The article by Carl Veller and Graham M. Coop discusses the challenges of interpreting population- and family-based genome-wide association studies (GWASs) in the presence of genetic and environmental confounding. While GWASs aim to estimate the direct genetic effects of alleles on phenotypes, these estimates can be biased by confounding factors such as population structure, assortative mating, and selection. The authors present a theoretical analysis showing that family-based estimates of direct effects can be biased by genetic confounding, contrary to common interpretation. They illustrate this using models of assortative mating, population stratification, and stabilizing selection on GWAS traits. Additionally, they show that family-based estimates of indirect genetic effects, based on comparisons of parentally transmitted and untransmitted alleles, can also be significantly biased. The study highlights the importance of understanding and addressing these confounding factors to improve the accuracy of GWAS results.The article by Carl Veller and Graham M. Coop discusses the challenges of interpreting population- and family-based genome-wide association studies (GWASs) in the presence of genetic and environmental confounding. While GWASs aim to estimate the direct genetic effects of alleles on phenotypes, these estimates can be biased by confounding factors such as population structure, assortative mating, and selection. The authors present a theoretical analysis showing that family-based estimates of direct effects can be biased by genetic confounding, contrary to common interpretation. They illustrate this using models of assortative mating, population stratification, and stabilizing selection on GWAS traits. Additionally, they show that family-based estimates of indirect genetic effects, based on comparisons of parentally transmitted and untransmitted alleles, can also be significantly biased. The study highlights the importance of understanding and addressing these confounding factors to improve the accuracy of GWAS results.