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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by grants from the National Natural Science Foundation of China (82373588, 82125032, 81930095 and 81761128035), Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (2021YJRC02), Innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20211100), the Science and Technology Commission of Shanghai Municipality (19410713500 and 2018SHZDZX01), the Shanghai Municipal Commission of Health and Family Planning (GWV-10.1-XK07, 2020CXJQ01, 2018YJRC03) and Sichuan Science and Technology Program (2021JDR0189). The funders of the study had no role in the study design, data collection, data analysis, or data interpretation; writing or reviewing of the manuscript; and decision to submit the manuscript for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data. The genetic instruments for puberty timing were obtained from the corresponding literature at . Data on plasma metabolites GWAS can be found at [www.omicscience.org][1]. Full summary data on adulthood BMI were obtained from the MRC Integrative Epidemiology Unit OpenGWAS project (). Full summary data on birth weight and childhood BMI were obtained from the Early Growth Genetics Consortium ([egg-consortium.org][2]). The replication analyses were conducted using data from the UKB () and the summary level data were obtained at . I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online. The genetic instruments for puberty timing were obtained from the corresponding literature at . Data on plasma metabolites GWAS can be found at [www.omicscience.org][1]. Full summary data on adulthood BMI were obtained from the MRC Integrative Epidemiology Unit OpenGWAS project (). Full summary data on birth weight and childhood BMI were obtained from the Early Growth Genetics Consortium ([egg-consortium.org][2]). The replication analyses were conducted using data from the UKB () and the summary level data were obtained at . [1]: http://www.omicscience.org [2]: http://egg-consortium.org