Testing linkage and gene x environment interaction: comparison of different affected sib-pair methods

The aim of this study was to compare, under different models of gene-environment (G x E) interaction, the power to detect linkage and G x E interaction of different tests using affected sib-pairs. Methods considered were: 1) the maximum likelihood lod-score (MLS), based on the distribution of parental alleles identical by descent (IBD) in affected sibs; 2) the sum of the MLS (sMLS) calculated in affected sib-pairs with 2, 1, or 0 sibs exposed; 3) the predivided sample test (PST), which compares the IBD distribution between affected sib-pairs with 2, 1, or 0 sibs exposed; 4) the triangle test statistic (TTS), which uses the IBD distribution among discordant affected sib-pairs (one exposed, one unexposed); and 5) the mean interaction test (MIT), based on the regression of the proportion of alleles shared IBD among affected sib-pairs on the exposure among sib-pairs. The MLS, sMLS, and MIT allow detection of linkage. However, the sMLS and MIT account for a possible G x E interaction without testing it. In contrast, the PST and the TTS allow detection of both linkage and G x E interaction. Results showed that when exposure cancels the effect of the gene, or changes the direction of this effect (i.e., the protective allele becomes the risk allele), the PST, sMLS, and MIT may provide, under some models, greater power to detect linkage than the MLS. Under models where exposure changes the direction of the effect of the gene, the TTS test may also be more powerful than the other tests accounting for G x E interaction. Under the other models, the MLS remains the most powerful test to detect linkage. However, only the PST and TTS allow the detection of G x E interaction.