Age at menarche (AAM) is considered a protective factor against non-alcoholic fatty liver disease (NAFLD).

Interaction tests indicate that the relationship between AAM and NAFLD is influenced by diabetic status and race.

Genetically predicted AAM has a potentially unidirectional negative causal association with NAFLD.

This study aimed to explore the causal relationship between age at menarche (AAM) and non-alcoholic fatty liver disease (NAFLD), leveraging data from the 2017–2020 National Health and Nutrition Examination Survey (NHANES) alongside Mendelian randomization (MR) analyses. Notably, this research represents the first attempt to link AAM to NAFLD using genetic methodologies, thereby providing novel insights into the interplay between these two conditions.

Cross-sectional data from 2730 participants were analyzed using logistic regression to evaluate the association between AAM and NAFLD risk. A two-sample MR study was performed to investigate causal relationships, utilizing genetic data from large-scale genome-wide association studies (GWASs). The inverse variance weighted (IVW) method served as the primary MR analysis approach.

A significant negative association between AAM and NAFLD was found in Model 3 (OR = 0.85, 95 % CI: 0.74–0.97). Participants in the highest AAM quintile exhibited a 68 % reduction of NAFLD prevalence compared to those in the lowest AAM quintile (OR = 0.32, 95 % CI: 0.11–0.97). MR analysis confirmed a potential negative causal association (discovery: OR = 0.81, 95 % CI: 0.73–0.90; validation: OR = 0.80, 95 % CI: 0.66–0.96).

Our findings indicate a potential causal association between AAM and NAFLD, suggesting that early AAM may serve as a potential risk marker for NAFLD. This highlights the importance of incorporating AAM into clinical risk assessment tools and developing targeted prevention strategies for at-risk populations. Further research is needed to clarify the underlying mechanisms and to explore the potential benefits of early intervention.

Age at menarche

Non-alcoholic fatty liver disease

National Health and Nutrition Examination Survey

Mendelian randomization analysis

Causality

© 2025 The Authors. Published by Elsevier Inc.