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