Ethical Considerations in Psychiatric Genetics

Since the 1980s, molecular genetics researchers have found more than 1,000 mutations associated with highly penetrant genetic disorders such as HD, cystic fibrosis, and muscular dystrophy (7). These triumphs of gene finding have been followed by the availability of clinical genetic testing to detect carrier status and to predict whether at-risk individuals actually develop disease. During the early days of gene-finding research, media reporters, experts, and public figures tended to describe DNA in awe-inspiring, even mystical terms, for example, as the “code of life,” the “book of life,” “central to our core” (20), “uniquely powerful and uniquely personal” (23), “the language in which God created man” (24), and a “future diary” (23) that could foretell the rest of one's life. Such language suggests that there will be tremendous benefits to learning genetic information, and great harm if the privacy of one's genetic “future diary” were violated.

This deterministic view of genetics formed the backdrop for early conceptual and empirical ethics studies. Investigations of highly penetrant disorders enabled a cataloging of risks and benefits of predictive genetic testing in the research and clinical context (25). These risks and benefits can be categorized as medical (i.e., interventions to reduce the impact of the illness or biological side effects of interventions) and psychosocial (i.e., peace of mind, life planning, psychological distress, social stigmatization, and discrimination) (13, 26–28). Patient-centered safeguards, such as confidentiality protections, careful attention to the informed consent process, and genetic counseling, were put in place to protect individuals against potential harms and to enhance autonomous decision making (13). Thorny ethical issues arising in specific testing contexts were identified and described, such as the person with a known predisposition to HD who refuses to disclose this information to family members (29, 30), parents who seek to have minor children tested for adult-onset conditions with no preventive treatment (31–33), or pregnant couples wishing to obtain prenatal testing and abortion for a mild genetic disability that does not preclude a satisfactory quality of life (16, 17).

Highly penetrant disorders are rare in the overall population, however, and they are not necessarily good models for understanding either the genetics or the “genethics” of the vast burden of human illnesses (26) including the major psychiatric diseases, which have complex inheritance. Complex inheritance disorders, sometimes called multifactorial illnesses, are caused by a combination of at least two and perhaps hundreds of genes and nongenetic factors such as environmental and epigenetic influences (i.e., patterns of DNA methylation and histone modification) (34). It now appears that multiple genes are involved in the etiology of most mental disorders, each gene contributing a small amount of increased risk (7).

Unlike genetic tests for highly penetrant disorders, tests for individual genetic variants associated with most cases of psychiatric disorders have been expected to have low predictive power (an absolute increase or decrease in risk on the order of a few percentage points), and the risk variants have been expected to be common in the population (7). Eventually, it may be possible to test for a combination of susceptibility variants to achieve much greater predictive power (35), although genotyping alone will never provide results with 100% power because of the contributions of environment and epigenetic factors.

The lack of certainty associated with susceptibility genotyping is likely to engender a number of ethical dilemmas. For example, in the future it may be possible to use genotyping in the research context to help identify individuals who are at increased risk of developing mental disorders. Such individuals may then be enrolled into protocols designed to test interventions to prevent or ameliorate disease. The potential benefits of this line of research are tremendous, but they must be balanced against the risks of genetic labeling. For example, a child who is considered to be at elevated risk for schizophrenia may be viewed negatively by others, and the effects of this knowledge on the developing sense of self may be devastating. More well-known risks include the harms associated with any interventions provided to high-risk individuals (36–38). Will it be ethical, for example, to conduct studies in which antipsychotic medications are administered to adolescents whose genotype suggests that they have a 20% risk of schizophrenia, given that the majority of those treated will incur unnecessary biological and psychosocial risks? What if the likelihood of illness is slightly higher or lower, the disorder more or less stigmatized, or the intervention more or less benign?

Regarding the clinical use of susceptibility genotyping, it has been argued that low predictive power will prevent such tests from ever being viable (39). It appears, however, that commercial interests may propel psychiatric susceptibility testing onto the market in advance of empirical evidence of clinical utility. In 2007, for example, a diagnostic genetic test for bipolar disorder based on variants in the GRK3 gene became available from an Internet-based laboratory (40). Results of this test were to provide risk estimates for bipolar disorder of 2% or 3% (versus 1% at baseline). Other psychiatric genetic tests have been proposed as well (41).

