What do we know (or don’t we know) about the genetics of psychiatric disorders?
• There seem to be many different genetic variations (and types of variation, eg, SNPs and CNVs) that can increase an individual’s vulnerability to psychiatric illness, few of which (if any) are necessary or sufficient to develop a psychiatric disorder
• It is highly likely that all of the variations that can contribute to genetic vulnerability for psychiatric disorders have not yet been identified
• A single genetic variation may confer vulnerability to different psychiatric diagnoses as opposed to each variant conferring vulnerability to a single discrete diagnosis
• Even well-replicated data that demonstrate (with a compelling P value) that a genetic variation plays a role in the etiology of a disorder do not mean that the variation necessarily confers a large amount of vulnerability to psychiatric illness or that genetic testing for it in the clinical setting is warranted; this type of information speaks only about the confidence that the variation plays some kind of role
• Although we have traditionally thought of gains or losses of sections of DNA as causative of certain phenotypes, CNVs do not seem to cause psychiatric disorders; rather, they simply increase vulnerability
• Not all of the genetic variations that can contribute to vulnerability to psychiatric disorders are necessarily inherited—there is some evidence that de novo mutation rates (for both SNPs and CNVs) are higher among individuals with psychiatric disorders than among the general population
• We still do not have a clear understanding of the effects of having multiple genetic variations (eg, an individual’s cumulative risk for a psychiatric disorder could be a function of simple additive effects of each variation, or the effects could be multiplicative)
• The mechanisms by which the genetic variations that have been identified increase vulnerability to psychiatric disorders remain unclear
Genetic testing for psychiatric disorders
Genetic testing to diagnose psychiatric disorders. Given our present knowledge, in general there is essentially no meaningful role for genetic testing in establishing, confirming, or refining a psychiatric diagnosis in routine psychiatric practice.
Genetic testing to predict psychiatric disorders. Conditions such as 22q11.2 deletion syndrome that are known to be associated with a greater chance of psychiatric illness are relatively rare in the general population (the syndrome occurs at a rate of approximately 1 in 4000 births). But there will be rare situations in which it may make sense to test for a genetic syndrome in a young person who currently has no psychiatric problems—if he or she has a parent in whom the syndrome has been diagnosed. In this scenario, identifying the presence of the syndrome provides the information that there is an approximately 30% chance that psychotic symptoms will develop in the young person. It also indicates that regular psychiatric monitoring can allow early intervention strategies to be implemented if psychiatric issues do emerge.
Aside from these rare situations, the best strategy for predicting risk for psychiatric disorders is based on analysis of a detailed 3-generation psychiatric family history. While data provide empirical information about the chance for similar conditions to develop in relatives of individuals with psychiatric disorders, direct application of these figures to individuals in clinical practice can be misleading and inaccurate. However, a genetic counselor can provide accurate, individualized information about risk in the context of supportive counseling. So, for individuals with a personal or family history of psychiatric disorders who are interested in understanding the chances for other family members to be similarly affected, referral to a genetic counselor for documentation and interpretation of detailed psychiatric family history information is appropriate (see Part A: Additional Resources).
Direct-to-consumer genetic testing. Some companies are providing information about risk for psychiatric disorders, such as schizophrenia and bipolar disorder, directly to the consumer that is based on testing of a small selection of genetic variants that have been implicated in these conditions (eg, www.23andme.com). Physicians of all specialties will increasingly be confronted with patients who need help in understanding the personal meaning and implications of these types of genetic test result. The discussion presented above (and in Part B: Additional Resources) may help physicians in this task; however, referral to genetic counseling services for patients who present with questions in this regard is also appropriate.
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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