MENTAL DISORDERS AND GENETICS: WHAT WE KNOW TODAY

MENTAL DISORDERS AND GENETICS: WHAT WE KNOW TODAY

Mental Illness

Mental illnesses profoundly affect an individual's ability to think, feel, and act. They are also very common, affecting as many as one in five Americans over their lifetimes, irrespective of age, gender, or race. Four percent of the Nation's population lives with severe mental illnesses. The annual cost to the United States for treatment, social service and disability payments, lost productivity, and premature mortality is more than $150 billion.1 The diagnosis, treatment, and prevention of mental illnesses continue to be crucial to improving the quality of life for affected individuals, as well as to reduce health care costs.

Researchers and clinicians have worked for decades to reduce the suffering of those with these disabling disorders, and current treatments can alleviate symptoms for many. Unfortunately, none of these treatments offer sustained relief. Better treatments depend on discovering the causes of these disorders.

Although mental disorders were recognized as illnesses in the mid-18th century, suspicion and fear often overshadowed understanding. Gradually, trepidation has been replaced by knowledge as the fields of psychiatry, behavioral science, neuroscience, biology, and genetics have progressed. Through research conducted in each of these domains, a shared finding arises: the risk of developing an illness is increased if another family member is similarly affected, suggesting a strong hereditary component.

This finding of familial risk has been documented through twin studies, which use two types of twin pairs for exploring the role of inheritance. Identical or monozygotic twins come from the same fertilized egg and share 100 percent of their genes.2 Fraternal or dizygotic twins come from two different fertilized eggs and share only 50 percent of their genes, just as any biological siblings would. To evaluate heritability, the rate of the disorder in monozygotic twins is compared with the rate in dizygotic twins. If the rate among monozygotic twins is significantly higher, then heredity is an important factor. For instance, in bipolar disorder, if one monozygotic twin is affected, then the other has a 60 to 80 percent chance of also having the disorder. In contrast, a dizygotic twin of an affected individual has only an 8 percent chance of having the disorder. Similarly, a monozygotic twin of a person with schizophrenia has a 46 percent chance of being affected, whereas a dizygotic twin has only a 14 percent chance of being affected.

Despite strong evidence for genetic susceptibility, no specific gene has been unambiguously identified for common forms of mental disorders. Many researchers believe that this is due, in part, to the critical role that the environment plays in modulating genetic susceptibility in mental disorders. Citing the twin studies above, researchers point out that monozygotic twins are not always concordant (i.e., do not share the disorder). Clearly, if twins with the same genes do not both have the disorder, there is strong evidence for the role of environmental factors.

Researchers may differ on their estimates of the amount that genes and the environment each contribute to the onset of mental disorders, but once a genetic component is reliably implicated, the search for the source and the location of the apparent genetic component underlying the mental disorder can begin. The estimate of the influence of environmental factors on the disorder provides an index of how difficult the search will be.

Models of Genetic Transmission

When people get sick, they want to know what disease they have and whether it can be treated. Their next question is often, 'How did I get this disease?' Patients understand that knowing something about the causes of the illness can help their treatment and possibly prevent the spread of the disease. This intuitive link is the essence of medical research. The more learned about the natural course of the disease, the easier it is to test ideas about how the disease may be spread or cured. As ideas about treating the disorder are tested, the understanding of the disease becomes more sophisticated.

Genetic causes of certain diseases have been known for many years. The mutation in hemoglobin that leads to sickle-cell anemia was discovered more than 40 years ago. Many people are familiar with this kind of recessive genetic disorder, in which both parents pass along the affected form of the gene, resulting in the child's illness. More recently, investigators identified the gene for Huntington's disease, a serious disorder characterized by progressive deterioration of physical and mental functioning. Huntington's disease is caused by classic dominant transmission: people who receive just one affected gene from either parent develop the disease. These two types of transmission, in which dominant or recessive genes cause a disorder, are called 'simple Mendelian models' because they are based on the rules of heredity codified by Gregor Mendel more than a century ago through his work with pea plants.

Most common medical diseases do not follow the rules of Mendelian inheritance. Instead, these complex disorders are influenced by multiple susceptibility genes, each of which contributes to the disorder. These genes may interact in com-plicated ways to increase or decrease susceptibility. The more genes necessary for a disorder, the harder it is to detect any one of them. This difficulty is magnified by the role of environmental factors.

