De Novo Mutation in Schizophrenia

Several studies in the last 5 years have shown that newly arising (de novo) mutations contribute to the genetics of schizophrenia (SZ). This will replenish genetic variants removed by natural selection and could, in part, explain why SZ prevalence has remained stable in the general population despite low fecundity. The strongest evidence to date for the association between SZ and de novo mutation comes from studies of de novo copy number variation (CNV), where the rate of de novo CNV mutation is shown to be increased in cases when compared with controls, and genes disrupted by these mutations are enriched for those encoding proteins involved in synaptic function and development. Previous estimates have shown high levels of negative selection operating against SZ associated CNVs, and we provide an updated estimate of these levels of selection using the most recently published data. Recent studies involving next-generation sequencing technology have provided preliminary evidence that de novo single-nucleotide mutations might also increase risk of SZ. However, these are very small in scale, and the results can only be considered as preliminary.