News · May 29, 2025

David Healy Award 2025 presented to Lindsay Guare

The David Healy Award for best Oral Presentation by an Early Career Scientist was presented to Lindsay Guare at the closing ceremony of the 16th World Congress on Endometriosis for her work on Expanding the Genetic Landscape of Endometriosis: Integrating Multi-omics with a Genome-wide Meta-analysis of Over 900,000 Genetically Diverse Women

L Guare¹, J Das¹, A Rajagopalan¹, L Caruth¹, S Namba², Y Okada², Y Shirai³, Y Yamamoto³, A Akerele⁴, J Jaworski⁴, D Velez-Edwards⁴, A Hill⁵, J Shortt⁵, N Elhadad⁶, G Jarvik⁷, L Kottyan⁸, Y Luo⁹, W Wei¹⁰, C Weng⁶, S Chapman¹¹, Y Shi¹¹, W Zhou¹¹, A Mulford¹², A Sanders¹², B Brumpton¹³, E Moreno¹³, T Chen¹⁵, V Rovite¹⁴, Y Lin¹⁵,S Setia- Verma¹

¹University Of Pennsylvania, Philadelphia, United States
²The University of Tokyo, Japan
³Osaka University, Suita, Japan
⁴Vanderbilt University Medical Center, Nashville, United States
⁵Colorado Center for Precision Medicine, Aurora, United States
⁶Columbia University, New York City, United States
⁷University of Washington, Seattle, United States
⁸Cincinnati Children’s Hospital Medical Center, Cincinnati, United States
⁹Northwestern University, Evanston, United States
¹⁰Vanderbilt University, Nashville, United States
¹¹The Broad Institute, Cambridge, United States
¹²Endeavor Health, Evanston, United States
¹³Norwegian University of Science and Technology, Trondheim, Norway
¹⁴Latvian Biomedical Research and Study Centre, Latvia
¹⁵National Health Research Institutes, Maoli County, Taiwan

Country: United States of America Introduction/Background

Endometriosis is a complex heritable disorder requiring comprehensive genomic investigation

across diverse populations. Previous studies have been somewhat limited by European-centric data. The Global Biobank Meta-Analysis Initiative (GBMI) enables large-scale genomic analysis across multiple genetic ancestry groups, complemented by computational multi-omic and single cell analyses to understand disease mechanisms.

Materials and Methods

We performed a Genome-Wide Association Study (GWAS) meta-analysis across 14 biobanks worldwide, with 31% non-European samples. Multiple endometriosis phenotype definitions were analyzed, including broad and surgically-confirmed cases. Post-GWAS analyses included ancestry-stratified heritability estimation and fine-mapping. We conducted Transcriptome- wide and Proteome-wide association analyses, followed by single-cell analyses of implicated genes. Integration of multi-omic data through Mergeomics analysis enabled comprehensive pathway enrichment assessment.

Results

The GWAS (N=928,413 : 44,125 cases) identified 45 significant loci using a broad phenotype definition, including seven previously-unreported signals and the first genome-wide significant locus (POLR2M) in African ancestry. Narrow phenotypes and surgically confirmed cases replicated known loci near CDC42 and SYNE1. Observed heritability was consistent (10-12%) across ancestral groups. Cross-ancestry fine-mapping revealed putative causal variants in 38 loci. Multi-omic imputed association analyses identified 11 significantly-associated gene transcripts (two previously unknown: DTD1 and CCDC88B), two intronic splicing events (within PGR and NSRP1), and one protein, RSPO3. In silico single-cell analyses prioritized 18 disease-relevant cell types including venous cells and macrophages. The results of these analyses specified key players in enriched molecular pathways involving immunopathogenesis, angiogenesis, Wnt signaling, and balance between proliferation, differentiation, and migration of endometrial cells as major hallmarks in genomics of endometriosis.

Conclusion

This diverse GWAS combined with transcriptomic, splice-omic, proteomic, and single-cell analyses revealed novel genetic associations and molecular mechanisms in endometriosis. The identification of ancestry-specific variants and pathway interactions provides multiple targets for developing precise therapeutic interventions across diverse populations.

Key words: Genome wide association analyses, multi-omic data integration, diverse populations

Back

News · November 30, 2023

David Healy Award 2023 presented to Marcela Haro

The David Healy Award for best Scientific Abstract was presented to Marcela Haro at the closing ceremony of the 15th World Congress on Endometriosis for her work on how Heterogeneous Immune Responses Underlie Subtype-Specific and Patient-Specific Heterogeneity in Endometriosis.

Haro M1,2, Fonseca M1,2, Abbasi F1,2, Goodridge H3,4, Siedhoff M5, Jefferies C6, Truong M5, Wright K5, Anglesio M 7,8, Medeiros F9, Lawrenson K1,2,10,11, Yu P10,2
1Women’s Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, United States of America, 2Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center , Los Angeles, United States of America, 3Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America, 4Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America, 5Division of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, United States of America, 6 Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, United States of America, 7 Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada, 8British Columbia’s Gynecological Cancer Research (OVCARE) Program, University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, Canada, 9Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America, 10Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, United States of America, 11Center for Bioinformatics and Functional
Genomics, Cedars-Sinai Medical Center, Los Angeles, United States of America

Introduction:
Endometriosis is characterized by endometrial-type glands and stroma growing outside of the uterine cavity, evading the typical cell-intrinsic and cell-extrinsic safeguards (including immune surveillance) that should prevent cells from surviving at ectopic locations. Chronic inflammation and dysregulation in the immune response contribute to the pathogenesis of endometriosis, however, little is understood regarding how immune dysregulation contributes to the extensive heterogeneity that characterizes endometriosis.

Aim:
This research seeks to phenotype the immune repertoire in endometriosis and explore the dysregulation in the molecular signals in the tissue microenvironment that influences immune cell recruitment and function.

Materials and Methods:
Single cell RNA sequencing was applied to >370,000 cells from endometriosis, eutopic endometrium, unaffected ovary and endometriosis-free peritoneum. All specimens were subjected to pathology review and genotyping for somatic variants in commonly mutated genes.

Results:
Endometriosis patients could be stratified into ‘immune-hot’ or ‘immune-cold’ subgroups based on the presence of lymphoid aggregates and germinal centers proximal to lesions. B-cells and plasma cells were particularly enriched in endometriosis. Elevated autoreactive antibodies, B-cell survival and recruitments signals and an interferon signature are seen in endometriosis.

Conclusion and impact:
Extensive heterogeneity in immune responses to endometriosis may explain, at least in part, the heterogenous presentations and symptoms associated with disease. Ongoing experiments are exploring the therapeutic potential of the anti-CD20 monoclonal antibody for patients with elevated B-cell dysfunction. This research is providing clinically relevant insights into the role of B-cells in the pathogenesis of endometriosis and potential targets for both diagnosis and therapeutics.

 

Back