Genetic and transcriptional characterization of a region on chromosome 7p15.2 that shows pleiotropy between endometriosis and fat distribution
Lead Research Organisation:
University of Oxford
Department Name: Wellcome Trust Centre for Human Genetics
Abstract
Endometriosis is a common women's health problem characterised by the presence of deposits resembling endometrium (lining of the uterus) on ectopic sites in the pelvis, causing chronic inflammation, severe pelvic pain and reduced fertility. Family studies indicate that the disease can be inherited. In a recent study comparing genetic information from 5,675 women with endometriosis and 9,331 controls, we found a genetic variant on chromosome 7 associated with moderate-severe endometriosis. In an independent study involving 190,803 individuals, the same genetic region was found to be associated with fat distribution (waist-hip ratio). The signal is located between genes, and it is unclear how the variant - or those in its vicinity - act on transcription of DNA and ultimately on the development of endometriosis or differences in fat distribution. We are collecting endometriotic tissue, endometrium, subcutaneous abdominal fat and blood from women undergoing a laparoscopy for symptoms of endometriosis, or for tubal sterilisation. Using these samples, we will investigate whether DNA transcription in the region of interest is different between women with moderate-severe endometriosis and controls, and between tissues. We will also explore all known genetic variants in the region, and investigate how these affect transcription levels. Implicated variants will be investigated for association with endometriosis risk, and waist-hip ratio, in up to 10,936 women. The proposed work will provide crucial information on gene regulation in the implicated region and its effect on clinical phenotypes, information required for the translation of the genome-wide association findings into clinical meaningful results that can inform the development of new (non-invasive) diagnostic methods and identification of novel drug targets.
Technical Summary
We have identified a pleiotropic signal in an inter-genic region of ~ 900 Kb on chromosome 7p15.2, from genome-wide association (GWA) studies of moderate-severe endometriosis and differential fat distribution (waist-hip ratio, adjusted for body mass index; WHR-adjBMI). Genome-wide expression analysis in subcutaneous adipose tissue identified a local transcript that was significantly associated with the WHR-adjBMI GWA SNP. It is unclear whether: 1) this transcript is differentially expressed in relevant tissues from women with endometriosis; 2) there are other associated known or novel transcripts in the region; and 3) which genetic variants in the region are involved in their regulation. We are collecting endometriotic tissue, endometrium, sc abdominal fat, and whole blood from women undergoing a laparoscopy for: a) symptoms suggestive of endometriosis; and b) sterilisation. We propose to assess differential expression of novel and known transcripts in the 1Mb region of interest in tissues from 100 stage B endometriosis cases and 200 controls, and investigate association with endometriosis and WHR-adjBMI. Genetic variants genotyped and imputed across the region will be tested for association with transcripts (eQTL analyses); eQTL variants significantly associated will be tested for association with phenotypes in 10,936 endometriosis cases and controls. The information to be gained from the proposed study is crucial for the understanding of the GWA findings and their translation into clinically meaningful results, which include the development of non-invasive diagnostic methods (biomarkers) for endometriosis and the development of novel treatments.
Planned Impact
The beneficiaries of our proposed research are women with endometriosis and their families; employers; health care providers; and pharmaceutical industry. Endometriosis is a heritable chronic inflammatory disease and a major women's health problem, causing severe pelvic pain and reduced fertility, estimated to affect up to 10% of women of reproductive age. Characterised by the presence of endometrial-like tissue in sites outside the uterus, it can only be diagnosed reliably through surgery. As the cause remains unknown, treatment options are limited and are invasive. These include hormonal drugs to suppress ovarian function, surgical ablation of endometriotic lesions and, in the severest of cases, removal of the pelvic organs. Endometriosis has been shown to have a major impact on health-related quality of life and work productivity. Women may require multiple admissions for surgery and/or prolonged treatment with costly drugs with problematic side-effects. In 2002, the annual direct and indirect economic costs of endometriosis were estimated between $2.2 and $22 billion in the US alone.
