Lifelong impacts of puberty timing on human plasma metabolic profiles

There has been uncertainty regarding the long-term impact of puberty timing on human plasma metabolites. This lack of clarity can be attributed to the influence of confounding factors present in conventional observational studies. To determine the causal effect of puberty timing on plasma metabolites, we employed a two-sample Mendelian randomization (MR) analysis, complemented by MR mediation analysis assessing the direct effect. We utilized data from a large-scale meta-analysis of genome-wide association studies (GWAS) on puberty timing, consisting of 329,345 women of European ancestry, and a meta-analysis of GWAS on plasma metabolites, involving up to 86,507 individuals. Our findings provide moderate evidence supporting a causal effect of puberty timing on 23 out of 174 plasma metabolites. After excluding 7 single nucleotide polymorphisms (SNPs) related to birth weight and childhood adiposity, causal effects remained for 16 metabolites. Through two-step MR analysis, we observed strong evidence that adulthood adiposity mediated the causal relationships of puberty timing on 35 plasma metabolites. We also observed moderate evidence for an independent causal effect of puberty timing on 10 metabolites through multivariable MR analysis. We further used metabolomic data measured in the UK Biobank (UKB) to perform a replication analysis to validate the causal effect estimated. Nine amino acids were identified in the UKB, and the replication analysis supported our main findings.