Introduction

The considerable impact of molecular genetics on medicine, most visibly in terms of diagnosis, (1) has raised expectations of similar advances in psychiatric aetiology and nosology, hopes that have been partly realized with the successful identification of genetic mutations in the dementias and some forms of mental retardation. Moreover, even if the mixed success in applying molecular approaches to common psychiatric conditions might be taken as an indication that genetics will remain a peripheral subject for psychiatry, it is at the very least likely that the genetic bases of psychosis and depression will soon be unravelled. (23) Once this has been worked out, psychiatrists will need to have a grasp of sufficient molecular genetics to communicate diagnostic advances to their patients.

But there is another reason why molecular genetics will soon be a basic tool for psychiatrists. Mental states emerge from activity in neural systems, which are being delineated with increasing sophistication by neuroscientists down to the level of anatomical, cellular, and now molecular components. Changes in mental states, whether environmentally or genetically determined, have biological correlates, which in some circumstances can be observed (for instance by functional magnetic resonance imaging). We now know that persistent changes in mental function involve alterations in gene expression, as research into memory has demonstrated; animal studies show that learned behaviour results in molecular changes in synaptic connections.

We are close to a point at which it is possible to correlate changes in gene expression with changes in behaviour. Thus genetic approaches to psychiatry are not limited to understanding inherited disease. They have become central to a biological understanding of psychiatric disorders, and all psychiatrists will need to have some familiarity with molecular biology.(4)

Expositions of molecular genetics are hampered by the rapid pace of change in the field and an associated proliferation of jargon. In this chapter the background essential for appreciating the issues currently reported in the research literature is outlined and an attempt is made to cover areas of molecular genetics that are likely to become relevant with the completion of the Human Genome Project and the ability to screen every gene for sequence differences that may be disease related. The chapter starts with a basic introduction to DNA structure and function, which is followed by an outline of the ways in which disease genes are identified.

The second part of the chapter reviews the molecular pathology of psychiatric disorders (still limited to rare single-gene disorders). Research that is likely to have an impact on clinical practice in the near future is covered in the last two sections, which deal with the biological basis of mental processes and the genetic effects on common psychiatric disorders. Work in both areas is still in its infancy, but is progressing fast.

The section on the neurobiology of learning and memory shows how genetic influences on cognitive processes can be interpreted as acting at the level of a neural system (spatial memory), the first time such a feat has been achieved and no doubt a paradigm for further developments. In the last part of this chapter, the scant data on the molecular basis of complex genetic disorders and their implications for psychiatric disorders are reviewed. Despite a huge amount or work, we still do not have good candidates for susceptibility genes, except in the case of diabetes. The complexities encountered in that disorder are again paradigmatic and indicate that we will need a sophisticated knowledge of genetics to make sense of the coming results of mapping susceptibility genes for common psychiatric disorders.

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