Two independent GWASs have implicated an inter-genic region on 7p15.2 in the development of moderate-severe endometriosis and fat distribution. This is the first time a strong, replicated genetic association signal has been found for endometriosis, however, the mechanism through which this inter-genic region acts on endometriosis risk is unclear. Understanding how known and novel transcripts in this region are regulated by genetic variants is crucial for understanding their pleiotropic role in endometriosis pathogenesis and fat distribution, and for the translation of GWA findings into clinically meaningful results through the development of new, non-invasive diagnostic pathways and identification of new drug targets.
Two independent GWASs have implicated an inter-genic region on 7p15.2 in the development of moderate-severe endometriosis and fat distribution. This is the first time a strong, replicated genetic association signal has been found for endometriosis, however, the mechanism through which this inter-genic region acts on endometriosis risk is unclear. Understanding how known and novel transcripts in this region are regulated by genetic variants is crucial for understanding their pleiotropic role in endometriosis pathogenesis and fat distribution, and for the translation of GWA findings into clinically meaningful results through the development of new, non-invasive diagnostic pathways and identification of new drug targets.
Publications
Becker CM
(2014)
World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research.
in Fertility and sterility
Brawn J
(2014)
Central changes associated with chronic pelvic pain and endometriosis
in Human Reproduction Update
Dunselman GA
(2014)
ESHRE guideline: management of women with endometriosis.
in Human reproduction (Oxford, England)
Fassbender A
(2014)
World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: IV. Tissue collection, processing, and storage in endometriosis research.
in Fertility and sterility
Horikoshi M
(2016)
Genome-wide associations for birth weight and correlations with adult disease
in Nature
Johnson NP
(2013)
Consensus on current management of endometriosis.
in Human reproduction (Oxford, England)
Kukushkina V
(2017)
DNA methylation changes in endometrium and correlation with gene expression during the transition from pre-receptive to receptive phase
in Scientific Reports
Kuznetsov L
(2017)
Diagnosis and management of endometriosis: summary of NICE guidance.
in BMJ (Clinical research ed.)
Montgomery GW
(2014)
The future for genetic studies in reproduction.
in Molecular human reproduction
Description | RCOG Endometriosis Guidelines |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Description | EU Innovative Medicine Initiative |
Amount | € 4,200,000 (EUR) |
Organisation | European Union |
Sector | Public |
Country | European Union (EU) |
Start | 04/2018 |
End | 03/2021 |
Description | EU Twinning scheme |
Amount | £1,064,607 (GBP) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 01/2016 |
End | 12/2018 |
Description | RO1 |
Amount | $2,495,525 (USD) |
Organisation | National Institutes of Health (NIH) |
Sector | Public |
Country | United States |
Start | 08/2016 |
End | 07/2021 |
Title | EPHect SOPs for collection, processing and storage of fluid specimens |
Description | Standard operating protocols for the collection of biological fluid specimens in endometriosis research |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | Published only 2 months ago, the protocols are already in use at four endometriosis research centres in the UK, Belgium, and USA. |
URL | http://endometriosisfoundation.org/ephect/#2 |
Title | EPHect SOPs for collection, processing and storage of tissue biospecimens |
Description | Standard operating protocols for the collection, processing and storage of biological tissue samples in endometriosis research |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | Published only 2 months ago, the protocols are already in use at four endometriosis research centres in the UK, Belgium, and USA. |
URL | http://endometriosisfoundation.org/ephect/#2 |
Title | EPHect Standard Clinical Questionnaire |
Description | Standardised clinical and epidemiological assessment tool in endometriosis research |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | Published only 2 months ago, the instrument is already in use at four endometriosis research centres in the UK, Belgium, and USA. |
URL | http://endometriosisfoundation.org/ephect/#2 |
Title | EPHect Standard Surgical Form |
Description | Standardised endometriosis surgical assessment instrument |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | Published only 2 months ago, the instrument is already in use at four endometriosis research centres in the UK, Belgium, and USA. |
URL | http://endometriosisfoundation.org/ephect/#2 |
Description | Collaborative Alliance between Bayer HealthCare and Oxford University |
Organisation | Bayer |
Department | Bayer HealthCare |
Country | Germany |
Sector | Private |
PI Contribution | This scientific Alliance aims to identify novel drug targets for endometriosis. I am the PI for genetic & translational studies. |
Collaborator Contribution | Bayer HealthCare is a full partner in the Alliance, contributing knowledge, and research output. |
Impact | No outputs as yet. |
Start Year | 2015 |
Description | Endometriosis Penotyping and biobanking Harmonisation project (EPHect) |
