Five environmental factors/covariates (i.e., sex, age, PA, SB, and smoking) were used for the direct GEI tests. Sex was coded as 0 or 1 for female or male. Age was an integer number ranging from 40 to 74. PA was assessed by a three-level categorical score (i.e., low, intermediate, and high) based on the short form of the International Physical Activity Questionnaire (IPAQ) guideline (67). SB was an integer number defined as the combined time (hours) spent driving, non–work-related computer using, or TV watching. The smoking factor “ever smoked” was coded as 0 or 1 for never or ever smoker. More details about the definition and derivation of environmental factor PA, SB, and smoking can be found in note S5, fig. S2B, and table S1B.

We performed a GEI analysis to test the interaction effect between the top vQTL SNP and one of the five environmental factors based on the following modely=μ+βgxg+βExE+βgExgxE+ewhere y is the phenotype, μ is the mean term, xg is the mean-centered SNP genotype indicator, and xE is the mean-centered environmental factor. We used a standard ANOVA analysis to test for βgE and applied a stringent Bonferroni-corrected threshold 1.33 × 10−4 [i.e., 0.05/(75 × 5)] to claim a significant GEI effect.

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