In the current study, we investigated the influence of using skewed sum scores on estimated gene-by-environment interaction effects (GxE) for life satisfaction and happiness with perceived social support. To this end, we analyzed item-level data from a large adult twin sample (Ns between 3610 and 11,305) of the Netherlands Twin Register. Item response theory (IRT) models were incorporated in unmeasured (univariate) GxE models, and measured GxE models (with social support as moderator). We found that skewness introduced spurious GxE effects, with the largest effect for the most skewed variable (social support). Finally, in the IRT model for life satisfaction, but not for happiness, heritability estimates decreased with higher social support, while this was not observed when analyzing sum scores. Together, our results indicate that IRT can be used to address psychometric issues related to the use of sum scores, especially in the context of GxE, for complex traits like well-being.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10519-023-10137-y.