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By Steven E. Hyman, M.D.
Director
National Institute of Mental Health
The past few years have seen the coming of age of molecular genetics in psychiatry. Along with molecular, cellular, and integrative neuroscience and behavioral science, the new genetics adds crucial dimensions to the scientific mission of the National Institute of Mental Health (NIMH)-to conduct and support research that will lead to more effective diagnosis, treatment, and, eventually, prevention of mental disorders. In this article, I review issues that underpin the high priority that the NIMH assigns to genetics research that promises to accelerate our understanding of the causes of mental© disorders, help isolate environmental risk factors, and yield powerful new tools for the development of novel therapies.
The goal of psychiatric genetics is to identify precise gene variants that predispose a person to mental illness. Pursuit of this goal is all the more urgent given our increasing certainty that vulnerability to all severe mental disorders has a genetic component. Genes contain information for the production of proteins, which perform a variety of functions and are the critical building blocks of cells. Small DNA sequence variations called alleles occur among individuals in each of the approximately 80,000 to 100,000 genes in the human genome. An allelic variation may have no functional effect, but also may cause a protein to be made in a different amount, at a different time or place in cells, or with a different structure than normal.
For some human diseases, a single gene provides the lion's share of risk or may even be the sole cause of illness. There are two basic types of single gene disorders-dominant and recessive. In a dominant gene disorder even a single defective copy is sufficient to cause disease. In Huntington's disease, for example, a defect in one copy of a given gene causes cells in the brain to sicken and die. In a recessive disorder, by contrast, disease occurs only if a person inherits two defective copies of the gene, one from each parent; that is, loss of function has to be complete. Inheriting two nonfunctional versions of a certain chloride channel, for instance, causes the recessive genetic disorder cystic fibrosis. Both dominant and recessive genetic diseases are rare in the general population.
What has crystallized in recent years is the fact that unlike Huntington's disease and cystic fibrosis, mental disorders do not appear to be caused by any single dominant or recessive mutation in a gene. Rather, much like common diseases such as hypertension, coronary artery disease, or diabetes mellitus, mental disorders result from a malignant interaction of multiple genetic and environmental factors. Variant alleles of many different genes act in concert to create a vulnerability, which may be converted into illness as a result of developmental events or exposure to as yet unknown environmental risk factors. Another complicating factor is that alleles that create vulnerability may not be harmful mutations, but are potentially problematic only in combination with specific gene variants at other locations in the genome.
In genetically complex diseases such as psychiatric illnesses, identifying genes that contribute to vulnerability has proven extremely difficult. Detecting multiple genes, each contributing only a small effect, requires large sample sizes and new technologies to permit us to link or associate genetic variations with disease. Fortunately, these are becoming rapidly available even as their development and refinement continue. One example is seen in DNA microchips, which will permit simultaneous scanning of multiple variants of a person's entire genome. This and other research will be enhanced by the projected completion, early in the next decade, of a reference sequence of all human genes, and a major project to identify hundreds of thousands of small variants (single nucleotide polymorphisms, or SNPs) in the human genome.
In pace with these efforts, neurobiological studies exploring where and when mental illness vulnerability genes might be expressed and how they might function in neural cells and systems are generating information that may yield candidate genes for involvement in the pathogenesis of mental disorders. Neurobiological insights will converge with genetic information to provide an understanding of how-at the molecular and genetic levels-mental disorders occur. Some of the important tools for this endeavor will include genetically modified mice that may, for example, express human disease vulnerability genes. This newly acquired knowledge will provide, in turn, novel targets for the rational development of therapies.
The advances I am describing are not science fiction, even though their ultimate application may be a few years off. Across medicine, the race to solve genetically complex disorders is on and psychiatry must and will be a competitor. The NIMH has reorganized its approach to genetics and strengthened its interactions with large-scale gene-sequencing projects at the National Institutes of Health, including the human genome project and the joint project to discover SNPs. As scientists and clinicians, psychiatrists and professionals in allied disciplines at the NIMH and elsewhere are challenged to ensure that mental disorders will be among the first complex genetic disorders to be understood.