Oral Presentation Women's Health Forum 2021

Genetic insights into endometriosis risk and pathogenesis (#14)

Sally Mortlock 1 , Fei Yang 1 , Sushma Marla 1 , Raden I Kendarsari 1 , Jenny N Fung 1 , Sarah J Holdsworth-Carson 2 , Jane E Girling 2 3 , Martin Healey 2 , Restuadi Restuadi 1 , Samuel Lukowski 1 , Rupert Levien 1 , Wan Tinn Teh 2 , Yang Wu 1 , Zhihong Zhu 1 , Ting Qi 1 , Jian Yang 1 , Allan McRae 1 , Peter A.W Rogers 2 , Brett McKinnon 1 4 , Grant Montgomery 1
  1. Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia
  2. University of Melbourne, Department of Obstetrics and Gynaecology, and Gynaecology Research Centre, Royal Women’s Hospital, Parkville, VIC, Australia
  3. Department of Anatomy, University of Otago, Dunedin, New Zealand
  4. Department of Obstetrics and Gynaecology, Inselspital University Hospital of Berne, Berne, Switzerland

Endometriosis is a chronic gynaecological disease affecting 11% of reproductive-age women. It is estimated that 50% of the variation in endometriosis risk is explained by genetics. Recent developments in high throughput genotyping technology and genome-wide association studies (GWAS) have allowed us to test effects of millions of genomic variants in thousands of samples to map genetic risk factors for complex diseases. The most recent meta-analysis being completed by the International Endometriosis Genetics Consortium includes 24 endometriosis GWAS including 60,674 cases of European and East-Asian descent and identified 42 genomic loci associated with endometriosis. We are conducting functional characterisation of risk loci in relevant tissues and cell types. Endometrium is the likely source of cells initiating endometriosis and genes in risk loci are enriched in female reproductive tissues. We have generated gene expression and methylation datasets in endometrium and have applied advanced statistical approaches to link genetic risk factors with functional consequences (changes in expression and methylation) identifying multiple target genes for endometriosis including genes influencing pain-related pathways, sex-hormone signalling, uterine development, oncogenesis, inflammatory adhesion and angiogenesis. Genetics is also being used to improve endometriosis diagnosis and treatment by linking molecular profiles with phenotypic data to identify disease subtypes and develop endometriosis risk scores for risk prediction and patient stratification. Recent analysis has provided evidence that some risk variants have bigger effects in severe and infertile endometriosis and that specific variants may confer risk for different sub-types of endometriosis through distinct pathways. Genetic research in endometriosis can help improve diagnostic and treatment pathways by improving our understanding of the molecular mechanisms contributing to the pathogenesis of endometriosis, identifying potential drug targets, characterising disease subtypes and providing opportunities for personalised treatments and improving the ability to stratify patients according to risk.