Rare and common genetic variants linked with schizophrenia

1 August 2008

New research has identified new genetic variants associated with the disease schizophrenia, the most common major psychiatric disorder (affecting around 1 in 100 of the UK population), which causes altered perceptions of reality typified by delusions and hallucinations. Two large-scale international collaborative research studies by the International Schizophrenia Consortium (ISC) and SGENE Consortium, both published in the journal Nature,  looked independently at copy number variations or CNVs (regions of deletions or duplications in the DNA sequence) in the genomes of several thousand patients with schizophrenia; CNVs have already been associated with the disease (see previous news).

Both projects identified specific genetic abnormalities associated with schizophrenia in sites on chromosomes 1, 15 and 22 (the latter having been previously associated with increased risk of the disease). The new mutations are rare, thought to be present in no more than 1% of the general population, but appear to confer a substantially increased risk (3 to 15-fold) of developing the disease, of around 3-fold for the site on chromosome 1, and 12- and 15-fold for the two sites on chromosome 15. The ISC paper found that structural chromosomal changes (especially single, rare ones) occurred at a generally higher frequency in individuals with schizophrenia than controls [The International Schizophrenia Consortium. Nature. 2008 Jul 30 doi:10.1038/nature07239].The SGEBE paper suggests that rare variants may account for a larger proportion of genetic susceptibility towards schizophrenia than is the case for other complex diseases; the reasoning is that, since the disease is associated with much lower rates of reproduction than normal, genetic variants tend to be lost from the population more rapidly than usual [Stefansson H et al. Nature 2008 Jul 30. doi:10.1038/nature07229].

Dr Pamela Sklar of the ISC said: "We've only explained a tiny fraction of why people might develop schizophrenia and much more work needs to be done to connect specific changes to the full spectrum of other types of genetic factors that might influence schizophrenia as well as the way in which those might interact with the environment" (see press release).

A third publication in the journal Nature Genetics used a genome-wide association study (GWA) to identify a number of more common genetic variations linked with a slightly increased risk of schizophrenia [O’Donovan MC et al. Nat. Genetics 2008 Jul 30 doi:10.1038/ng.201]. One locus was also found to show association with an increased risk of bipolar disorder, leading the authors to propose that it might influence risk to a broader psychosis phenotype.

Comment:  Researchers have prudently warned that the new findings, whilst of value, are not likely to be applicable as susceptibility tests for schizophrenia, since there are probably many different genetic ‘routes’ to the disease (see BBC news). However, besides informing work on the biological mechanisms that underlie the development of schizophrenia, findings could potentially also contribute towards improved means of diagnosing the condition and distinguishing it from other psychiatric conditions such as bipolar disorder (see ScienceDaily news).

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