The ethical implications of the commercialization of psychiatric genotyping will be discussed later in this article. For now, we will consider difficulties particular to working with probabilistic tests, such as the hurdles that must be overcome to ensure informed consent and to avoid misinterpretation of tests. A growing literature suggests that patients' interpretation of risk estimates is extraordinarily complex (42–46) influenced by cognitive, affective, and cultural factors. We know very little about how individuals will understand and act upon the results of tests that provide subtle information about the risk of highly stigmatized disorders. Furthermore, moral questions arise about what level of absolute risk increase is sufficient for specific applications, such as prenatal testing or clinical susceptibility testing to aid life planning.

Existing empirical evidence sheds some light on one aspect of this issue: how the probabilistic nature of genetic information may affect consumer interest in genetic testing. A number of investigators have surveyed patients and families about their attitudes toward genetic testing for psychiatric illnesses and have generally found keen interest in clinical genotyping (47–59) Early survey instruments tended to present psychiatric genetics in highly deterministic terms, but later work has emphasized the probabilistic nature of genetic testing. If we consider only the studies that specifically mentioned that psychiatric susceptibility testing might not be 100% predictive, the data still demonstrate that patients and families see a substantial benefit to genetic testing for the purposes of life planning and early diagnosis (49, 50, 53, 55, 56, 58). Patients and families appear to be more focused on the perceived benefits of testing and less focused on the risks than clinicians or researchers (56). This disparity may be the result of the layperson's lack of awareness of the risks of genetic testing. It may also be that individuals who have intimate experience in living with mental illness are more attuned to the benefits of information that could guide treatment or future plans.

Another possibility is that consumers' interest in genetic information is related to an exaggerated sense of the risk of recurrence of mental disorders. Evidence of such an association was provided by Austin et al. (57) in a web-based survey of 116 family members of individuals with mental illnesses who were identified through a consumer web site regarding psychosis. Most respondents incorrectly estimated the risk for psychosis in the sibling of an affected person, with 45% overestimating the risk and 8% underestimating the risk. The investigators found that the overestimation of risk was associated with more positive views toward predictive genetic testing in general and specifically during pregnancy. This finding is consistent with the existing literature on prenatal testing for other disorders, whose uptake appears more dependent upon individuals' perception of risk than actual risk (60). It is also consistent with studies of interest in testing for genetic susceptibility to breast and ovarian cancer (61).

The ethical principles of beneficence and nonmaleficence suggest that careful attention must be paid to the psychosocial effects of psychiatric genetics to maximize the personal and social benefits and to minimize the risks. Understanding these risks and benefits is also necessary to fulfill the ethical duty of respect for persons, which requires researchers and clinicians to provide information about the likely results of medical interventions to obtain fully informed consent. Finally, justice requires consideration of the potential social harms that may befall individuals and groups as a result of their participation in clinical and research activities.

In theory, psychosocial effects may be especially strong in the case of psychiatric disorders. Mental illnesses affect emotions, cognitions, and behavior; as such, they may seem more inextricably bound to one's personhood than disorders that are exclusively somatic. Given the pervasive stigma of mental illness, people who are thought to be susceptible to these disorders may be more vulnerable to discrimination and stigmatization. Furthermore, because many psychiatric disorders begin in young adulthood, genetic information about disease susceptibility may be obtained relatively early in life, with unknown results on an individual's developing sense of self and future prospects. The sections below will consider empirical evidence regarding the likely quality and magnitude of three types of psychosocial effects in psychiatric genetics—psychological consequences, insurance and employment discrimination, and social stigmatization.

By its nature, genetic information has implications and consequences for third parties: biological relatives. This phenomenon is not unique to genetics; for example, information about infectious diseases also applies to a patient's contacts (19, 20). As with infectious diseases, the impact of genetic information on third parties can present an ethical dilemma between the need to protect an individual's confidentiality and the third party's “right to know” information that may bear on his or her health. This conflict was the central question in a New Jersey court case brought by a woman with an autosomal dominant form of colon cancer, whose father had died of the same disease. The father's physician had not informed the patient or his family that the illness was heritable and could be prevented with colectomy. The New Jersey Superior Court ruled in favor of the plaintiff, finding that a physician had a “duty to warn” those at risk of avoidable harm due to genetic conditions (81).

