Psychiatry in the Postgenomic Era

Kathy L. Kopnisky, PhD
Steven E. Hyman, MD

Dr. Kopnisky is assistant to the director, and Dr. Hyman is director, both at the National Institute of Mental Health in Bethesda, MD.

Abstract
A rough draft of the human genome sequence is now available in the public domain and the “finished” sequence of the 3 billion base pair genome will be available. Genes play a critical role in the risk of mental illness, but deciphering their role has proven to be extremely difficult. It is only with information from the genome project that we can succeed in finding risk conferring genes, but other challenges, including the boundaries of the illnesses themselves, still await us. Even while this research is proceeding, we should question how genomics and genetics will change our understanding of mental illness and, ultimately, the practice of psychiatry.

Introduction
As we enter the 21st century, we are still uncertain about the mechanisms underlying mental disorders. Powerful imaging technologies have been developed that permit the examination of the working brain. Technologies for postmortem examination of the brain have steadily improved. Genetic information will markedly enhance such approaches, at a minimum by decreasing the heterogeneity of populations studied while providing tools for molecular and cellular studies of pathogenesis. Based on experience in other areas of medicine, it appears absolutely necessary to use genetics to identify the genes that produce risk of mental disorders if we are to ultimately understand the disease processes. Beyond insights into the pathogenesis of mental disorders, gene discovery will undoubtedly provide important insights into normal brain function as well. Moreover, discovery of risk genes should hasten the development of treatments that are not simply aimed at symptoms, but that alter the disease process.

Why is it that gene discovery is so important and why has the task been so difficult? The importance of genes as tools of investigation lies in the complexity of what it is that we are trying to understand. The brain is the most complex object in the history of human scientific inquiry and mental disorders represent problems with the highest integrated functioning of the human brain—thinking, emotion, and behavioral control. To succeed in understanding, we will need both “top down” approaches (moving from epidemiology to neurocircuitry systems on to genes) and “bottom up” approaches (moving from genes and proteins to cell biology to neurocircuitry to pathophysiology) and we will need to find ways of ultimately combining these approaches.

While the precise definition of a “gene” can be arguable, in the simplest terms a gene is considered to be a stretch of DNA that encodes one (or a family of related) RNAs and ultimately their protein
products. Genes provide not only the sequences of possible proteins that can be synthesized but also information about where, when, and under what circumstances these proteins will be made; proteins, in turn, are the building blocks of cells. Such regulatory information is far less well understood than information that codes for RNAs. We are still learning to identify stretches of DNA involved in the regulation of gene expression. Important clues are coming from the sequencing of mammalian species other than humans (eg, the recently completed mouse sequence). DNA regions that are conserved by evolution across species are likely to be functionally important, and these will include regulatory regions.
Disease risk genes can be defined as genes that contain a variation in DNA sequence that leads a change in location, timing, levels of gene expression, or the nature of the RNA or protein encoded by the gene, such that it contributes to risk of mental illness. Genetic variations may take the form of “mutations,” which are clearly deleterious errors (eg, an error that would truncate a protein or block its expression altogether) or polymorphisms, which might produce slight alterations in expression pattern or function, but which cannot be said to be clearly abnormal. The most common type of variation in the human genome is the substitution of a single nucleotide base for another; such variations are referred to as single nucleotide polymorphisms (SNPs).

Discovery of disease risk genes means that we will be able to ask fundamental pathophysiologic questions. We hope to be in a position to ask how one version of a gene (allele) confers vulnerability toward or protection against disorders such as manic depressive illness or schizophrenia, while a slightly different version of the same gene does not. Additionally, by determining at what point during brain development a relevant gene is activated, we will be able to detect the earliest moments during which normal development gets diverted to result in such illnesses as the autism spectrum disorder or perhaps schizophrenia. Most importantly, protein products of gene expression function in complex biochemical networks that subserve all cellular functions. Identification of genes that confer risk of mental illness will point us toward biochemical pathways that, in turn, may suggest entirely novel treatments or even preventive interventions for mental illness.

