Large-scale genome-wide association study to determine the genetic underpinnings of female genital tract polyps

STUDY QUESTION Can a large-scale genome-wide association study (GWAS) meta-analysis identify the genomic risk loci and associated candidate genes for female genital tract (FGT) polyps, provide insights into the mechanism underlying their development, and inform potential overlap with other traits, including endometrial cancer? SUMMARY ANSWER GWAS meta-analysis of FGT polyps highlighted the potentially shared mechanisms between polyp development and cancerous processes. WHAT IS KNOWN ALREADY Small-scale candidate gene studies have focused on biological processes such as estrogen stimulation and inflammation to clarify the biology behind FGT polyps. However, the exact mechanism for the development of polyps is still elusive. At the same time, a genome-wide approach, which has become the gold standard in complex disease genetics, has never been used to uncover the genetics of the FGT polyps. STUDY DESIGN, SIZE, DURATION We performed a genome wide association study (GWAS) meta-analysis including a total of 25,100 women with FGT polyps (International Classification of Disease, ICD-10 diagnosis code N84) and 207,193 female controls (without N84 code) of European ancestry from the FinnGen study (11,092 cases and 94,394 controls) and the Estonian Biobank (EstBB, 14,008 cases and 112,799 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS A meta-analysis and functional annotation of GWAS signals were performed to identify and prioritise genes in associated loci. To determine associations with other phenotypes, we performed a look-up of associated variants across multiple traits and health conditions, a genetic correlation analysis, and a phenome-wide association study (PheWAS) with ICD10 diagnosis codes. MAIN RESULTS AND THE ROLE OF CHANCE Our GWAS meta-analysis revealed ten significant (P < 5 x 10-8) genomic risk loci. Two signals, rs2277339 (P = 7.6 x 10-10) and rs1265005 (P = 1.1 x 10-9) (in linkage disequilibrium (LD) with rs805698 r2 = 0.75), are exonic missense variants in PRIM1, and COL17A1 genes, respectively. Based on the literature, these genes may play a role in cellular proliferation. Several of the identified genomic loci had previously been linked to endometrial cancer and/or uterine fibroids. Thus, highlighting the potentially shared mechanisms underlying tissue overgrowth and cancerous processes, which may be relevant to the development of polyps. Genetic correlation analysis revealed a negative correlation between sex hormone-binding globulin (SHBG) and the risk of FGT polyps (rg = -0,21, se = 0.04, P = 2.9 x 10-6), and on the phenotypic level (PheWAS), the strongest associations were observed with endometriosis, leiomyoma of the uterus and excessive, frequent and irregular menstruation. LARGE SCALE DATA The complete GWAS summary statistics will be made available after publication through the GWAS Catalogue (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION In this study, we focused broadly on polyps of FGT and did not differentiate between the polyp subtypes. The prevalence of FGT polyps led us to assume that most women included in the study had endometrial polyps. Further study on the expression profile of FGT polyps could complement the GWAS study to substantiate the functional importance of the identified variants. WIDER IMPLICATIONS OF THE FINDINGS The study findings have the potential to significantly enhance our understanding of the genetic mechanisms involved, paving the way for future functional follow-up, which in turn could improve the diagnosis, risk assessment, and targeted treatment options, since surgery is the only line of treatment available for diagnosed polyps. TRIAL REGISTRATION NUMBER: Not applicable