Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment. Display omitted •Sequence variants can have complex effects on lipid levels through interactions•Variants at FUT2 and ABO interact on blood lipid levels and coronary artery disease•Alcohol consumption modifies the effect of a variant in ADH1B on lipids and CAD•Blood lipid composition in APOE-ε2 homozygotes differs substantially from others Epistatic interactions between variants and gene-environment interactions can have complex phenotypic effects. By using blood lipid data from 743,736 individuals from three populations, it was shown here how these intricate interactions can have large effects on lipid levels and consequently coronary artery disease risk.