Identifying the Molecular Genetic Basis of Behavioral Traits

Stephanie L. Sherman, Ph.D. and Irwin D.Waldman, Ph.D.

Th ere has been no better time to be a researcher in the field of human genetics. Although positions as a collaborator of Gregor Mendel or of Watson and Crick may have held similar charms, never has research in human genetics had a greater armamentarium. The number of identified and cloned genes has been growing at an exponential rate, so that the whole human genome should be sequenced by 2005. "High-tech" laboratory techniques such as polymerase chain reaction (PCR) have made it possible to genotype many loci from only a small initial quantity of DNA, allowing "low-tech" procedures for the collection of DNA in as unobtrusive a manner as imaginable (e.g., buccal brushes). Statistical developments are enabling human genetics researchers to locate genes and quantify their effects on both diseases and "normal-range" traits in more effective and efficient ways. It is little wonder that a month does not pass without some dramatic new finding in human genetics.

For a variety of reasons, the promise of interesting new findings has been actualized to a much greater extent for the genetics of medical diseases than for the genetics of psychiatric disorders or behavioral traits, although the recent advances mentioned above are just as pertinent for both fields. While the major genes underlying diseases such as Huntington disease, cystic fibrosis, Duchenne muscular dystrophy, and breast cancer have been located and cloned, a succession of initial positive findings and subsequent failures to replicate those findings have been reported for psychiatric disorders, including schizophrenia, bipolar disorder, and Tourette syndrome.

Why the recurrent disappointments for psychiatric disorders? A number of reasons come readily to mind. First, many issues in the accuracy and validity of the classification of psychiatric disorders remain to be resolved. Although the classification and diagnosis of medical diseases are continually evolving, they are at a much more advanced stage than those for their psychiatric counterparts. Second, as a corollary of these issues in classification and diagnosis, it is likely that genetic influences of psychiatric disorders act at the level of component traits rather than at the level of the disorders per se. For example, specific genes that influence schizophrenia are more likely to affect its component symptoms or symptom dimensions such as thought disorder, flat affect and anhedonia, attentional dysfunction, and hallucinations, than to act at the level of the overall disorder. Hence, searches for specific genes for psychiatric disorders per se may not be as fruitful as searches for genes that influence specific symptom dimensions of these disorders. Third, it has been suggested that there may be genetic heterogeneity for psychiatric disorders, both in the sense of independent genetic influences for a particular disorder and in the sense that different genes may affect distinct subtypes of disorders. Fourth, psychiatric disorders and behavioral traits may best be construed as "complex traits" from a genetic standpoint, making them more like diabetes and cardiovascular disease than Huntington disease and cystic fibrosis. That is, such traits are not inherited in a simple Mendelian pattern, but most likely are due to the effects of many genes, each playing a weak role in the development of the trait. The issues involved in finding genes for complex traits are formidable and are described later in this chapter. In our opinion, it is likely that new statistical genetic methods for complex traits will be needed to find genes for psychiatric disorders and behavioral traits. The purpose of this chapter is to describe some of these methods for finding genes for complex traits, as well as to present some examples of recent successes in the domains of psychiatric disorders and behavioral traits.

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