The flip side of this situation is the family member who does not wish to know his or her genotype, but who will be deprived of the “right not to know” if a relative is tested. This conflict may occur in certain unusual clinical situations, for example, when an adult grandchild of a person with a highly penetrant genetic disorder wishes to have predictive testing, but the grandchild's parent does not. Such ethical dilemmas are not likely to become commonplace, however, in psychiatric practice. The complex inheritance of mental disorders means that susceptibility testing for these illnesses will provide less directly pertinent information about risks to relatives than testing for Mendelian disorders with clear autosomal dominant, recessive, or X-linked patterns of inheritance.

More far-reaching ethical issues arise because genetic information may also be used to characterize larger groups of related persons, including communities and populations. There are public health benefits to conducting molecular genetic research on complex inheritance diseases using samples from ethnically and geographically diverse populations, as well as scientific benefits to using samples derived from genetically isolated populations (82). Such groups include the Hutterites, Old Order Amish, Ashkenazi Jews, Pima Native Americans, and isolated subpopulations in Colombia, Costa Rica, Finland, Guatemala, Iceland, Japan, and Sardinia.

Molecular research that compares frequencies of genetic variants associated with stigmatized disorders among subpopulations may unintentionally feed racist beliefs if results are misinterpreted to mean that a given group is especially prone to the disease (82). Growing concerns about group stigmatization based on genetic research have led some minorities to contemplate “opting out of genetic research until it's clear we're not going to use science to validate prejudices” (83). Indeed, in April 2010 Arizona's Havasupai Native American tribe won a $700,000 settlement with Arizona State University because university researchers had used the tribal members' DNA to study ancestry and mental illnesses such as schizophrenia. Although research participants had signed consent forms, many believed the study would be limited to diabetes and found the other research topics stigmatizing or culturally objectionable. As part of the settlement, blood samples were returned to the tribe (84).

The possibility of population-based stigma and discrimination represents a significant burden on groups being studied, which must be balanced by benefits to the same community from the very same research (14). To some bioethicists, the emerging importance of this issue has suggested a need to reconceptualize the dominant ethical considerations in genetic research from autonomy-based ethics to a more communitarian ethics that focuses on the risks and benefits of research for communities and populations rather than for individual participants (14).

Psychiatric genetics, as a body of scientific knowledge and a set of clinical activities, is far from being fully mature. There is scientific consensus that the common mental disorders are heritable and that a number of genetic variants are likely to be involved in most illnesses (7), but there is no firm consensus about which specific genes are associated with which mental illnesses, with the exception of APOE and AD (34). In the clinical setting, genetic testing for susceptibility and for drug metabolism and response is just beginning to be applied in psychiatry, but we have few or no data to guide us about their medical and psychosocial outcomes. In the future, it should be possible to make carefully reasoned judgments about the utility and morality of specific types of psychiatric genetic activities, but until then we will also grapple with ethical issues particular to an innovative and evolving technology.

Methodologies for psychiatric genetic research have changed dramatically in recent years, the result of sequencing the human genome and completing the International HapMap project to characterize human variation across the genome (85) along with technological advances that enable rapid and relatively inexpensive genotyping. Genetic protocols are becoming grander in scale (e.g., studies of genetic variation among populations of entire countries), in longitudinal sweep (protocols in which DNA is banked for future study), and in the complexity of information that they gather (genotypic data that are linked with phenotypic data, including complex and continually updated medical records). The rapid development of the “genome era” of medical research has ushered in new ethical concerns (14, 86–88). Today's investigators and research participants are unlikely to anticipate all future research uses of genetic material in stored samples, for example, and there is as yet no firm consensus about whether and how informed consent should be obtained for future projects (89–95). There is also a lack of agreement concerning measures to protect confidentiality of study data while allowing multiple investigators access to genotypic information linked to medical records or other phenotypic data (86–89). Institutional review boards may therefore lack consistent methods for evaluating informed consent forms, confidentiality protections, and other protocol elements (96).

Another set of ethical issues concerns whether and how new applications should be introduced clinically. It will require considerable research funding and many years to gather detailed information about the psychosocial and medical outcomes of genetic counseling and testing for specific psychiatric disorders. Even our understanding of the full implications of testing for a single genetic variant may be incomplete for many years. Because of the phenomenon of genetic pleiotropy (i.e., when a single gene has multiple biological effects), a test for a genetic variant that is associated with one condition today may in the future be found to yield information about susceptibility to another condition (97). For example, the APOE genotype is associated not only with the risk of AD but also with the risk of cardiovascular disease (98). Another example is the serotonin transporter gene, which is associated with response to selective serotonin reuptake inhibitors (99). Pharmacogenetic testing for variants of this gene is now clinically available as an aid in selecting an antidepressant treatment (100). The serotonin transporter gene has also been associated, however, with a large number of psychiatric syndromes. In the future, information that had been sought solely for pharmacogenetic purposes may yield unwanted and unanticipated information about the risk of other conditions (97).