We are painfully aware that the majority of drug-based therapeutics currently used to treat mental disorders was discovered serendipitously while being used to treat other medical conditions. For too long we have relied on the clever exploitation of these findings which led to the use of initial reference compounds, such as chlorpromazine or imipramine, from which our current treatments evolved. Today, we sorely need pathophysiologically-based pharmaceuticals that are safer and more efficacious for the treatment of illnesses such as schizophrenia, manic depressive illness, major depression and a host of anxiety disorders. Our field needs pathophysiologically relevant protein targets for drug development. As discoveries are made regarding the identity of the genes and protein products involved in specific disorders, the development of truly novel pharmacologic compounds is increasingly likely.

Challenges to Identification of Mental Illness Genes
Why has the discovery of disease risk genes for mental illness been so difficult? Unlike the situation for diseases such cystic fibrosis or Huntington’s disease, both of which are caused by a single gene in either a Mendelian dominant or recessive pattern, family and genetic linkage studies of mental illnesses have demonstrated that the pattern of inheritance of risk for these disorders is highly complex, comprised of both genetic and environmental components. Based upon Lander and Kruglyak’s1 seminal paper establishing guidelines for determining the statistical significance of linkages associated with disease, evidence indicates that most psychiatric disorders are polygenic. One case in point, Botstein and colleagues2 excluded the possibility that bipolar illness is the result of a monogenic or even bigenic disorder based upon results from a full-genome scan of linkages associated with bipolar disorder.

Additional challenges in tackling the genetics of complex psychiatric disorders lies in the realization that no specific gene or group of genes is sufficient or necessary for producing a mental illness, clearly unlike in the cases of cystic fibrosis or Huntington’s disease. In other words, it may be that there are multiple genetic pathways leading to similar disease
phenotypes. Each disease risk gene may contribute a small increment of risk and some may have no role at all in subsets of families. Thus the “signal” provided by risk genes may be very small and technically difficult to discern. Or, it is possible that there is a single dominant gene (or group of genes) which confer most of the risk to a given men
tal illness, but because there may be several such dominant-like genes in the population, it is statistically difficult to identify them.

In addition to polygenic and multiple small-effect genes, the complexity of deciphering contributors to mental illness is further complicated by “epigenetics”—the heritable regulation of gene expression or activity that does not involve changes in DNA sequence. For instance, it is well recognized that methylation (which typically silences but occasionally activates gene expression) of specific DNA sequences is frequently based upon whether the sequence is of maternal or paternal allelic origin.3 It is not yet known what confers these heritable modifications, but they ultimately result in functional differences during development. For example, the regulation of X chromosome inactivation in mammalian females (XX) is a classic example of epigenetics.4

As prefaced earlier, multiple gene-gene and gene-environment interactions ultimately coalesce to produce genetically complex phenotypes.5,6 A clear role for the environment in eliciting one particular neuropsychiatric brain disease was brought to the foreground when individuals taking an illicit drug containing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) acquired phenotypic symptoms and brain pathology indistinguishable from Parkinson’s disease.7 In general, it appears that in certain psychiatric illnesses, such as bipolar disorder and schizophrenia, genetics plays a greater role in pathophysiology, whereas in others, such as depression and anxiety disorders, the environment is thought to have a greater modulatory role. Regardless, the role of the environment is indisputable. For example, despite sharing 100% of their DNA, monozygotic twins do not exhibit 100% concordance for schizophrenia,8 manic-depressive illness, or any other mental disorder. Furthermore, findings from adoption studies show that the biological relatives of adopted children who are affected with mental illness are more likely to suffer from the mental illness than are the foster parents or foster family members.9,10

Gene hunting in psychiatry has been made yet more difficult as a result of a few additional factors. First, there are no laboratory tests for which a mental disorder phenotype is unambiguously determined. The diagnoses of mental disorders relies on behavioral and phenotypic diagnostic criteria as listed in the Diagnostic and Statistical Manuals of Mental Disorders, Fourth Edition11 (DSM-IV), or the International Classification of Diseases12 (ICD). Second, several illnesses can have overlapping features. For instance, a subset of patients diagnosed with manic-depressive illness or schizophrenia both present with psychotic symptoms, and the distinction between schizophrenia and schizophreniform disorders, for example, is often subtle and uncertain.

The definitive discrimination