Organisation | Harvard University |
Department | Harvard Medical School |
Country | United States |
Sector | Academic/University |
PI Contribution | My team has led the Endometriosis Phenotyping and biobanking Harmonisation project (EPHect), involving a Working Group of 30+ academic collaborators and three major industrial partners. I am Principal Investigator of the project. The aim of EPHect is to provide a consensus on phenotypic data collection instruments and biological sample collection protocols to further large-scale collaborative research into endometriosis, including that funded by our MRC award. The instruments developed were recently published in four open access papers. |
Collaborator Contribution | My collaborator Dr Stacey Missmer of the Harvard group is co-PI of the EPHect project. |
Impact | PMIDs: 25150390, 25256930, 25256929, 25256928 |
Start Year | 2014 |
Description | Oxford Bayer Collaboration on Endometriosis and Fibroids |
Organisation | Bayer |
Department | Bayer HealthCare |
Country | Germany |
Sector | Private |
PI Contribution | PI and collaborator on various projects under this umbrella; joint funding |
Collaborator Contribution | Joint funding; research input |
Impact | Just started |
Start Year | 2014 |
Description | UK Endometriosis Network |
Organisation | University College London |
Department | Institute for Women's Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My research team is a founding member of this UK-based collaboration. We have twice yearly meetings to discuss research progress in endometriosis, and strategy meetings for the purpose of research directions and funding applications |
Collaborator Contribution | The partners in this collaboration contribute equally, in terms of knowledge transfer in endometriosis and contribution to strategy discussions. |
Impact | No outputs as yet |
Start Year | 2015 |
Description | UK Endometriosis Network |
Organisation | University of Aberdeen |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My research team is a founding member of this UK-based collaboration. We have twice yearly meetings to discuss research progress in endometriosis, and strategy meetings for the purpose of research directions and funding applications |
Collaborator Contribution | The partners in this collaboration contribute equally, in terms of knowledge transfer in endometriosis and contribution to strategy discussions. |
Impact | No outputs as yet |
Start Year | 2015 |
Description | UK Endometriosis Network |
Organisation | University of Edinburgh |
Department | MRC Centre for Reproductive Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My research team is a founding member of this UK-based collaboration. We have twice yearly meetings to discuss research progress in endometriosis, and strategy meetings for the purpose of research directions and funding applications |
Collaborator Contribution | The partners in this collaboration contribute equally, in terms of knowledge transfer in endometriosis and contribution to strategy discussions. |
Impact | No outputs as yet |
Start Year | 2015 |
Description | UK Endometriosis Network |
Organisation | University of Liverpool |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My research team is a founding member of this UK-based collaboration. We have twice yearly meetings to discuss research progress in endometriosis, and strategy meetings for the purpose of research directions and funding applications |
Collaborator Contribution | The partners in this collaboration contribute equally, in terms of knowledge transfer in endometriosis and contribution to strategy discussions. |
Impact | No outputs as yet |
Start Year | 2015 |
Description | EURAPAG 15th Congress |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation focused on genetics of endometriosis in adolescents, including comorbidities. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.eurapag2021.eu |
Description | Festival of Genomics and Biodata, London. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Presentation on improving women's health through genomic approaches. |
Year(s) Of Engagement Activity | 2023 |
Description | IXth Asian Congress on Endometriosis |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation on the advances in understanding the genetics of endometriosis. |
Year(s) Of Engagement Activity | 2021 |
Description | International Federation of Fertility Societies 24th World Congress presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation at global conference on the Genetics of Endometriosis |
Year(s) Of Engagement Activity | 2022 |
Description | Patient information day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | We presented results of the research funded at a Patient Research Information Day, organised by Endometriosis UK on 17th November 2018 N/A |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.endometriosis-uk.org/civicrm/event/info%3Fid%3D627%26reset%3D1#.XG7knC2cZQI |
Description | RCOG Guidelines in Endometriosis |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Type Of Presentation | Workshop Facilitator |
Geographic Reach | National |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Guideline update for the diagnosis and treatment of endometriosis in the UK National guideline for all healthcare professionals in the UK |
Year(s) Of Engagement Activity | 2013 |