In model A, a genotype has a causal effect on a social or behavioral risk factor and through this pathway influences disease risk indirectly (Ottman, 1990; Ottman, 1996). This model differs markedly from the others because it does not involve interaction in either the statistical or biological sense. One hypothetical example would be a genetic influence on the behavior of alcohol consumption, which would be expected to affect risk for cirrhosis of the liver and other alcohol-related diseases. In this model a behavioral risk factor, alcohol consumption, is an intervening or mediating variable in the relation of a genotype to health. Although this model does not involve interaction, it is important for the consideration of the joint effects of genetic, social, and behavioral factors on health. An understanding of the intervening factors relevant to the effects of genes on health may facilitate the development of methods to prevent adverse health outcomes associated with genetic effects. For example, dietary treatment is used to prevent mental retardation in individuals with phenylketonuria, an autosomal recessive condition characterized by a deficiency of the enzyme needed to convert phenylalanine to tyrosine. Removal of phenylalanine from the diet prevents the buildup of blood levels of phenylalanine (the intervening variable), which would otherwise have a toxic effect on brain development. In the alcohol consumption example above, programs targeted to drinking behavior in individuals with a genetic susceptibility could reduce the risk of liver disease.

Model B postulates that a social or behavioral factor has a direct causal relationship to disease, and a genotype exacerbates this relationship without having any effect on disease when acting by itself. Returning to the example of alcohol drinking behavior, this model might involve a genetic influence on alcohol metabolism that leads to exacerbation of the health effects of drinking behavior. No effect of the genotype would be expected in the absence of exposure to drinking. In model C, a genotype is assumed to have a direct effect on disease risk, and the social or behavioral factor exacerbates this effect, without influencing disease risk when acting by itself. An example might involve a genetic influence on liver disease that is exacerbated by even small amounts of drinking (i.e., levels that do not influence risk in persons who do not carry the high-risk genotype). In model D, both a genotype and a social or behavioral risk factor are required to influence risk—neither affects risk in the absence of the other. Such a model might involve an alcohol-sensitivity genotype, heavy drinking, and liver disease—the assumption being that only individuals who drink heavily and who have a genetically mediated sensitivity to the effects of drinking develop disease. Finally, in model E both a genotype and a social or behavioral factor influence disease risk in the absence of the other factor. Although models B, C, and D involve interaction regardless of the scale of measurement, in model E the joint effect