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.

Keywords: Mendelian randomization; age at natural menopause; docosahexaenoic acid; polyunsaturated fatty acids; reproductive longevity.

Figure 1

Overview of the study design and three fundamental assumptions. Abbreviations: BMI, body mass index; POI, primary ovarian insufficiency; SNP, single nucleotide polymorphism; DHA, docosahexaenoic acid; UKB, UK Biobank; n, number of individuals; GWAS, genome-wide association study; LD, linkage disequilibrium; MR, Mendelian randomization; WM, weighted median; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier; AAM, age at menarche; ANM, age at natural menopause; NBDC, National Bioscience Database Center. FADS, fatty acid desaturase.

Figure 2

Forest plot of MR causal estimates for plasma PUFAs (five omega-3 and five omega-6 PUFAs) on age at natural menopause. Abbreviations: PUFA, polyunsaturated fatty acids; N_SNP, number of single nucleotide polymorphism; SNP, single nucleotide polymorphism; CI, confidence interval.

Figure 3

Forest plot of MR causal estimates for plasma DHA on age at natural menopause in two ancestries with replication analyses. Abbreviations: DHA, docosahexaenoic acid; CI, confidence interval.

Figure 4

The meta-analyses of two sources of European GWASs of total omega-3 (a) and DHA (b) on ANM and AAM. The size of the red squares indicates the weight of each cohort included in the meta-analysis. The center of the black diamond represents the point estimate of the combined effect size, while the width of the diamond depicts the 95% CI. Abbreviations: ANM, age at natural menopause; AAM, age at menarche; DHA, docosahexaenoic acid; UKB, UK biobank; GWAS, genome-wide association study; CI, confidence interval.