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The Human Genome project has provided an abundance of genetic information, including identification of many disease-causing genes. Clinical applications, genetic counseling and the potential ethical issues raised by the availability of genetic testing are all areas of concern in gene research. Will genetic counseling in classical genetic diseases help to provide guidelines for behavioral disorders?
Many people who have family members afflicted by psychiatric disorders wonder if mental illness is inherited. In fact, over the last several decades, research has provided clinicians with information and empirical risk estimates for some psychiatric disorders. Despite the large body of work, clinical implications of psychiatric genetic data have only recently become apparent. This reflects both increased media attention to genetics, as well as the growing sophistication of patients and their families.
In this article we will address two clinical applications of genetic information. First, we will discuss genetic counseling, which provides general principles to help clinicians communicate genetic risks to patients and family members. Genetic counseling is a well-established medical subspeciality, typically applicable to many rare non-psychiatric medical disorders. Second, we will discuss the potential adverse consequences and the ethical implications raised by the availability of genetic testing. We will illustrate ethical issues using lessons learned from genetic testing in classical Mendelian diseases and discuss established guidelines that may apply to psychiatric disorders.
Purpose of Genetic Counseling
There has been explosive growth in the number of disease genes identified over the past several years, giving clinicians more information about the heritability of many diseases. However, new knowledge can-and often does-create confusion. There are still several misconceptions concerning human genetics and psychiatric illness. The primary purpose of genetic counseling, therefore, is to correct misunderstandings about the heritability of psychiatric disorders, such as:
1.) If a disorder is genetic, it inevitably occurs in those who carry the harmful gene(s). The influence of genetic factors in psychiatric disorders is highly variable. More commonly, environmental and genetic interactions influence most psychiatric conditions. Furthermore, genetic and environmental influences are likely to differ between individuals and have variable impacts on each individual. Thus, the expression of a single disorder is not necessarily the same in each affected individual. It is also possible that an individual who carries the susceptible gene will not develop the disorder.
2.) If a disorder is genetic, it is untreatable. Although many genetic conditions are currently untreatable (for example, Huntington's disease), most psychiatric disorders respond to some form of treatment. Similarly, while the underlying genetics cannot yet be changed, the expression of those genes can be treated. Individuals with identified psychiatric genetic disorders may mitigate the effects of the disorder through medical treatment, psychotherapeutic intervention and lifestyle changes. In addition, much scientific effort has been invested in gene therapy, with the eventual goal of reversing the effects of the deleterious gene. While this may sound like science fiction, gene therapy may become a reality in the future.3.) Genetic counseling is associated with eugenics and genocide. In fact, contemporary genetic counseling is non-directive, with an emphasis on individual autonomy and informed decision-making. The goal of genetic counseling is to disseminate current scientific knowledge concerning the disorder at hand and to aid the consultand (the person seeking genetic counseling) in making the best possible decision.As with other medical conditions, some psychiatric disorders are inherited while others are not. Genetic counseling serves to educate consultands and provide them with information concerning the disorder of interest. The Table* outlines the seven stages of genetic counseling. Multiple visits may be necessary to complete all stages. Genetic counseling should be tailored to the specific needs of the individual and their family. Interested readers are referred to the chapter entitled "Clinical Applications of Psychiatric Genetics" in Genetics in Mental Disorders: A Guide for Students, Clinicians, and Researchers (1999; Guilford Press) for additional details.
Testing in Adult-Onset Disorders
DNA-based tests are the newest technique in testing for genetic disorders. These techniques require direct examination of the DNA molecule (e.g., determination of the number of repeated DNA sequences in the Huntington's disease gene). Other genetic tests include those that detect gene products (e.g., biochemical tests, such as one that screens for phenylketonuria) and those that detect chromosomal changes by microscopic examination of fluorescent chromosomes (e.g., fluorescent in-situ hybridization techniques to screen for velocardiofacial syndrome). Genetic tests are currently used in a variety of situations, including:
According to GeneTests <www.genetests.org>, genetic tests are currently available for over 700 diseases. For many at-risk individuals, the availability of genetic tests gives them the opportunity to relieve uncertainty and to appropriately plan for their future.
For treatable disorders, a positive test can result in a higher level of surveillance as well as intervention to reduce risk. Unfortunately, only a few genetic tests are definitive (e.g., the test for Huntington's disease, which is 99% predictive). In other single-gene disorders, although the presence of a mutation is highly predictive of the disorder (as in some forms of familial early-onset Alzheimer's disease [AD], in which age of onset is consistently before the age of 60), genetic testing is more complicated. Testing for mutations in one of the three known causative genes (presenilin 1) is clinically available. Testing is recommended only in individuals with age of onset of AD younger than 60 and who have another affected family member with early-onset AD. Although apparent sporadic cases of early-onset AD exist, there is still the possibility of false paternity or early death of an asymptomatic parent who carried the mutation. Testing is not recommended for people with late-onset AD, both sporadic and familial.
