often is population specific and can represent the unique demographic and mutational history of the population.
In some cases, genetic diseases also are associated with locus heterogeneity, meaning that a deleterious mutation in any one of several genes can give rise to an increased risk of the disease. This is a finding common to many human diseases including Alzheimer’s disease and polycystic kidney disease. Both allelic heterogeneity and locus heterogeneity are sources of variation in these disease phenotypes since they can have varying effects on the disease initiation, progression, and clinical severity.
Environmental factors also vary across individuals and the combined effect of environmental and genetic heterogeneity is etiologic heterogeneity. Etiologic heterogeneity refers to a phenomenon that occurs in the general population when multiple groups of disease cases, such as breast cancer clusters, exhibit similar clinical features, but are in fact the result of differing events or exposures. Insight into the etiology of specific diseases as well as identification of possible causative agents is facilitated by discovery and examination of disease cases demonstrating etiologic heterogeneity. The results of these studies may also highlight possible gene-gene interactions and gene-environment interactions important in the disease process. Identifying etiologic heterogeneity can be an important step toward analysis of diseases using molecular epidemiology techniques and may eventually lead to improved disease prevention strategies (Rebbeck et al., 1997).
As opposed to the Mendelian approach, the second approach to studying how variations in genes contribute to variations in disease risk focuses on understanding the genetic susceptibility to diseases as the consequence of the joint effects of many genes, each with small to moderate effects (i.e., polygenic models of disease) and often interacting among themselves and with the environment to give rise to the distribution of disease risk seen in a population (i.e., multifactorial models of disease). This approach has been used primarily for understanding the genetics of birth defects and common diseases and their risk factors. As described below, several steps are involved in developing such an understanding.
As a first step, study participants are asked to provide a detailed family history to assess the presence of familial aggregation. If individuals with the disease in question have more relatives affected by the disease than individuals without the disease, familial aggregation is identified. While familial aggregation may be accounted for through genetic etiology, it may also represent an exposure (e.g., pesticides, contaminated drinking water, or diet) common to all family members due to the likelihood of shared environment.
When there is evidence of familial aggregation, the second step is to focus research studies on estimating the heritability of the disease and/or its risk factors. Heritability is defined as the proportion of variation in disease