Successfully tracking disease-related genes requires a population of individuals with the genetic variant and a means of identifying the genes in the population. Ideally, the definition of a disease should be clear enough so that all of the diagnosed individuals have relatively uniform symptoms, improving the chances for unambiguously identifying affected individuals for study. In sickle-cell anemia, for instance, experts and nonexperts can look through a microscope and see if the specific deformation of the blood cell - and therefore the disease - is present. For mental disorders, however, no clear biological test has been found. Further, investigators have had trouble discriminating specific forms of mental disorders, such as distinguishing someone exper-iencing depression as part of a depressive disorder from someone experiencing depression as part of bipolar disorder (also called manic-depressive disorder). Nonetheless, much progress has been made over the years, and researchers have developed procedures to permit the reliable and valid diagnosis of many mental disorders.

Understanding genetic influences on mental disorders and other complex diseases is further complicated by the fact that a given susceptibility gene may or may not result in the disorder. This ambiguity could be due to environmental influences or interactions with other genes. As an added complication, various combinations of genes may all lead to the same disorder.

Mental disorders will be considerably more difficult to understand than sickle-cell anemia and Huntington's disease. Such challenges are daunting, but with the tools and the talent available today, they are not insurmountable. The search for susceptibility genes in mental disorders will be exciting and potentially life-changing for many.

The Tools of the Trade: Models for Locating Genes

The human genome is the complete set of genetic instructions for an individual, one version from the mother and one from the father. Though the DNA from any two people is roughly 99.9 percent identical, the variation in this tenth of a percent is the source of human biological diversity. Inherited susceptibility to various diseases, which occurs when a particular form of the gene fails to give correct instructions for a trait or function, is one small part of this diversity. Researchers look for this unidentified gene by constructing finer and finer maps of known gene locations and functions or by comparing the DNA of affected and unaffected individuals.

The first phase of identifying a disease-related gene is the collection of diagnostic information and blood samples from an appropriate set of affected individuals and their relatives. Typically, blood samples are drawn from family members, and the blood cells are transformed to preserve them. These transformed cells, called cell lines, can then be used to make DNA in unlimited quantities, allowing many researchers access to this resource. The art of this collection phase is in identifying appropriate families. Those in which affected individuals have very similar symptoms are preferable, since members of such a similar group are more likely to carry the same form of the gene than a symptomatically diverse family. At this stage, having valid and definitive criteria that accurately determine a particular diagnosis may make the difference between success and failure. The actual research designs selected in molecular genetics studies and the selected participants are closely allied, as indicated below:

Linkage studies are widely used to detect and locate genes that determine susceptibility to mental disorders. These studies are often based on the identification of large, densely affected families so that the inheritance patterns of known sections of DNA (called 'markers') can be compared to the family's transmission of the disorder. If a known marker can be correlated with the presence or absence of the disorder, this finding narrows the location of the suspect gene. Great strides in linkage analysis, including laboratory and statistical methods, are increasing the power of this method and decreasing its cost.

Linkage-disequilibrium studies in isolated populations capitalize on the likelihood that the susceptibility genes for a particular disorder probably came from one or a few founding members. Whether the isolation is geographic or cultural, there are fewer individuals in the community's genealogies and therefore fewer variations of the disease genes within the population. This limited variation makes the search easier. In addition, the groups of markers that surround each of these susceptibility genes are likely to have the same limited variation, which further simplifies identification.

Association studies depend on the investigator hypothesizing that a specific gene or genes may influence the disorder. In this type of study, the investigator examines whether those people with the disorder have a different version of the gene than those without the disorder among related or unrelated individuals.

Pinpointing the likely genetic anomaly in linkage and linkage-disequilibrium studies occurs once an investigator narrows the search to a fairly small region in the genome. That 'small' region, however, may still be large enough to contain DNA that codes for dozens of traits, and the investigator must now choose which parts of the region to study further. Because the NIH Human Genome Project is well on the way to identifying the location of all genes, this mapping of the human genome will greatly simplify the identification of possible susceptibility genes. Once the genes in a narrow DNA region are cataloged, they may each be tested and the susceptibility gene identified.

