ABSTRACT
Complex diseases are characterized by modest disease risk heritability and multifaceted interactions with environmental influences (Figure 2.1). This category includes most of the common diseases (cancer, cardiovascular diseases, behavior disorders, allergies, autoimmunity; the so-called diseases of civilization). The complexity arises from the fact that we cannot accurately predict the expression of the phenotype from knowledge of the effects of individual factors (genes or environment) considered alone; however, identifying and understanding the causal link between gene variation and disease risk is crucial to achieve the full biological description of the pathogenic processes. The genetic component in these disorders is not strictly Mendelian (dominant, recessive, or sex-linked), but rather results from the action of allelic variants in several genes. Crude theoretical modeling of human population history suggested that variants that have a high population frequency are likely to be responsible for complex traits — the common disease-common variant hypothesis. Other observers argue that these common variants are too old to be responsible for complex diseases affecting non-African populations — the common disease-rare variant hypothesis. In either case, their incomplete penetrance and moderate individual effect probably reflect epistatic interactions and post-genomic events; these include genes that rearrange somatically to encode a vast variety of immune receptors, post-transcriptional regulatory mechanisms, and incorporation of retroviral sequences (Table 2.1). An additional layer of difficulty is encountered when genetic heterogeneity, whereby specific genes or alleles influence susceptibility and pathogenesis in some individuals but not in others is considered (Figure 2.2).
