Individually, the variations that were identified did not seem to play a large role in vulnerability to psychiatric disorders. At most, an individual variation doubled an individual’s risk of developing a psychiatric disorder over the background population risk. When considered in terms of absolute risk, this simply means that if the population risk for schizophrenia is 1%, an individual with one of the variations identified from a GWAS might have, at most, a 2% risk for the same condition. Thus, testing for these variations (at least individually) provides little information of meaningful clinical utility; we still lack information about the effects of having different combinations of these variations. Some researchers felt that these data demonstrated that the idea that psychiatric disorders are caused by multiple common variants, each of small effect, was wrong, and they proposed that psychiatric disorders might instead arise as a result of a large array of individually rare variants, each of which contribute a large effect.4,5
Copy number variations
It has been well known for some time that deletions or duplications—even those that are too small to be seen with a microscope—can cause rare genetic syndromes that present clinically with many different manifestations, which can include psychiatric disorders. The archetype is 22q11.2 deletion syndrome, which is associated with a risk of approximately 30% for psychosis. This was the impetus to look at the role of copy number variations (CNVs) in psychiatric disorders.
CNVs are sections of DNA larger than 1 kb but that are too small to be seen with a microscope and are gained or lost compared with a reference genome. Although CNVs occur less frequently in the human genome than SNPs, they are still relatively (and perhaps surprisingly) common. CNVs occur not only among populations of individuals in whom specific pathologies have been identified but also in the general population. Certain specific CNVs have been shown to occur more frequently among populations of individuals with psychiatric disorders than among the general population.6-8
In some cases, a single CNV seems to confer risk for more than 1 psychiatric diagnosis (for a review, see O’Donovan et al9). CNVs can be inherited or can occur spontaneously in a de novo fashion. Although it can be tempting to assume that a de novo CNV in an affected individual who has no affected family members is pathogenic, this is not necessarily the case. Essentially, interpreting the clinical significance of most CNVs (beyond those with clearly defined phenotypes, such as 22q11.2 deletion syndrome) is extremely challenging.
Current thinking about the genetics of psychiatric disorders
A consensus is emerging that both common SNPs, each of small effect, and rarer CNVs, each of larger effect, are likely to contribute to the development of psychiatric disorders.10 Recent data show that there seems to be an increased frequency of de novo genetic variations (both SNPs and CNVs) among populations of persons with psychiatric disorders compared with the general population.8,11 However, the distributions of the frequencies of variation overlap between the two groups, which precludes using this information to distinguish between those with and those without a psychiatric disorder, or to predict risk of psychiatric illness.
Dr Austin is Associate Professor of Psychiatry and Medical Genetics on the Faculty of Medicine at the University of British Columbia, and is a research scientist at the BC Mental Health and Addictions Research Institute in Vancouver. She reports no conflicts of interest concerning the subject matter of this article.
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