Genetic diversity, genome organization, and investigation of the etiology of psychiatric diseases.

Recent advances in our understanding of the structure and organization of the human genome have strong implications for investigations of the diagnosis and etiology of psychiatric disorders. The concept of human genes as contiguous regions of DNA has been discarded and replaced by the concept of a gene split in separate pieces that must be spliced in order to make its protein products. The 'one gene - one enzyme' concept has also been modified to allow for the observation that many functional proteins are composed of multiple subunits, each coded by separate genes, whose expression is regulated by many other genetic and environmental factors. Consequently, the development of a complex phenotype cannot be predicted from knowledge of even the entire DNA sequence, and exploratory methods that rely entirely on genetic linkage analysis are unlikely to be fruitful. It is recommended that investigations reverse the natural development sequence and begin with studies at a phenotypic level, proceeding down to the genotypic level. Studies at a purely clinical level can define independent familial subtypes, which can in turn be studied at several levels of observation (social, physiological, biochemical, genetic) to identify multiple biosocial risk factors. Recent advances in genetic epidemiology now provide quantitative methods to detect major gene effects, resolve cultural inheritance from biological inheritance, and identify the influence of multiple risk factors on the development and expression of psychiatric disease.