A conditional synergy index to assess biological interaction

In genetic studies of complex diseases, a crucial task is to identify and quantify gene–gene interactions which are often defined as deviance from genetic additive effects. This statistical definition, however, does not need to reflect the biological interactions of genes. We propose a new method to detect gene–gene interactions. This new approach exploits the concept of synergy and antagonism that is appropriate to capture biological relationships. The conditional synergy index (CSI) describes the extent of interaction on the penetrance scale. We develop the CSI for two-locus disease models and cohort data. The index assumes genotypes to be dichotomized into risk-genotypes (exposed) and non-risk-genotypes (unexposed) but it does not assume the loci to be in linkage equilibrium. We investigate the performance of the CSI and compare it to classical epidemiological interaction measures like Rothman’s synergy index (S) and the attributable proportion due to interaction (AP). In addition, the performance of an estimator of this new parameter is illustrated in a practical example.