Global study shows the experience of endometriosis is rooted in a person’s genetics

Researchers at the University of Oxford, in collaboration with 25 research institutions in 11 countries, have published the largest study to date of the genetic basis of endometriosis [1].

This study included DNA from 60,600 women* with endometriosis and 701,900 controls. It revealed compelling evidence of a shared genetic basis for endometriosis and other causes of pain (seemingly unrelated to endometriosis), including migraine, back pain, and multi-site pain.

Why was this study conducted?

We know that endometriosis can run in families, and therefore that genetic factors (heritability) play a role in how it develops in some women but not in others [2,3].

The question is: are we deep wired to endure this pain?

Very little is known about the causes of endometriosis, and studying genetics – by comparing the DNA code in women with and without the disease – can give us clues to the biological processes that are the basis for how the disease starts and how it progresses.

Using different datasets of women with and without endometriosis, some of which had unprecedented detailed data on surgical findings and pain experience collected using standardised criteria**, allowed the investigators to generate a treasure trove of new information about genetically driven endometriosis subtypes and pain experience.

What did the study show about endometriosis?

The study revealed that ovarian endometriosis has a different genetic basis from other disease manifestations. It has long been recognised that endometriosis has at least three subtypes: (superficial) peritoneal endometriosis, cystic/ovarian endometriosis, and deep endometriosis [3,4].

The results from this study confirm that these subtypes may have different origins – and, therefore, may respond differently to different types of treatments. If we understand that subtypes of endometriosis may develop and progress differently, it may be possible to design new medical treatments targeting each specific subtype’s behaviour.

The investigators, lead by Nilufer Rahmioglu (senior research scientist at the Wellcome Centre for Human Genetics, University of Oxford) found 42 areas across the genome that have variants that increase the risk of endometriosis.

Dr Nilufer Rahmioglu
University of Oxford

Dr Rahmioglu explains:

By linking the genetic variants in these 42 areas to the profiles of molecules in endometrium and blood, we identified a range of genes that were differently expressed in these tissues and therefore had a likely role in disease development.

This list of genes is helpful to advance work to develop new treatments, better targeted to different subtypes of disease. For instance, we found that some genetic variants were more associated with ovarian ‘cystic’ endometriosis than with superficial disease, which typically spreads throughout the pelvis.

Pain and specific genes: what does that mean?

What the investigators noted in particular is that many of the implicated genes play a role in pain perception and maintaining that pain. Indeed, they found that there was a shared genetic basis for endometriosis and a range of other chronic pain types, including: migraine, back pain, headache, neck/shoulder pain, hip pain and multi-site pain.

This could be related to what is known as ‘sensitisation of the central nervous system’. It means that individuals who suffer from one pain condition are more likely to suffer other pain conditions. These findings open up the possibility of designing new pain-focused (non-hormonal) treatments, or repurposing existing pain treatments, for endometriosis.

Professor Krina Zondervan
University of Oxford

Senior author, Professor Krina Zondervan (co-director of the Endometriosis CaRe Centre, and head of the Nuffield Department of Women’s & Reproductive Health, University of Oxford), concludes:

Endometriosis is now recognised as a major health issue affecting millions of women’s lives***. This study involved the analysis of DNA from more than 60,000 women with endometriosis worldwide, in an unprecedented collaboration of 25 academic and industry groups contributing their data and time.

We have gained a wealth of new knowledge on the genetics underlying endometriosis. This will help the research community in their efforts to come up with new and better treatments for endometriosis – and possibly even new ways of diagnosing the disease.

Notes

*
Individuals with endometriosis included in this study were born female. Endometriosis can affect women and those assigned female at birth, and in very rare instances those born male [4].

**
The World Endometriosis Research Foundation Endometriosis Phenotyping and Biobanking Harmonisation project (EPHect) developed standards for data and sample collection in endometriosis research, which have been adopted by >55 research centres to date.

***
Endometriosis is recognised as an important women’s health condition with huge unmet need

References

1. Rahmioglu N, et al. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nat Genetics 2023;55(3):423-436.
2. Moen and Magnus. The familial risk of endometriosis. Acta Obstet Gynecol Scand 1993;72:560-4.
3. Zondervan KT, et al. Endometriosis. N Engl J Med 2020;382:1244-56.
4. Horne and Missmer. Pathophysiology, diagnosis, and management of endometriosis. BMJ 2022;379:e070750.

See also

• International study pinpoint endometriosis genes
• Genetic mutation may shed new light on different types of endometriosis
• Genome-wide association study identifies variations in the DNA of women that predispose them to developing endometriosis
• Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian inheritance on chromosome 7p13-15