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Methods: Instrumental variables for 486 circulating metabolites (N = 7824) and 731 immunophenotypes (N = 3757) were derived from a genome-wide association study (GWAS) meta-analysis. FinnGen contributed data on 14 female reproductive disorders. A bidirectional two-sample Mendelian randomization study was performed to determine the relationships between exposures and outcomes. The robustness of results, potential heterogeneity, and horizontal pleiotropy were examined through sensitivity analysis. Results: High levels of mannose were found to be causally associated with increased risks of gestational diabetes (GDM) (OR [95% CI], 6.02 [2.85\u201312.73], p = 2.55 \u00d7 10\u22126). A genetically predicted elevation in the relative count of circulating CD28\u2212CD25++CD8+ T cells was causally related to increased female infertility risk (OR [95% CI], 1.26 [1.14\u20131.40], p = 1.07 \u00d7 10\u22125), whereas a high absolute count of NKT cells reduced the risk of ectopic pregnancy (OR [95% CI], 0.87 [0.82\u20130.93], p = 5.94 \u00d7 10\u22126). These results remained consistent in sensitivity analyses. Conclusions: Our study supports mannose as a promising GDM biomarker and intervention target by integrating metabolomics and genomics.<\/jats:p>","DOI":"10.3390\/biom14010116","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T08:12:37Z","timestamp":1705392757000},"page":"116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Potential Causal Association between Plasma Metabolites, Immunophenotypes, and Female Reproductive Disorders: A Two-Sample Mendelian Randomization Analysis"],"prefix":"10.3390","volume":"14","author":[{"given":"Hui-Hui","family":"Shen","sequence":"first","affiliation":[{"name":"Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8135-2209","authenticated-orcid":false,"given":"Yang-Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"},{"name":"Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan-Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 10, Poyang Lake Road, Tuanpo Xinchengxi District, Jinghai District, Tianjin 301617, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Ji\u2019nan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang-Feng","family":"Ye","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138632, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9276-0722","authenticated-orcid":false,"given":"Ming-Qing","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"},{"name":"Shanghai Medical College, Fudan University, Shanghai 200032, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1016\/S0140-6736(19)30690-7","article-title":"Populations, decreasing fertility, and reproductive health","volume":"393","author":"Skakkebaek","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Alesi, S., Ghelani, D., Rassie, K., and Mousa, A. 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