Genetic Testing and Psychiatric Disorders
A Statement from the International Society of Psychiatric Genetics
(based on a draft proposed by the appointed Task Force to Review the Genetic Testing for Psychiatric Disorders Statement of 3/20/13; revised 7/12/13; further revised and augmented by members of the Genetic Testing Working Group and sent to the Board of Directors, 4/4/2014; approved 4/22/14; revised 1/26/2017)
Background & Aims
As the primary and largest scientific society focused on the genetics of psychiatric disorders worldwide, the International Society of Psychiatric Genetics recognizes the growing attention given to clinical genetic testing and the questions raised about the value of such testing in psychiatry. We have convened an expert panel to review the available evidence and provide some guidance for the mental health and general medical communities. This statement is based on the best available published evidence to date, and will be reviewed periodically to keep pace with this rapidly changing field.
Views are still evolving about several related issues that we will not handle here. These include the extent and format of genetic test data made available to patients and referring clinicians, prenatal genetic testing, and genetic testing in children. Our recommendations assume that all testing will be done in accordance with local laws and regulations. We discuss the issue of informed consent for genetic testing; testing in individuals who cannot provide informed consent is not covered here.
The main measures for a diagnostic test are analytic validity (does the test accurately measure what it is supposed to measure?) and clinical validity (is there adequate scientific evidence to support the correlation between the genetic variant and a particular health condition or risks?) Regular quality control measures in clinical laboratories are needed to assure analytic validity. Replication is a critically important criterion for clinical validity. A valid test can then be evaluated for clinical utility (is the test likely to provide unique information to improve patient outcomes?). For a detailed discussion of these issues see ref 1.
Genetic Tests to assist Diagnosis and Identification of High-Risk Individuals
There is a history of successful use of genetic tests for several neuropsychiatric disorders, including developmental disorders (e.g., phenylketonuria or PKU, Fragile X syndrome, and Down syndrome or Trisomy 21) and some neurodegenerative diseases (e.g., Huntington’s disease or HD). Depending on the disease, such tests can be used to (1) screen at-risk individuals before onset of symptoms or clinical diagnosis, thus helping guide preventive treatment or long-term planning, or (2) establish the diagnosis after symptoms have appeared. The widely used tests for PKU, Fragile X, and HD have clearly established analytical and clinical validity as well as clinical utility. Although there are no effective therapies yet for Fragile X or HD, confirming the diagnosis provides the clinician and the family with useful information about how the patient’s illness is likely to progress and can help anticipate the needs of patients and their caregivers.
[Patients with dementia are often cared for by psychiatrists. However, there does not appear to be a consensus in the field regarding the appropriate use of genetic tests, such as APOe4, in differential diagnosis of symptomatic individuals with dementia. This subject will not be addressed here. We defer to other sources for the evolving expert opinion in this area, e.g., ref 2.]
In contrast to the disorders mentioned above, major adult psychiatric and substance use disorders, like other common disorders, are generally not caused by single genes or mutations. Genome-wide association studies have found numerous DNA variants that change a single DNA base and which are reproducibly correlated with schizophrenia, bipolar disorder, nicotine dependence, and other mental health problems at accepted levels of statistical significance. However, none of the variants found so far is necessary or sufficient to bring about a psychiatric disorder. Instead, variants increase or decrease risk by a small fraction (much less than 2-fold). Hence, testing one or a few of these variants in isolation is not clinically relevant and not worth pursuing for diagnostic use. More research is needed to determine if testing very large numbers of low-risk variants in aggregate (known as polygenic score or risk allele burden testing) may offer some utility for clinical practice.
A different scenario is presented by chromosomal microdeletions and microduplications (also known as copy number variants or CNVs), which lead to loss or gain of one or many genes within a particular chromosomal region. CNVs may be inherited or arise anew (de novo) during human reproduction. Some inherited and de novo CNVs can confer a substantial risk for disease. However, known CNVs lack diagnostic specificity. A given CNV may increase risk for a range of adult psychiatric illnesses, intellectual disability, autism spectrum disorders, or epilepsy, and may also occur in apparently healthy people. More large, population-based studies are needed to establish the lifetime risk for psychiatric disorder in individuals who carry specific CNVs.
