Association of plasma branched-chain amino acids with overweight: A Mendelian randomization analysis

Objective: A Mendelian randomization (MR) framework was applied to disentangle the causal effect of branched-chain amino acids (BCAAs) and overweight/obesity in Chinese adolescents. Methods: Circulating BCAA levels were measured by liquid chromatography coupled with mass spectrometry. A total of 7 BCAAs and 12 BMI-associated common variants identified from released genome-wide association study results were genotyped. Furthermore, a bidirectional MR approach was undertaken to disentangle the causal effect of BCAAs and overweight/obesity, using two-stage regression. Results: Using the inverse variance-weighted strategy and the weighted genetic scoring instruments, the estimated odds ratio per 1-arbitrary-unit increase in the total BCAA level on overweight and obesity odds after adjusting for age and sex was 2.40 (95% CI: 1.38 to 3.42, p < 0.001) and 2.55 (95% CI: 1.35 to 4.82, p = 0.004), respectively. Furthermore, additional MR tests were undertaken using a reversed model, testing the causal effect of increasing BMI variants on total BCAA level. By contrast, no evidence that increased BMI was causally associated with the total BCAA level (estimated β associated with 1-kg/m² increase in BMI = 0.05, 95% CI: −0.17 to 0.28, p = 0.642) was observed. Conclusions: In summary, BCAAs may be causally associated with overweight/obesity or, rather, a congenital dysmetabolism of BCAAs could be a cause of overweight/obesity in adolescents.