Dissecting the genetic determinants and biological associations between body mass index and female reproductive disorders based on genome-wide association study

Abstract

Background: While the phenotypic link between body mass index (BMI) and some female reproductive disorders is well established, the genetic architecture and causal relationships have not been systematically studied. We aimed to create an atlas of the shared genetic associations of BMI and 16 female reproductive disorders and to identify their common risk loci, biological pathways, and potential mechanisms.

Methods: We assessed the genetic correlations between BMI and 16 reproductive disorders using summary data from large-scale genome-wide association studies. Cross-trait pleiotropic analysis identified shared loci and genes, while functional annotation and tissue-specific analysis revealed relevant biological pathways and tissues. Multi-trait colocalization analysis examined the role of hormones and metabolites in these traits. Additionally, bidirectional Mendelian randomization (MR) analysis was employed to assess causal relationships between BMI and reproductive outcomes. We also conducted summary data-based MR (SMR) analysis to identify potential drug targets.

Results: Our results revealed a significant genetic correlation between BMI and eight female reproductive diseases. Furthermore, we identified 50 shared pleiotropic loci between BMI and these traits, with 21 of them showing significant colocalization, suggesting a complex shared genetic architecture across the genome. In addition, the top biological pathways and tissues enriched with these pleiotropic loci were associated with RNA metabolism, macromolecule biosynthesis, type B pancreatic cell apoptosis, various brain regions, and the pituitary. Moreover, multi-trait colocalization indicated that insulin, lipid metabolites, glucose, glycine, and glutamine mediate shared mechanisms between BMI, gestational diabetes mellitus (GDM), and endometrial cancer. MR analysis suggested BMI may cause several reproductive diseases, with only GDM affecting BMI reversely. Finally, SMR analysis revealed EIF2S2P3 and MCM6, which may have a causative effect on both BMI & GDM and BMI & gestational hypertension.

Conclusion: Our results suggest a significant genetic link between BMI and eight female reproductive diseases, highlighting a shared and causal genetic basis. Reducing BMI in women may serve as an effective strategy to lower the risk of female reproductive disorders. The identified pleiotropic loci, genes, and shared pathways could provide new therapeutic targets for both obesity and reproductive diseases, along with their comorbidities.

Clinical trial number: Not applicable.

Keywords: Body mass index; Female reproductive disorders; Genetic architecture; Hormones; Metabolites.

Fig. 1

The overall design followed in the study is shown. BMI, body mass index; PCOS, polycystic ovary syndrome; GDM, gestational diabetes mellitus; GH, gestational hypertension; PE, pre-eclampsia or eclampsia; EC, endometrial cancer; EnOC, endometrioid ovarian cancer; SAB, spontaneous abortion; UFs, uterine fibroids, UPs, uterine polyps; ICP, intrahepatic cholestasis of pregnancy; FGR, poor fetal growth, PPH, postpartum hemorrhage, PTB, preterm labor and delivery; LDSC, linkage disequilibrium score regression; HDL, high-definition likelihood; PLACO, pleiotropic analysis under composite null hypothesis; MAGMA, multimarker analysis of GenoMic annotation; COLOC, colocolization analysis; SMR, summary-data based Mendelian randomization; HyPrColoc, Hypothesis Prioritization Colocalization. TSH, thyroid stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; FSH, follicle-stimulating hormone; LH, luteinizing hormone; GH, growth hormone; and PRL, prolactin

Fig. 2

Bar plots of genome-wide pleiotropic results. (A) MAGMA gene-set analysis; (B) MAGMA tissue-specific analysis. The red dotted line indicates a significance threshold of 0.05 after multiple corrections, while the blue line represents a threshold of 0.05. BMI, body mass index; PCOS, polycystic ovary syndrome; GDM, gestational diabetes mellitus; GH, gestational hypertension; PE, pre-eclampsia or eclampsia; EC, endometrial cancer; EnOC, endometrioid ovarian cancer; SAB, spontaneous abortion

Fig. 3

Bidirectional Mendelian randomization analysis between BMI and multiple female reproductive disorders. (A) The causal effect of BMI on female reproductive disorders. (B) The causal effect of female reproductive disorders on BMI. BMI, body mass index; PCOS, polycystic ovary syndrome; GDM, gestational diabetes mellitus; GH, gestational hypertension; PE, pre-eclampsia or eclampsia; EC, endometrial cancer; EnOC, endometrioid ovarian cancer; SAB, spontaneous abortion