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Shared genetic architecture and cellular convergence between female reproductive disorders and pulmonary function: a genome-wide cross-trait analysis.

Enting Ji·Ze Wang·Shuting Ning·Yao Lu·Hongxia Ma
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Abstract

Female reproductive disorders (FRDs), including polycystic ovary syndrome, endometriosis, uterine leiomyomata, and infertility, have been epidemiologically associated with impaired pulmonary function. However, it remains unclear whether this cross-organ link reflects shared genetic etiology and, if so, which cellular mechanisms mediate it. We performed a systematic genome-wide cross-trait analysis of three FRDs and lung function traits (FEV₁, FVC, FEV₁/FVC) using GWAS summary statistics from individuals of European ancestry, integrating genetic correlation, bidirectional causal inference, pleiotropy mapping, and single-cell enrichment analyses. We identified significant negative genetic correlations between FRDs and lung volume traits, most prominently for FVC (rg range: - 0.077 to - 0.178). Bidirectional causal analyses indicated that FRDs have a detrimental effect on lung volume, with higher FRD genetic liability associated with reduced lung volume. Cross-trait meta-analysis identified 17 pleiotropic variants across 11 loci, with the 19q13.2 (LTBP4) and 12q13.13 (HOXC6/HOXC9) loci showing strong evidence of shared causal variants. Critically, single-cell analyses revealed that shared genetic risk converged on mesenchymal lineages across organs, specifically alveolar adventitial fibroblasts in the lung and stromal/smooth muscle cells in the endometrium. Transcriptome-wide analyses further nominated the estrogen-responsive gene RERG as a convergent gene linking these conditions with lung function. Our study revealed a shared genetic architecture between female reproductive disorders and lung function traits, providing a basis for further mechanistic investigations and potential clinical evaluation. Furthermore, our findings suggest that shared fibroproliferative and hormone-responsive pathways may offer insights into the biological mechanisms underlying these conditions.

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FemaleHumansGenome-Wide Association StudyLungPolycystic Ovary SyndromePolymorphism, Single NucleotideEndometriosisQuantitative Trait LociLeiomyomaInfertility, FemaleFemale reproductive diseasesGenetic architectureGenome-wide cross-trait analysisLung functionJournal Article

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Enting Ji, Ze Wang, Shuting Ning, Yao Lu, Hongxia Ma. 2026-09-01. Shared genetic architecture and cellular convergence between female reproductive disorders and pulmonary function: a genome-wide cross-trait analysis.. https://doi.org/10.1007/s10142-026-02029-1

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Journal Article resourceFemale subjectGenome-Wide Association Study subjectHumans subjectInfertility, Female subjectJournal Article subjectLung subjectPolycystic Ovary Syndrome subjectPolymorphism, Single Nucleotide subjectlung function subject

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