Genetically Determined Plasma Docosahexaenoic Acid Showed a Causal Association with Female Reproductive Longevity-Related Phenotype: A Mendelian Randomization Study

Abstract

Background: Female reproductive aging remains irreversible. More evidence is needed on how polyunsaturated fatty acids (PUFAs) affect the female reproductive lifespan. Objectives: To identify and validate specific PUFAs that can influence the timing of menarche and menopause in women. Methods: We utilized a two-sample Mendelian randomization (MR) framework to evaluate the causal relationships between various PUFAs and female reproductive longevity, defined by age at menarche (AAM) and age at natural menopause (ANM). Our analyses leveraged summary statistics from four genome-wide association studies (GWASs) on the plasma concentrations of 10 plasma PUFAs, including 8866 to 121,633 European individuals and 1361 East Asian individuals. Large-scale GWASs for reproductive traits provided the genetic data of AAM and ANM from over 202,323 European females and 43,861 East Asian females. Causal effects were estimated by beta coefficients, representing, for each increase in the standard deviation (SD) of plasma PUFA concentration, the yearly increase in AAM or ANM. Replications, meta-analyses, and cross-ancestry effects were assessed to validate the inference. Conclusions: Higher plasma DHA was identified to be associated with delayed natural menopause without affecting menarche, offering a potential intervention target for extending reproductive longevity.