Genome study offers clues for endometriosis pathogenesis

Genome study offers clues for endometriosis pathogenesis


A large-scale genome analysis has identified five new genetic regions that appear to play a role in endometriosis.

The results don’t pinpoint the genes themselves, only the approximate location within the genome, but researchers suspect that some of these locations influence regulatory networks that switch genes on and off, perhaps driving pathogenesis. They identified the genomic regions in or near CCDC170, SYNE1, FSHB, FN1 and 7p12.3 as being likely to harbor endometriosis risk loci.

Endometriosis is a complex disease, and genetic factors are thought to account for about half of the variation seen among patients, with the other half apparently influenced by environmental factors.


Perspectives on Endometriosis Management

The study is the largest analysis of genetic variations to date and confirms some findings from earlier efforts, as well as offering some novel insights.

The study identified 14 regions of the genome that appear to be important in endometriosis. “Arguably, four or five are regions that we didn’t know about previously,” Grant Montgomery, PhD, a professorial research fellow at the University of Queensland Institute for Molecular Bioscience in Brisbane, Australia, said at the 13th World Congress on Endometriosis in Vancouver. The study was also published online in Nature Communications (2017 May 24;8:15539. doi: 10.1038/ncomms15539).

Within those 14 regions, the researchers looked at single-nucleotide polymorphisms (SNPs), which are specific locations in the genome where a single base varies within the population. The team identified 10 new SNPs, bringing the total of known endometriosis-linked SNPs to 19. Some SNPs appear to be involved in hormone metabolism, but they hardly tell the whole story. The 19 known SNPs together account for just 1.75% of the phenotype variance in endometriosis and 5.19% of the phenotypic variance in Grade B (moderate to severe) endometriosis cases.

The researchers conducted a meta-analysis that encompassed 17,045 endometriosis cases and 191,596 controls, including women with European (93%) and Japanese (7%) ancestry. The analysis looked at a total of 6,979,035 SNPs.

In the original studies, researchers determined the identity of the base at each SNP in both patients and controls, and noted locations where the frequency of one base type differed between women with and without endometriosis.

Some of the SNPs highlighted in the new analysis appear to regulate hormone metabolism, including the Wnt signaling pathway, which has also been associated with ovarian cancer risk. The work also reinforced evidence implicating a common variant in the GREB1 gene (growth regulation by estrogen in breast cancer 1), which as its name implies, plays a role in how estrogen drives cell proliferation in breast cancer.

The team found evidence of three other regions that play a role in switching GREB1 on and off, and overall evidence suggests that variations in multiple genes in the same pathway may be acting to increase estrogen-sensitivity and the risk of endometriosis.

Those and other findings could open up a new understanding of the biology behind endometriosis.

“Hopefully that biology will lead to a better understanding of new therapeutic options later on,” Dr. Montgomery said. “I think there’s a few steps before we actually get to that.”

There are likely more endometriosis-linked SNPs to be found, but it’s also possible that the 19 known SNPs are influencing one another. “I think that’s the work of the next 4 or 5 years,” Dr. Montgomery said. “One, to identify the genes in each of these regions, and then to see how they function and particularly how they interact together.”

Dr. Montgomery received support from the Wellcome Trust and the Australian National Health and Medical Research Council. He reported having no financial disclosures. Some of his study coauthors are employees of the biotechnology firm deCODE Genetics, a subsidiary of AMGEN.

Jim Kling is a writer for Ob.Gyn. News

Dr. Grant Montgomery presented his research at the World Congress of on Endometriosis in Vancouver.