To state that most complex diseases are caused by an interaction between genome and environment is a cliché. Such interactions, while likely, have for the most part not been demonstrated, and we should be cautious about universally subscribing to this belief without evidence. Since the quantification of environmental influences is notoriously difficult, it is likely that such a demonstration will remain a formidable challenge. At least, the definition of gene-based pathways for disease will provide a framework for the systematic investigation of exogenous influences. This is one of the goals of the recently announced Genes, Environment, and Health Initiative of the National Institutes of Health. There is increasing interest in genomewide assessments of epigenetic modification brought about by a greater understanding of the ubiquitous nature of such modifications and the availability of genome-scale sequences, which makes such investigation tenable from a practical perspective. It is hoped that greater understanding of the epigenome, particularly in the context of genetic variation and gene expression, will offer a direct and quantifiable link between putative environmental influences and pathways relevant to pathogenesis.