The Promise of Genetic Research

The discovery of specific gene forms related to mental disorders holds great promise for advancing diagnosis and treatment of the mental disorders. Genetic characterization of affected individuals will offer insight into molecular and biochemical subcategories of the disorder that clinicians may not be able to discern. This more accurate diagnosis can direct better tailoring of today's treatments and initiate new lines of treatment development targeted specifically to the contributing factor. Even if there are many factors required to fully understand complex mental disorders, interventions aimed at just one factor may be a successful prevention or treatment strategy.

Genetic identification will permit predictive screening for mental disorders to help affected individuals and their families prepare medically, emotionally, and financially and make helpful lifestyle changes. Predictive screening will greatly increase the feasibility of prevention studies, since interventions can be tailored for and provided to individuals at high risk of developing a given disorder.

THE WORKGROUP'S DELIBERATIONS

Overview

The Workgroup was charged by Dr. Hyman to advise the Institute on the opportunities for moving forward in understanding the genetics of mental disorders. To fulfill this charge (see Charge to the Workgroup), the Workgroup's initial deliberations focused on the Institute's current portfolio. Abstracts for every funded extramural genetics grant were reviewed, as were descriptions of the four intramural genetics laboratories. For a wider perspective, letters were mailed to all NIMH genetics grantees funded during fiscal year 1996, asking for advice on the pressing issues in molecular genetics. Advocacy groups and professional societies also were canvassed by mail. The Institute's extramural and intramural staff were invited to meet with the Workgroup to describe their programs, the activities they had undertaken, and their future goals. To more personally reach the community of researchers, senior and junior investigators were invited to meet with the Workgroup. Representatives of international collaborations, private industry, and other institutes also addressed the Workgroup. A list of speakers is presented in Appendix C. Finally, the Workgroup commissioned a summary of the published findings on the genetics of mental disorders by Dr. Steven Moldin, a member of NIMH's extramural staff.

Charge to the Workgroup

The Workgroup is charged with reviewing the Institute's extramural and intramural research portfolio and developmental activities in molecular genetics. Based on these findings and the Workgroup's broad understanding of the field, the Workgroup should make recommendations regarding future research initiatives by disorder, necessary infrastructure development, and administrative changes that the Institute should undertake to facilitate the search for the genes that influence mental disorders.

Status of the NIMH Extramural Research Program

The Workgroup began the extramural portfolio review by examining the Institute's holdings during fiscal year 1996. Although just a year's effort, this sampling contains work that was submitted, reviewed, and funded over the last 4 to 5 years. Given the rapidly developing field of molecular genetics, this retrospective assessment appeared sufficient.

Using a broad definition of genetics research (i.e., grants that involve genetic approaches or will have ramifications for understanding genetics), NIMH sponsored 318 grants for a total of $81.8 million in fiscal year l996. Using a narrow definition of genetics research (i.e., grants that involve genetic approaches), NIMH supported 173 grants involving genetic approaches to neuroscience, behavioral, and clinical phenomena for a total of $44.5 million in fiscal year 1996. This amount is a sizable portion of the NIMH budget, approximately 10.1 percent of its non-AIDS l996 extramural research budget of $438.6 million. The portfolio was found to be diverse and promising. The breadth of the non-clinical research is an important investment that will serve the field well in developing new approaches for isolating susceptibility genes and in responding to the anticipated discovery of such genes.

The Workgroup focused its attention on the equally diverse clinical genetics portfolio. For this portion of the NIMH funded grants, the Workgroup also reviewed information culled by the NIMH staff regarding the 107 clinical genetics grants. This overview provided a summary of approaches, progress, opportunities, and needs. Of the 107 grants, 6 pertain to statistical model development and 7 to the analysis of existing data sets; 39 are new data collection efforts. Table 1 provides an overview of the disorder areas in which the new data collections are underway. In these new collection efforts, 52 percent are linkage studies, and 48 percent are association studies with or without a linkage component. The Workgroup also considered the populations under study, genotyping strategies,3 and statistical analysis plans.

