To quantify polygenic effects, i.e. undetected genetic effects, in large-scale association studies, we propose a generalized estimating equation (GEE) based estimation framework. We develop a marginal model for single-variant association test statistics of complex diseases that generalizes existing approaches such as LD Score regression and that is applicable to population-based designs, to family-based designs or to arbitrary combinations of both. We extend the standard GEE approach so that the parameters of the proposed marginal model can be estimated based on working-correlation/linkage-disequilibrium (LD) matrices from external reference panels. Our method achieves substantial efficiency gains over standard approaches, while it is robust against misspecification of the LD structure, i.e. the LD structure of the reference panel can differ substantially from the true LD structure in the study population. In simulation studies and in applications to population-based and family-based studies, we illustrate the features of the proposed GEE framework. Our results suggest that our approach can be up to 100% more efficient than existing methodology.

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