Assessing the causal role of body mass index on cardiovascular health in young adults: Mendelian randomization and recall-by-genotype analyses

ABSTRACT Background Mendelian randomization (MR) studies of body mass index (BMI) and cardiovascular health in mid-to-late life suggest causal relationships, but the nature of these has not been explored systematically at younger ages. Using complementary MR and recall-by-genotype (RbG) methodologies, our objective was to estimate the causal effect of BMI on detailed measures of cardiovascular health in a population of young healthy adults. Methods and Findings Data from the Avon Longitudinal Study of Parents and Children were used. For MR analyses, a genetic risk score (GRS) comprising 97 independent single nucleotide polymorphisms (SNPs) and constructed using external weighting was used as an instrument to test the causal effect of each unit increase in BMI (kg/m 2 ) on selected cardiovascular phenotypes measured at age 17 (N=7909). An independent enriched sample from the same cohort participated in a RbG study at age 21, which enabled more detailed cardiovascular phenotyping (N=418; 191/227 from the lower/upper ∼30% of a genome-wide GRS distribution predicting variation in BMI). The causal effect of BMI on the additional cardiovascular phenotypes was assessed by comparing the two recalled groups. Difference in mean BMI between RbG groups was 3.85kg/m 2 (95% CI: 2.53, 4.63; P =6.09×10 11 ). In both MR and RbG analyses, results indicated that higher BMI causes higher blood pressure (BP) and left ventricular mass (indexed to height 2.7 , LVMI) in young adults (e.g. difference in LVMI per kg/m 2 using MR: 1.07g/m 2.7 ; 95% CI: 0.62, 1.52; P=3.87×10 −06 and per 3.58kg/m 2 using RbG: 1.65g/m 2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results indicated a causal role of higher BMI on higher stroke volume (SV; difference per 3.58kg/m 2 : 1.49ml/m 2.04 ; 95% CI: 0.62, 2.35; P =0.001) and cardiac output (CO; difference per 3.58kg/m 2 : 0.11l /min/m 1.83 ; 95% CI: 0.03, 0.19; P =0.01). Neither analysis supported a causal role of higher BMI on heart rate. Conclusions Complementary MR and RbG causal methodologies, together with a range of appropriate sensitivity analyses, showed that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. These consistent results support efforts to prevent or reverse obesity in the young.