When testing at-risk individuals, an affected family member should be tested first to confirm the molecular diagnosis of the family. In the absence of this information, a negative test could simply indicate that the family has another genetic form of dementia. Testing for mutations in the two other genes (amyloid precursor protein and presenilin 2) is only available on a research basis. Testing for mutations causative for AD is not useful in predicting the age of onset, severity or type of clinical symptoms, or rate of progression of the disease.
The apolipoprotein E4 (APO E4) should not be used in presymptomatic testing. Although 35% to 60% of AD cases have an E4 allele, its presence is not highly diagnostic of AD. Furthermore, epidemiologic data in presymptomatic individuals with longitudinal follow-up are not well-established. In addition, there is consensus that children at risk for adult-onset disorders should not be tested in the absence of clinical symptoms. Additional information on testing guidelines for AD and other genetic disorders is available on GeneClinics' Web site <www.geneclinics.org>.
In more common diseases, such as adult-onset cancers and coronary artery disease, only age-adjusted risk estimates can be provided. Likewise, most psychiatric disorders are presumed to be multifactorial (e.g., due to multiple genes and gene-environmental interactions). Many uncertainties regarding future presymptomatic testing in psychiatric disorders remain. Testing guidelines for individual disorders depends on who is at risk for specific disorders, the accuracy of risk prediction, the best age to provide test results and how the genetic test results are to be used to improve the lives of those tested.
Informed consent is the guiding principle behind the ethics of clinical practice and genetics research and testing. Consultands who choose to undergo genetic testing for clinical reasons should be thoroughly informed about the risks and benefits of the procedure and should always have the option to terminate the process. The counselor should discuss the potential social consequences of genetic testing with consultands. Unlike other laboratory tests, genetic tests may also reveal information about other family members, who, in turn, may or may not want access to this information. Part of the consent process should routinely describe the confidentiality of the data, although clinicians must inform the consultand that the genetic information is part of their medical records. Since stigmatization may occur as a consequence of test results, consultands should review their life and disability insurance prior to testing, as insurance companies have argued that they should have access to presymptomatic genetic testing results.
To compute the costs of health and life insurance, actuaries take into account many factors known to predict disease and death. Few people can argue with the rationale that smokers should pay higher health insurance premiums than non-smokers. Does a parallel argument justify the use of genetic information? Theoretically, insurance companies should have access to genetic profiles of individuals who apply for insurance. Should those who are at risk for untreatable or chronically debilitating disorders pay higher insurance premiums? Should insurance companies have the right to deny coverage to those individuals?
In the same vein, employers may want access to employee records regarding medical information including risk factors for genetic disorders since potential at-risk employees could eventually become less productive, and they may increase health care costs. Understandably, there is reason for concern that discrimination based on genetic testing could occur. Proponents have argued that employers should have access to genetic test results for disorders that may impair judgment and job performance in occupations involving the safety of the general public (e.g., commercial airline pilots and physicians).
The implications of the Human Genome Project have not escaped the attention of legislators. In the United States, several states have already enacted genetic privacy laws. In general, these laws limit the use of genetic data by insurance companies. However, the idea that genetic data should be treated differently from other clinical data has been hotly debated. Society can anticipate additional ethical and legal debates. Indeed, such debates are likely to intensify as the ability to predict behavioral and personality traits becomes a reality. Society will then have to decide the ethical, legal and social implications of this new knowledge. Much work is ongoing as part of the Ethical, Legal, and Social Implications Program of the Human Genome Project. (For additional information, please visit <www.nhgri.nih.gov/ELSI/> or <www.ornl.gov/hgmis/elsi/elsi.html>.)
The Human Genome Project will undoubtedly provide an abundance of data to assist researchers in identifying the genes that contribute to human behavioral disorders. With the working draft of the human genome in hand, identification of genes relevant to human behavior continues. The implications of genetic data for diagnosing and treating psychiatric disorders remain speculative. Clinical applications often arise during the mature phases of a scientific discipline. As psychiatric genetics enters into the gene identification era, more clinical applications will be discovered. Although the future of psychiatric genetics will answer many scientific and clinical questions, it will also raise many questions about the legal, ethical and social implications of these answers. Medical and scientific advances may bring many gifts to society in the form of new knowledge; as clinicians and scientists, we should approach this new knowledge with caution, as one of these gifts could be a Pandora's box.
*Table only available in publication.