The United Kingdom Biobank (UK Biobank) is a publicly available, longitudinal study of Great Britain residents 18. More broadly, our results motivate the development and application of causal inference methods that enable metabolomics studies, and ‘omics studies more generally, to validly estimate phenotypic effects of features with shared lifestyle and genetic factors. These findings are consistent with experimental BCAA studies and suggest that the observational literature has provided a highly flawed picture of BCAA phenotypic effects. In contrast to the observational literature demonstrating homogeneity of effect, our results suggested that BCAAs harbored distinct and often opposing causal effects on diverse phenotypes. Thus, we leveraged dense phenotypic and genotypic data from the UK Biobank and multivariable Mendelian randomization (MVMR) causal inference methods 17 to simultaneously estimate causal effects of leucine, isoleucine, and valine on 441 phenotypes spanning 17 categories. Observational study designs that can accurately estimate BCAA phenotypic effects are needed because it is infeasible to conduct experimental studies for the potentially large number of phenotypes potentially affected by BCAAs.Īdvances in genetics, large-scale biobanks, and causal inference statistical methods offer novel avenues to characterize BCAA effects more accurately. Yet, few BCAA observational studies have examined whether these shared factors bias BCAA phenotypic effects. Because observational studies cannot isolate the effects of individual BCAAs through dietary manipulation, as is possible in experimental studies, observational studies may be subject to bias from shared genetic and lifestyle factors that govern BCAA intake, synthesis, and degradation. However, the observational BCAA literature is inconsistent with experimental animal and human dietary restriction studies, which instead suggest that individual BCAAs exert heterogeneous phenotypic effects 14, 15, 16. These studies, performed across a wide spectrum of phenotypes, have reported that BCAAs exert homogeneous phenotypic effects 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. To quantify individual BCAA phenotypic effects, observational studies have examined BCAAs separately. Despite these high correlations, BCAA intermediates and final metabolites differ, motivating studies examining whether individual BCAAs harbor distinct metabolic effects. This correlation reflects shared enzymes governing synthesis and degradation as well as dietary patterns in which BCAAs are typically consumed together 2, 3. Accurately quantifying individual BCAA effects on metabolism and, more broadly, health and disease, has been challenging because circulating leucine, isoleucine, and valine concentrations are highly correlated. The three branched chain amino acids (BCAA) leucine, isoleucine, and valine are abundant essential nutrients that account for ~20% of total amino acids in muscle protein 1. More broadly, these findings motivate the development and application of causal inference approaches that enable ‘omics studies conducted in observational settings to account for the biasing effects of shared genetic and lifestyle factors. Our results suggest that the observational literature provides a flawed picture of BCAA phenotypic effects that is inconsistent with experimental studies and could mislead efforts developing novel therapeutics. These 52 associations include total causal effects of valine on diabetic eye disease, valine on albuminuria (odds ratio = 1.14, 95% CI = 1.08, 1.20), and isoleucine on angina (odds ratio = 1.17, 95% CI = 1.31, 1.76). For example, of the 117 phenotypes with evidence of a statistically significant total causal effect for at least one BCAA, almost half (44%, n = 52) are associated with only one BCAA. In n = 97,469 participants of European ancestry (mean age = 56.7 years 54.1% female), we estimate distinct and often opposing total causal effects for each BCAA. Hypothesizing that inconsistencies between observational and experimental BCAA studies reflect bias from shared lifestyle and genetic factors in observational studies, we used data from the UK Biobank and applied multivariable Mendelian randomization causal inference methods designed to address these biases. Observational studies suggest that BCAAs exert homogeneous phenotypic effects, but these findings are inconsistent with results from experimental human and animal studies. The branched chain amino acids (BCAA) leucine, isoleucine, and valine are essential nutrients that have been associated with diabetes, cancers, and cardiovascular diseases.
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