Identifying blood pressure loci whose effects are modulated by multiple lifestyle exposures

Although multiple lifestyle exposures simultaneously impact blood pressure (BP) and cardiovascular health, most analysis so far has considered each single lifestyle exposure (e.g., smoking) at a time. Here, we exploit gene–multiple lifestyle exposure interactions to find novel BP loci. For each of 6,254 Framingham Heart Study participants, we computed lifestyle risk score (LRS) value by aggregating the risk of four lifestyle exposures (smoking, alcohol, education, and physical activity) on BP. Using the LRS, we performed genome-wide gene–environment interaction analysis in systolic and diastolic BP using the joint 2 degree of freedom (DF) and 1 DF interaction tests. We identified one genome-wide significant (p < 5 × 10⁻⁸) and 11 suggestive (p < 1 × 10⁻⁶) loci. Gene–environment analysis using single lifestyle exposures identified only one of the 12 loci. Nine of the 12 BP loci detected were novel. Loci detected by the LRS were located within or nearby genes with biologically plausible roles in the pathophysiology of hypertension, including KALRN, VIPR2, SNX1, and DAPK2. Our results suggest that simultaneous consideration of multiple lifestyle exposures in gene–environment interaction analysis can identify additional loci missed by single lifestyle approaches.