Abstract MP17: Multivariable Mendelian Randomization Identifies Heterogeneity In The Effects Of Individual Branched Chain Amino Acids Across Metabolic, Cardiovascular, And Cognitive Phenotypes

Introduction: Experimental and observational evidence suggests that aberrant branched chain amino acid (BCAA; leucine, isoleucine, and valine) metabolism promotes insulin resistance and downstream disease, prompting interest in BCAA catabolism as a treatment target. Most published research has evaluated the three BCAAs in combination, although each BCAA may harbor distinct phenotypic effects, as valine is glucogenic, leucine is ketogenic, and isoleucine is glucogenic and ketogenic. Methods: Because studies examining individual phenotypic effects of BCAAs that account for the effects of other BCAAs have been limited by high correlation between BCAAs and strong confounding by dietary patterns and shared genetic loci, we applied a novel causal inference method developed to address these limitations: multivariable Mendelian randomization (MVMR). In a study of UK Biobank European ancestry participants, we examined 1,468 phenotypes that included metabolic, cardiovascular, cancer, cognitive, hematopoietic, and musculoskeletal domains. Polygenic risk score (PRS) instrumental variables were constructed using genotypic and circulating BCAA phenotypic data in European ancestry UK Biobank participants and the Crosspred method was used to correct for overfitting. Significant independent causal effects were defined as estimates with P- values< 1.1x10 -5 [0.05/(1,468 phenotypes*3 BCAAs)]. Results: The n=97,469 participants with measured BCAAs were on average middle aged (mean age=57), female (54%), and overweight [mean body mass index (BMI)=27]. Each BCAA PRS strongly predicted its circulating concentrations ( P- value<10 -100 ). MVMR methods did not identify any phenotypes for which all three BCAAs showed evidence of a directionally consistent and significant independent causal effect. However, there were numerous instances where BCAAs harbored independent and directionally inconsistent statistically significant effects. For example, significant positive causal effects for valine independent of isoleucine and leucine and significant negative causal effects for leucine independent of valine and isoleucine were identified for BMI, glycated hemoglobin, and type 2 diabetes; no significant independent causal effects for isoleucine with BMI, glycated hemoglobin, and type 2 diabetes were identified. In contrast, models without control for the effects of other BCAAs suggested that isoleucine, leucine and valine each had significant positive causal effects on BMI, glycated hemoglobin, and type 2 diabetes. When examining other phenotypes using MVMR, heterogeneity in the effects of individual BCAAs was detected for cardiovascular and cognitive phenotypes, among others. Conclusion: BCAAs may harbor distinct and opposing effects on metabolism, health, and disease, motivating further studies that examine the independent effects of these essential amino acids.