PHENOCOPIES VERSUS GENETIC-HETEROGENEITY - CAN WE USE PHENOCOPY FREQUENCIES IN LINKAGE ANALYSIS TO COMPENSATE FOR HETEROGENEITY

In this study we explore whether a phenocopy frequency (defined as a ' penetrance' for nondisease genotypes) can approximate or model genetic heterogeneity in a single-locus analysis. We simulated two types of h eterogeneity situations: 'sporadic models', where there are two forms of a disease, one genetic and linked to a marker and the other purely random, and 'genetic heterogeneity models', where the disease is cause d by either of two different loci, one linked to the marker and the ot her unlinked. We analyzed simulated data sets for linkage, assuming a single-locus analysis with varying phenocopy frequency, in analogy wit h earlier work on epistatic two-locus models. We found that in the pre sence of purely random sporadics, there was a difference between assum ing any nonzero phenocopy frequency and a zero frequency, but that the actual value of the assumed phenocopy frequency had little effect on the maximum lod score. In contrast, when both forms of disease are gen etic, and are generated under similar genetic parameters, assuming a p ositive phenocopy frequency will not, in general, compensate for the p resence of the unlinked form. However, when the modes of inheritance o f the two forms differ, the assumption of a nonzero phenocopy frequenc y does have an effect, either to increase or decrease the maximum lod score, depending on the modes of inheritance of the two disease forms. We conclude with practical recommendations for investigators, based o n these results.