Mental Health: A Report by the Surgeon General

That genes influence behavior, normal and abnormal, has long been established (Plomin et al., 1997). Genes influence behavior across the animal spectrum, from the lowly fruitfly all the way to humans. Sorting out which genes are involved and determining how they influence behavior present the greatest challenge. Research suggests that many mental disorders arise in part from defects not in single genes, but in multiple genes. However, none of the genes has yet been pinpointed for common mental disorders (National Institute of Mental Health [NIMH], 1998).

The human genome contains approximately 80,000 genes that occupy approximately 5 percent of the DNA sequences of the human genome. By the spring of 2000, the human genome project will have provided an initial rough draft version of the entire sequence of the human genome, and in the ensuing years, gaps in the sequence will be closed, errors will be corrected, and the precise boundaries of genes will be identified.

In parallel, clinical medicine is studying the aggregation of human disease in families. This effort includes the study of mental illness, most notably schizophrenia, bipolar disorder (manic depressive illness), early onset depression, autism, attention-deficit/hyperactivity disorder, anorexia nervosa, panic disorder, and a number of other mental disorders (NIMH, 1998). From studying how these disorders run in families, and from initial molecular analyses of the genomes of these families, we have learned that heredity—that is, genes—plays a role in the transmission of vulnerability of all the aforementioned disorders from generation to generation.

But we have also learned that the transmission of risk is not simple. Certain human diseases such as Huntington’s disease and cystic fibrosis result from the transmission of a mutation—that is, a deleteriously altered gene sequence—at one location in the human genome. In these diseases, a single mutation has everything to say about whether one will get the illness. The transmission of a trait due to a single gene in the human genome is called Mendelian transmission, after the Austrian monk, Gregor Mendel, who was the first to develop principles of modern genetics and who studied traits due to single genes. When a single gene determines the presence or absence of a disease or other trait, genes are rather easy to discover on the basis of modern methods. Indeed, for almost all Mendelian disorders across medicine that affect more than a few people, the genes already have been identified.

In contrast to Mendelian disorders, to our knowledge, all mental illnesses and all normal variants of behavior are genetically complex. What this means is that no single gene or even a combination of genes dictates whether someone will have an illness or a particular behavioral trait. Rather, mental illness appears to result from the interaction of multiple genes that confer risk, and this risk is converted into illness by the interaction of genes with environmental factors. The implications for science are, first, that no gene is equivalent to fate for mental illness. This gives us hope that modifiable environmental risk factors can eventually be identified and become targets for prevention efforts. In addition, we recognize that genes, while significant in their aggregate contribution to risk, may each contribute only a small increment, and, therefore, will be difficult to discover. As a result, however, of the Human Genome Project, we will know the sequence of each human gene and the common variants for each gene throughout the human race. With this information, combined with modern technologies, we will in the coming years identify genes that confer risk of specific mental illnesses.

This information will be of the highest importance for several reasons. First, genes are the blueprints of cells. The products of genes, proteins, work together in pathways or in building cellular structures, so that finding variants within genes will suggest pathways that can be targets of opportunity for the development of new therapeutic interventions. Genes will also be important clues to what goes wrong in the brain when a disease occurs. For example, once we know that a certain gene is involved in risk of a particular mental illness such as schizophrenia or autism, we can ask at what time during the development of the brain that particular gene is active and in which cells and circuits the gene is expressed. This will give us clues to critical times for intervention in a disease process and information about what it is that goes wrong. Finally, genes will provide tools for those scientists who are searching for environmental risk factors. Information from genetics will tell us at what age environmental cofactors in risk must be active, and genes will help us identify homogeneous populations for studies of treatment and of prevention.

Heritability refers to how much genetics contributes to the variation of a disease or trait in a population at a given point in time (Plomin et al., 1997). Once a disorder is established as running in families, the next step is to determine its heritability (see below), then its mode of transmission, and, lastly, its location through genetic mapping (Lombroso et al., 1994).

One powerful method for estimating heritability is through twin studies.8 Twin studies often compare the frequency with which identical versus fraternal twins display a disorder. Since identical twins are from the same fertilized egg, they share the exact genetic inheritance. Fraternal twins are from separate eggs and thereby share only 50 percent of their genetic inheritance. If a disorder is heritable, identical twins should have a higher rate of concordance—the expression of the trait by both members of a twin pair—than fraternal twins. Such studies, however, do not furnish information about which or how many genes are involved. They just can be used to estimate heritability. For example, the heritability of bipolar disorder, according to the most rigorous twin study, is about 59 percent, although other estimates vary (NIMH, 1998). The heritability of schizophrenia is estimated, on the basis of twin studies, at a somewhat higher level (NIMH, 1998).

Even with a high level of heritability, however, it is essential to point out that environmental factors (e.g., psychosocial environment, nutrition, health care access) can play a significant role in the severity and course of a disorder.

Another point is that environmental factors may even protect against the disorder developing in the first place. Even with the relatively high heritability of schizophrenia, the median concordance rate among identical twins is 46 percent9 (NIMH, 1998), meaning that in over half of the cases, the second twin does not manifest schizophrenia even though he or she has the same genes as the affected twin. This implies that environmental factors exert a significant role in the onset of schizophrenia.

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