ESPE Yearbook of Paediatric Endocrinology

Diabetes Obes Metab. 2025 Jan;27(1):184-195. doi: 10.1111/dom.16000. PMID: 39402736

Brief summary: This Mendelian randomization (MR) study used data from over 329,000 women to investigate the association between puberty timing and adult plasma metabolomic profiles.

Timing of puberty has been associated with cardiometabolic outcomes (1, 2, 3), but causality remains uncertain due to confounding factors. This study addressed this question by examining the lifelong metabolic consequences of puberty timing. Genome-wide association study (GWAS) summary statistics on age at menarche (AAM) were extracted from the ReproGen Consortium (n=329,345) (4), and associations with 174 plasma metabolites from 7 biochemical categories were tested in up to 86,507 individuals (5). Two-sample MR, two-step MR and multivariable Mendelian randomization (MVMR) were applied to assess both direct and mediated effects (6).

The authors found moderate evidence for causal relationships between puberty timing and 23 plasma metabolites, including 7 acylcarnitines, 8 amino acids, 2 biogenic amines, and 6 lysophosphatidylcholines. 16 associations remained robust after adjusting for childhood adiposity and birth weight. Two-step MR analysis suggested that many effects were mediated by adult adiposity, while MVMR analysis showed a moderate independent causal effect of puberty timing on 10 metabolites. Several of these metabolites are known to be associated with cardiovascular disease (7).

In conclusion, this study provides indication that puberty timing influences specific plasma metabolites, with part of this effect mediated by adult adiposity.

References: 1. Prentice P, Viner RM. Pubertal timing and adult obesity and cardiometabolic risk in women and men: a systematic review and meta-analysis. Int J Obes (Lond). 2013;37(8):1036-1043.2. Cheng TS, Day FR, Lakshman R, Ong KK. Association of puberty timing with type 2 diabetes: a systematic review and meta-analysis. PLoS Med. 2020;17(1):e1003017.3. Hulanicka B, Lipowicz A, Koziel S, Kowalisko A. Relationship between early puberty and the risk of hypertension/overweight at age 50: evidence for a modified barker hypothesis among polish youth. Econ Hum Biol. 2007;5(1):48-60.4. Day FR, Thompson DJ, Helgason H, Chasman DI, Finucane H, et al. Genomic analyses identidy hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet. 2017;49(§):834-841.5. Lotta LA, Pietzner M, Stewart ID, Wittemans LBL, Li C, et al. A cross-platform approach identifies genetic regulators of human metabolism and health. Nat Genet. 2021;53(1):54-64.6. Sanderson E, Davey Smith G, Windmeijer F, Bowden J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int K Epidemiol. 2019;48(3):713-727.7. Guasch-Ferré M, Zheng Y, Ruiz-Canela M, et al. Plasma acylcarnitines and risk of cardiovascular disease: effect of Mediterranean diet interventions. Am J Clin Nutr. 2016;103(6):1408-1416.