Large-scale genome-wide analyses of proteomic data identifies that sex hormones affect plasma glycodelin levels

Abstract Study question How is glycodelin, a glycoprotein secreted by reproductive tissues, causally related to reproductive diseases and traits? Summary answer We present evidence for a causal role of sex hormones in determining glycodelin levels, but limited evidence that glycodelin subsequently causally impacts reproductive traits. What is known already Glycodelin is expressed in female and male reproductive tissues and has four glycoforms (-A, -C, -F and -S), with the glycosylation pattern determining its function. Differences in the levels of glycodelin are associated with reproductive traits, including fertility, endometriosis, preeclampsia, and female-specific malignancies. Study design, size, duration We used cross-sectional data from the UK Biobank to investigate relationships between glycodelin and reproductive-related traits in men and women by performing genome-wide association studies (GWAS) and Mendelian randomization (MR) analyses. Participants/materials, setting, methods We included individuals of European genetic ancestry aged 40–69 in 2006–2010, with genetic data in the UK Biobank v3 release. We performed GWAS of glycodelin levels in 46,468 people, stratified by sex (21,368 men and 25,100 women) and menopause status (6,409 pre- and 18,691 post-menopausal women). We tested bidirectional casual associations between glycodelin levels and 19 reproductive-related traits using one- and two-sample MR analyses. Main results and the role of chance Nine genetic signals reached genome-wide significance (P<5×10-8) across the glycodelin phenotypes. A known genetic signal (rs9409964) near the PAEP gene, which encodes glycodelin, was most strongly associated (P<3×10-80 across all phenotypes), and had heterogeneous effects (effect (SD) per A allele of 1.31 in men vs 0.60 in women, and 0.4 in pre- vs 0.9 in post-menopausal women). Higher serum concentrations of bioavailable testosterone raised glycodelin in men (effect = 0.14 SD, IVW P=4.1×10-13), while effects in women depended on menopause status (pre-menopausal effect = -0.16 SD, IVW P=3.6×10-3; post-menopausal effect = 0.10 SD, IVW P=5.9×10-4). There was no strong evidence that differences in glycodelin levels were caused by, or were the cause of, other reproductive-related traits. Limitations, reasons for caution Proteomic measurements of glycodelin did not differentiate between glycoforms and were derived from blood and might not reflect levels in reproductive tissues. The sample size for the pre-menopausal GWAS was modest, reducing our power to detect relationships with reproductive conditions. Genetic instruments are assumed to be proxies for average lifelong exposure, which does not reflect variation in hormones and biomarkers over lifetime. Wider implications of the findings We suggest that reported associations of glycodelin with reproductive conditions are likely to result from the effects of sex hormones rather than being directly causal. These findings may help reconcile previously conflicting associations between glycodelin and reproductive traits. Competing Interest Statement A.M. is a co-founder and shareholder of OvartiX Limited. The other authors declare no competing interests. Funding Statement This work was funded by UK Research and Innovation (UKRI) under the UK government Horizon Europe funding guarantee [grant number EP/Y031970/1]. M.V. was supported by Cancer Research UK [grant number C18281/A29019]. This study was supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders of the study had no role in the design, data collection, data analysis, data interpretation or writing of the report. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The research utilised data from the UK Biobank resource carried out under UK Biobank application number 103356. UK Biobank protocols were approved by the National Research Ethics Service Committee. All participants provided written informed consent, and all study procedures were performed in accordance with the World Medical Association Declaration of Helsinki ethical principles for medical research. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability The genome-wide summary statistics generated by the study will made available in the NHGRI-EBI GWAS Catalog on publication.