A third ethical issue that derives from the newness of the psychiatric genome era is that it is unclear who should bear ethical and legal responsibility for its clinical applications. On one hand, most psychiatrists are not trained in genetic counseling and testing (101–103) and do not seem prepared to provide these services (54, 101, 102). On the other hand, the current number of certified genetic counselors and fellowship-trained clinical geneticists is likely to be too small to meet the projected need for future counseling and testing (104). Furthermore, the genetics professionals may not feel adequately trained to work with psychiatric patients (105). Increased education and training in psychiatric genetics appears necessary for both groups. A multidisciplinary approach to clinical care, involving both psychiatrists and genetic counselors, has also been suggested (103).

It is possible that the emerging phenomenon of direct-to-consumer (DTC) genetic testing via Internet laboratories may move psychiatric testing out of the clinic entirely (106–108). DTC genetic testing is now available for a variety of purposes—paternity testing, ancestry tracing, pharmacogenetic testing, and even whole-genome single nucleotide polymorphism genotyping to “help you read and understand your DNA.” (109)

DTC genetic testing is legal in many states, and there is little federal oversight, although professional groups such as the American Society for Human Genetics have raised many concerns (110). The rapid—and virtually unregulated—commercialization of genetic testing is worrisome, evoking memories of the naive treatment of fluoroscopy in the last century, when shoe stores across the United States offered “X-ray shoe fitters” as novelty devices that exposed countless individuals to significant levels of radiation (111, 112). There are few published data specifically regarding the ethical issues of DTC genetic testing in psychiatry, with the exception of the questionnaire survey of a small random sample of U.S. psychiatrists of Hoop et al. (59), in which 100% agreed that laws and regulations should require DTC advertising for genetic testing to be truthful and to describe risks as well as benefits, and 96% agreed that there should be restrictions on the DTC sale of psychiatric genetic testing kits.

Nevertheless, DTC genetic testing may offer some benefits, particularly for stigmatized illnesses, because individuals seeking testing may place a very high premium on privacy. The precedent of HIV testing may be relevant in this context. An over-the-counter kit for HIV testing is currently available, and in-home HIV testing has been proposed as a way to make such testing more anonymous, thereby decreasing its stigma, increasing the empowerment of health care consumers, and increasing the use of HIV tests among young people (113). An important difference between HIV testing and susceptibility testing for psychiatric illness, however, is that HIV-testing kits have high positive and negative predictive power, indicating less need to be concerned about the misinterpretation of test results. Another difference is the public health importance of knowing one's HIV status, enabling people to benefit from available treatment and to take steps to avoid infecting others; there are no similar benefits to psychiatric genetic testing at this time.

Finally, new and innovative technologies tend to be costly, which raises the ethical issue of distributive justice and the equitable distribution of social benefits and burdens. If clinical genotyping proves efficacious, it is unclear what the impact will be on existing health care disparities in the United States (114).

This article has attempted to highlight the diversity and fluidity of ethical concerns in psychiatric genetics and to identify areas in most urgent need of research. It is clear that the study of genetics/ethics, like the study of genetics itself, has moved further and further away from a reductionist stance and is now engaged in the process of uncovering complexity. The wide variety of psychiatric genetics activities described here cannot be squeezed into a “one size fits all” ethics.

During the past few decades, psychiatric genetics (like many emerging technologies) (118) has tended to provoke passionate debate and polarized views. Genetics is often described as either a boon or a scourge. These perspectives may become more entrenched if the early commercialization of psychiatric genetic testing becomes more widespread and especially if it results in demonstrable harm. It is to be hoped that that will not occur and that geneticists, social scientists, bioethicists, and clinicians will be challenged, instead, to look for new ways to collaborate and to learn more, in turn, about the true risks and the benefits of the genome era in psychiatry. Respectful dialogue among individuals with varied perspectives is no doubt the best way to begin to understand the complex interplay of biology, medicine, psychology, sociology, and ethics in psychiatric genetics.

I thank Dr. Laura Roberts for her helpful comments on this article, and Ann Tennier, ELS, and Krisy Edenharder for their skillful assistance in the preparation of this article.