Although CNVs that confer high risk are rare, taken together they may contribute to a significant fraction of cases of psychiatric disorders such as schizophrenia (ref 3). In the US, CNV analysis by microarray is already part of the recommended diagnostic workup for children with autism spectrum disorder, developmental delay, congenital anomalies, or intellectual disability (ref 4). Identification of pathogenic CNVs in adults with schizophrenia or other major mental illnesses may help patients and their families to better understand and accept the diagnosis within a medical context. Identification of pathogenic CNVs may also help diagnose psychiatric disorders that occur in the context of recognized syndromes with important medical and psychiatric implications. Examples include DiGeorge and Phelan-McDermid syndromes, and the imprinting disorder Prader-Willi.
Genetic Tests to Guide Optimal Treatment
While personal and family history are still the most important indicators, in some situations pharmacogenetic markers can supplement clinical information to help guide treatment decisions and reduce the risk of treatment failure or serious adverse events. For example, in patients who receive carbamazepine, the HLA-B*1502 marker that is common in people of Asian ancestry substantially increases risk of acute and serious skin disorders (ref 5).
Some CYP450 enzymes (e.g., CYP2D6, CYP2C19) are highly involved in metabolism of drugs, including antidepressants and antipsychotics. Variation in the genes that encode these enzymes can lead to differences in drug metabolism that can be predicted by genetic markers. Individuals with genetic markers of poor or rapid metabolism may be at higher risk for non-response or adverse events. In view of these findings, expert panels have started to publish dosing guidelines for some medications when CYP450 testing is available (ref 6). Other gene-drug pairings are under active investigation. Other factors that influence treatment outcome (such as use of other medications or treatment resistance) should be taken into account and studied further. Randomized, double-blind clinical trials are needed to establish the clinical utility of genetic testing in psychiatric drug treatment and clarify whether patients benefit substantially from pharmacogenetic testing.
We recommend clinicians follow good medical practice and stay current on changes to drug labeling and adverse event reports. Useful but not exhaustive lists of pharmacogenetic tests are maintained by the Clinical Pharmacogenetics Implementation Consortium (CPIC; ref. 6) and the US Food and Drug Administration (ref 7).
Reporting of Incidental or Secondary findings
Genetic technologies such as next generation sequencing permit readout of an individual’s whole exome or whole genome sequence, and chromosomal microarray screening detects copy number variation across the entire genome. While useful in some contexts, genome-wide screens such as these may generate secondary or incidental findings of potential importance for medical conditions unrelated to the clinical complaint for which these tests were originally performed. Such unanticipated findings may highlight a preventable illness or one that could benefit from early intervention. Some authorities, such as the American College of Medical Genetics (ACMG), recommend that clinicians report some unanticipated findings back to individual patients (ref 8), although this recommendation was not intended for, and remains controversial in, purely research settings.
While we concur with the ACMG recommendations regarding reporting of actionable findings to the referring clinician, a decision to inform a patient about such finding(s) must weigh several factors. These include the seriousness of the implicated disease, the potential medical consequences of nondisclosure, the patient’s stated wish to be informed about such findings (ideally established during pre-test counseling), the patient’s capacity to appreciate the prognostic implications of such finding(s), the patient’s ability to participate in any preventive or therapeutic interventions that might be recommended, and the potential negative impact of disclosure on the patient’s psychological condition, insurability, and quality of life.
Studies have so far found little evidence that returning genetic results poses substantial psychological or behavioral harms (ref 9). However, these studies primarily focused on individuals who were not at high risk for adverse psychological consequences. More research is needed to understand how patients with active psychiatric disorders respond to the unanticipated disclosure of a genetic finding with major implications for health or longevity for themselves and for their close family members.
In general, we support informing patients of potentially actionable findings unless there are compelling reasons to withhold the information. For example, when test results become available during the active phase of an episodic psychotic illness, it may be reasonable to postpone disclosure of non-urgent findings until psychiatric stabilization has been achieved.
Psychological, ethical and clinical implications in genetic testing
When offering any genetic testing, there is a difficult balance between the risks and benefits of acting on a test result. Although psychological preparation for diagnosis and treatment may be among the potential benefits, possible risks include stopping or avoiding beneficial treatments, changing life plans, or deciding to terminate a pregnancy. These risks can have adverse impacts on an individual or a family, particularly when subject to misinformation, incomplete data, or misinterpretation.