Table 1

Disorders of interest

Disordera Frequency %

Mood disorder 14.5b 37

Schizophrenia 11 28

Childhood disorder 7.5b 19

Alzheimer's disease 3 8

Anxiety disorder 3 8

aMood disorder = bipolar or depressive disorder; childhood disorder = affective disorder, attention-deficit hyperactivity disorder (ADHD), or Tourette's syndrome; anxiety disorder = panic disorder or obsessive-compulsive disorder.

bOne grant focused on two disorders.

The educational backgrounds of the principal investigators (PIs), as described in the grant applications, are summarized in Table 2. Grantees requested consultation from molecular or statistical geneticists in 77 and 69 percent of the grants, respectively.

Table 2

Background of principal investigators (n=39)

Background Number %

Ph.D. in genetics or related field; M.D. medical geneticist 9 23

Postdoctoral training in genetics 14 36

No degree or training in genetics 16 41

The Workgroup also reviewed the number of participants and families proposed for collection and the number currently collected. The figures for selected disorders appear in Table 3 and are based on data from the original grant applications and all available progress reports.

Table 3

Data collection

Disorder Proposed

Families Families

Collected Individuals

Collected Affected Individuals

Collected

Anxiety disorder 183 172 693 170

Childhood disorder 1,274 186 846 215

Mood disorder 560 325 4,977 880

Schizophrenia 1,095 719 5,155 1,700

NIMH undertook a special large-scale initiative in molecular genetics in 1989. The goal of the NIMH Genetics Initiative,4 which was well ahead of its time, was to collect enough families to find the genes that influence the onset of selected mental disorders. The Initiative also enabled the establishment of a national repository of demographic, clinical, diagnostic, and genetic data from individuals with bipolar disorder, schizophrenia, or Alzheimer's disease to aid researchers in identifying factors responsible for these disorders.

IRP's New Mission Statement

The IRP conducts basic, clinical, and translational research to advance understanding of the causes, treatments, and prevention of mental disorders through the study of normal and abnormal brain function and behavior. The IRP supports outstanding research that, in part, complements extramural research activities and utilizes the special resources of the National Institutes of Health. The IRP provides an environment conducive to the training and development of clinical and basic scientists. The IRP fosters standards of excellence in the provision of clinical care to research subjects and in the translation of research into effective treatment. The IRP serves as a national resource in response to requests made by the Administration, members of Congress, and citizens? groups for information regarding mental illness.

Diagnosis, family history, and DNA samples were collected using identical procedures across multiple sites. The collecting researchers were given a 12-month proprietary period to analyze their data, at the end of which the data were made available to other qualified investigators. The repository contains information on 862 individuals with Alzheimer's disease, 432 with bipolar disorder, and 270 with schizophrenia.

These researchers founded a valuable resource that is in high demand. Requesting investigators receive a file of demographic and diagnostic variables necessary for genetic analysis, with accompanying documentation, access to DNA samples, a code manual listing additional clinical and demographic data, and pedigree drawings. NIMH supports the repository through a contract and by requesters' fees.

Status of the NIMH Intramural Research Program

The Intramural Research Program (IRP) just underwent a significant review, which is reported in Finding the Balance: Report of the National Institute of Mental Health's Intramural Research Planning Committee (1997). The Committee strongly endorsed the role of the IRP and offered a new mission statement (see IRP's New Mission Statement). The report's 77 recommendations covered leadership, quality of science, training and mentoring, and clinical research as well as recruitment, retention, and retirement.

The Acting Director, Acting Deputy Director, and chiefs from each of the four IRP genetics laboratories briefed the Workgroup. This meeting occurred just as the IRP was beginning to implement the report's recommendations. Needless to say, this was a time of considerable flux, and the Workgroup was particularly appreciative of the IRP staff members' generosity in once again discussing their research programs. The Workgroup heard about each chief's approach to genetics, research plans, and collaborative activities. Written materials also were disseminated, which included selected publications, protocols, and strategy documents. These discussions and materials were enhanced by an overview from the IRP's Acting Director and Acting Deputy Director. In addition, NIMH budget staff provided overall figures for the Institute's IRP expenditures in this area. The Institute reports a total expenditure of $15.7 million in fiscal year 1995 and $10.3 million in fiscal year 1996 for the four separate genetics laboratories and any additional work in other laboratories with a secondary focus on genetics.