Abstract
Pelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus. We performed a genome-wide association study of POP using data from Iceland and the UK Biobank, a total of 15,010 cases with hospital-based diagnosis code and 340,734 female controls, and found eight sequence variants at seven loci associating with POP (P < 5 × 10−8); seven common (minor allele frequency >5%) and one with minor allele frequency of 4.87%. Some of the variants associating with POP also associated with traits of similar pathophysiology. Of these, rs3820282, which may alter the estrogen-based regulation of WNT4, also associates with leiomyoma of uterus, gestational duration and endometriosis. Rs3791675 at EFEMP1, a gene involved in connective tissue homeostasis, also associates with hernias and carpal tunnel syndrome. Our results highlight the role of connective tissue metabolism and estrogen exposure in the etiology of POP.
Highlights
Pelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus
To gain a further understanding of the variants associating with POP we explored how they correlate with other traits in combined data from Iceland and UK Biobank data (UKB) – a database with approximately 800 traits (P-value threshold = 0.05/800 = 6.3 × 10−5) – in addition to looking up all variants and their correlates (r2 > 0.5) in the genome-wide-association studies (GWASs)-catalog[34] (Supplementary Data 9, 10)
We conducted a meta-analysis of two GWAS for POP and discovered eight variants at seven loci that associate with POP
Summary
Pelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus. POP stages II-IV (a descent at or beyond the hymenal remnant), risk factors are number of children delivered, vaginal delivery, advancing age and BMI17, suggesting the role of tissue trauma, estrogen exposure and intra-abdominal pressure in the pathogenesis of POP. The etiology of POP is not fully understood, and is likely multifactorial, abnormality in the connective tissue supporting the vagina and pelvic organs or in the muscles in the pelvic floor have been proposed to contribute to the pathophysiology of the condition[21,22]. Higher serum concentration of procollagen III25 is found in women with joint hypermobility and in those with recurrent POP It is, unclear whether such changes in collagen metabolism cause POP or are the result of a trauma[26,27]. Previous candidate gene-, linkage- and genome-wide-association studies (GWASs) on POP, generally of small sample sizes, have not yielded sequence variants that associate with POP26,29–31
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