Control for environmental risk factors in assessing genetic effects on disease familial aggregation.

A probabilistic model was developed to assess the impact of two independent dichotomous familial risk factors on familial aggregation of a disorder in pairs of relatives where one member was ascertained as a proband or index subject (i.e., a case or control). Under this model, one risk factor is of primary interest (i.e., a susceptibility gene), while the effect of the other is to be controlled (i.e., an environmental risk factor). Familial aggregation was examined within strata defined by the status of proband and relative with respect to the environmental factor. The findings suggest that for proband-relative pairs, under both the additive and multiplicative models, an environmental factor can be controlled in the analysis based solely on the status of the proband. If the relation between the genetic and environmental factors is neither additive nor multiplicative, however, the analysis must take account of environmental risk factors in both proband and relative.