Role of new mutations in sporadic schizophrenia

11 June 2008

Schizophrenia is a complex psychiatric disease influenced by multiple genetic and environmental factors, affecting around 1% of the population (see press release). The disorder may be familial or non-familial (sporadic), the latter being cases where there is no family history of the disease in first- or second-degree relatives. Rare de novo (ie. new) copy number (CN) mutations have been shown to be risk factors for sporadic cases of autism spectrum disorders (see previous news).

New research published in Nature Genetics suggests that this type of mutation may also account for predisposition towards schizophrenia in sporadic cases [Bin Xu et al. (2008) Nat. Genet. doi:10.1038/ng.162]. DNA samples from family trios (subjects plus their biological parents) were analysed using computer programs to identify copy number variant (CNV) regions indicative of new CN mutations. Any regions that showed 50% overlap with a parental CNV were excluded, to ensure that inherited CNs or common CNVs from unstable genomic regions (with unusually high new mutation rates) were not counted as new mutations.

152 subjects with sporadic schizophrenia were compared with 159 unaffected controls from the same South African population. New mutations showed significant association with sporadic schizophrenia, occurring around eight times more frequently in affected subjects (10%) than unaffected controls (1.3%). In comparison, no new mutations were identified in an analysis of 48 subjects with familial schizophrenia. The researchers also looked at rare inherited mutations in the same cohorts, and found that they occurred only slightly (around 1.5 times) more frequently in the affected individuals than the controls.

The authors of the paper conclude that new mutations play an important role in the pathogenesis of sporadic cases of schizophrenia, much more significant than that of inherited mutations, although these could also contribute to disease vulnerability. It is suggested that this may explain in part why schizophrenia persists in populations despite the fact that individuals with the disease do not have as many children as those without it. Secondly, they propose that the observation that mutations at multiple different positions in the genome can contribute to schizophrenia causation may account for the difficulty in identifying genetic ‘risk’ variants that contribute significantly to predisposition to the disease.

Comment: This research contributes to a growing body of evidence that new mutations in multiple genomic regions (including genes thought to influence neurodevelopmental pathways) may be significant factors in the genetic contribution to sporadic cases of schizophrenia, as previously also suggested for autism spectrum disorder. It seems that seeking new mutations may be a solution to dissecting the complex genetic factors involved in multifactorial disorders that have proved refractory to analysis via standard genetic association studies, and could also contribute to understanding of genetic contributions to other common complex conditions such as diabetes and obesity.

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