Fig. 4: Ascertainment bias significantly impacts expressivity of clinically significant variants for LDL cholesterol conditions.

LDL cholesterol levels are shown for carriers and non-carriers of LDL cholesterol raising (top panels) or lowering (bottom panels) clinically significant variants in AMP-T2D-GENES. The variants carriers are stratified by whether they were identified in individuals phenotypically ascertained for extreme serum LDL cholesterol levels (Yes, Red) or in a separate unascertained population (No, Blue) (see “Methods”). The left panels show all clinically significant variant carriers. The right panels show carriers of the single variants that were present in both ascertained and unascertained individuals. Top left, LDL-raising variant Non-carriers N = 19,131, Carriers not ascertained on LDL cholesterol level N = 55, Carriers ascertained on LDL cholesterol level N = 18. Bottom left, LDL-lowering variant Non-carriers N = 19,151, Carriers not ascertained N = 35, Carriers ascertained N = 15. Mean and 95% CI are represented by the black circle and black lines, respectively. LDL cholesterol values are adjusted for lipid-lowering medication use as per methods. See also Supplementary Table 4.