Professional counseling is an important means to help patients understand these issues and ameliorate negative effects. The interpretation of genetic risk involves expertise in clinical genetics; supportive, psychotherapeutic, educational, or reproductive counseling may also be needed. Scalability of individual genetic counseling will be a challenge and needs to be addressed as the use of genetic testing increases. While we acknowledge that genetic counseling resources are limited in the context of mental health care, we recommend that any genetic tests ordered for diagnostic purposes and all genome-wide screens should include informed consent procedures and counseling by a professional skilled in both mental health and the interpretation of genetic test results.
Direct-to-consumer (DTC) genetic tests, which can be obtained without a physician’s order, are often used recreationally by people interested in learning more about their ancestry or common traits. The use of DTC genetic tests for medical purposes, however, is prohibited in many countries. The risks posed by medical DTC genetic testing have been addressed in previous statements from the American Society of Human Genetics, the European Society of Human Genetics, and the European Academy of Sciences (ref 10). While more research is needed, we do not recommend DTC genetic testing for medical purposes in patients with psychiatric illness or their families.
Need for Public and Professional Education
We advocate the development and dissemination of clinical and community education programs on psychiatric genetics and pharmacogenetics. Residency training and continuing education programs aimed at mental health professionals should provide sufficient background in genetics so that clinicians know when to recommend genetic testing and can counsel their patients and clients on its proper use and interpretation. Community education should seek to minimize stigma or other disadvantages related to life and health insurance or job security that individuals with psychiatric conditions could experience if they chose to obtain genetic testing in clinical settings. Genetic test results, like all medical records, are private data and must be safeguarded against unauthorized disclosure.
- Single genetic variants are not sufficient to cause psychiatric disorders such as depression, bipolar disorder, substance dependence, or schizophrenia. Thus there are no genetic tests that can establish a diagnosis of these conditions.
- Although they lack diagnostic specificity, certain copy number variants (CNVs) are more prevalent in individuals with autism spectrum disorders, schizophrenia, or other psychiatric disorders, especially when accompanied by intellectual disability. Identification of these CNVs may help diagnose rare conditions that have important medical and psychiatric implications for individual patients and may inform family counseling. Identification of de novo CNVs may also have a place in the management of serious psychiatric disorders, especially those that present atypically or in the context of intellectual disability or certain medical syndromes.
- Some pharmacogenomic tests are useful in reducing risk of adverse events in specific patients. Clinicians should be aware of and consider pharmacogenomic recommendations advanced by regulatory agencies, such as the US Food and Drug Administration, and expert groups, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC).
- Emerging data regarding clinical utility and cost-effectiveness of pharmacogenomic panels are trending in an encouraging direction, but their general use in unselected patients is not well supported by the present body of evidence. Double-blind, randomized clinical trials are needed to clarify whether patients benefit substantially from pharmacogenetic testing.
- Professional counseling can play an important role in the decision to undergo genetic testing and in the interpretation of genetic test results. We recommend that diagnostic and genome-wide genetic testing should include counseling by a professional with expertise in both mental health and the interpretation of genetic tests. Medical genetics consultation may be indicated when test results uncover a recognized genetic disorder or other findings with reproductive or other broad health implications.
- Whenever genome-wide testing is performed, the possibility of incidental (secondary) findings must be communicated in a clear and open manner, and procedures for dealing with such findings should be made explicit. The autonomy of competent patients regarding preferences for notification of incidental findings should be respected.
- We advocate the development and dissemination of clinical and community education programs to enhance knowledge of genetic medicine among trainees and mental health professionals, safeguard the privacy of genetic testing results, and reduce stigma.
- Expanded research efforts are needed to clarify the proper role of genetic testing and its clinical utility in psychiatric care.
- Genetic test results, like all medical records, are private data and must be safeguarded against unauthorized disclosure.
2. Cohn-Hokke et al. 2011; Sorbi et al. 2012; Loy et al. 2014
3. Gershon & Alliey-Rodriguez, 2013; Costain et al. 2013
4. Schaefer et al. 2013; Mefford et al. 2012
5. Amstutz, et al. 2014
6. Hicks et al 2017; Hicks et al. 2015; see also www.cpicpgx.org.
8. Green et al. 2013; ACMG Board of Directors. 2014
9. Green et al., 2009; Christensen et al., 2011, Francke et al., 2013
10. http://www.ashg.org/pdf/dtc_statement.pdf; https://www.eshg.org/fileadmin/www.eshg.org/documents/PPPC/2010-ejhg2010129a.pdf; http://www.easac.eu/fileadmin/Reports/EASAC_Genetic_Testing_Web_complete.pdf