARC function has particularly strong effects on disease risk”, say Owen et al.
The frequency of de novo mutations in general was not increased in schizophrenia patients relative to those reported previously in 731 controls. However, they had increased rates of nonsynonymous mutations affecting proteins with a reported role in schizophrenia, including those associated with the ARC complex and the N-methyl-D-aspartate (NMDA) receptor and those known to be repressed by fragile X mental retardation protein (FMRP).
In the other study, rare (minor allele frequency <0.1%) disruptive mutations in schizophrenia-linked genes were significantly more common in patients than controls, at 1547 versus 1383 mutations. Besides finding a rate high of mutations affecting the ARC complex genes, the team found increased levels in the post-synaptic density (PSD)-95 complex genes, which overlap with ARC complex genes.
Voltage-gated calcium ion channel genes had increased rates of rare mutations, but NMDA receptor genes did not, contrasting with the findings for de novo mutations.
Another discrepancy between the two studies was the finding of increased rates of de novo mutations in genes linked to autism and intellectual disability, but not of rare disruptive mutations, which were elevated only in FMRP targets.
“Although we cannot yet use rare mutations to partition patients into more homogeneous clinical subgroups, this will remain a central goal for future sequencing studies,” say Purcell et al.
They believe the current findings “are likely to foreshadow the definitive identification of individual genes in larger cohorts”.
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