Approaches to gene identification in neuro‐psychiatric and other complex disorders

The mapping of the human genome is of fundamental importance, but only the beginning of a full understanding of the relation between genes and the various external and internal factors that modify their expression. The epilepsies and psychiatric disorders are two groups of diseases for which both nature and nurture play pathogenetic roles. A deeper understanding of the interplay between these two aspects is a prerequisite for new and better treatments. To understand this complex interplay we need to know more about the plasticity of the central nervous system, the processes that generate and modify normal neuronal development and activity, the genetic basis for inborn disorders and factors which may trigger an abnormal gene expression. A full understanding also implies a detailed knowledge of all the steps from gene activation to the ®nal pathological condition. The many steps and mechanisms involved are potential targets of new drugs. The plasticity of the nervous system is much more remarkable than thought of just a few years ago. A better knowledge of the factors involved in facilitating and inhibiting regeneration may give hopes for new treatments after injuries to the central nervous system. Even more fascinating is the possible use of modi®ed stem cells to compensate for the loss of neurons in different kinds of neurodegeneration. A better understanding of the genetic processes involved will most likely make it possible to interfere in a speci®c way. The understanding of the genetic changes leading to pathological function in excitability or behavior can be explored in animal models. Only a few of these changes, however, may be directly related to human disease. The animal data have to be compared with data from humans. This is dif®cult, as only a few of the actual diseases are monogenetic and dominant. Thus, the majority of epilepsies and psychiatric disorders seems to involve both multiple genes and many external and internal factors. The variation in the relation between genotype and phenotype illustrates this complexity. External factors include environmental stressors in relation to psychiatric disorders and head trauma and febrile seizures in relation to epilepsy. Hormones are probably the most important internal factors in ̄uencing both the development and the function of the central nervous system. Thus, alterations in hormones are important both in relation to pathogenesis and symptomatology of epilepsy and psychiatric disorders. The full mapping of the genome will make possible a more direct approach for drug design aimed at interfering with gene expression or even modifying speci®c genes. It is most likely that many other drugs targets will be identi®ed both in epilepsy and psychiatry after mapping the genome. Even before that goal is achieved, however, the analysis of single nucleotide polymorphisms will be useful in optimizing drug treatment with respect to ef®cacy and side effects. In addition, the usefulness of ``old'' drugs may well be increased by a better insight in their mechanisms of action and by a better understanding of pathogenesis and pathophysiology in general. The balance between nature and nurture may never be fully explored. However, the mapping of the genome is ``the end of the beginning'' of a much more detailed understanding of the epilepsies and psychiatric disorders. The promising future is new treatment strategies and better care for patients. This Supplement presents a set of papers from the meeting ``Nature and Nurture in Epilepsy and Psychiatry ± Implications for New Treatment Strategies'' in Oslo, Norway June/July, 2000. We thank the authors for their effort in writing these papers and Glaxo Wellcome for supporting the publication.