Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci
Open accessAbstract
Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.
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Genome-wide association studies identified 10 or 15 loci with single-nucleotide polymorphisms associated with severe endometriosis, located in DNA sequences regulating target genes.
“Genomewide association studies identified 10 (50) or 15 (51) loci with single-nucleotide polymorphisms (52) associated with severe endometriosis, but located in DNA sequences regulating target genes (53).”
From Pathogenesis of endometriosis: The genetic/epigenetic theory (2019) · cites this paper as [50]
Genome-wide scanning resulted in 10 significant loci and a significant association of six of these.
“Genome-wide scanning resulted in 10 significant loci and a significant association of six of these (167, 168).”
From Pathogenesis of deep endometriosis (2017) · cites this paper as [168]
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“Additionally, associations between reduced obesity traits and endometriosis severity have been reported [26].”
BackgroundGaritazelaia, A., Rueda-Martínez, A., Arauzo, R., de Miguel, J., Cilleros-Portet, A., Marí, S., Bilbao, J. R., Fernandez-Jimenez, N., & García-Santisteban, I. (2021) · Life · doi:10.3390/life11010024 · Cited by 22 · see citing works
- Authors
- Rahmioglu, N., Macgregor, S., Drong, A. W., Hedman, A. K., Harris, H. R., Randall, J. C., Prokopenko, I., The International Endogene Consortium (IEC), T. G. C., Nyholt, D. R., Morris, A. P., Montgomery, G. W., Missmer, S. A., Lindgren, C. M., & Zondervan, K. T.
- Affiliations
- Centre for Human Genetics (GB)
- Brigham and Women's Hospital (US)
- Wellcome Sanger Institute (GB)
- QIMR Berghofer Medical Research Institute (AU)
- Broad Institute (US)
- Corresponding author
- Zondervan, K. T.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-10-08
- Volume
- 24
- Issue
- 4
- Pages
- 1185-1199
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4576730
- OpenAlex
- W2168646496
- Cited by
- 85
- References
- 46
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 13 · 2020: 8 · 2019: 6 · 2018: 15 · 2017: 10 · 2016: 6 · 2015: 4 · 2014: 1
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Human Molecular Genetics (publishedVersion, cc-by)
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- edoc (University of Basel) (acceptedVersion)
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- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Faculty of Health; Institute of Health and Biomedical Innovation
- edoc (University of Basel)
- Funders
- Brigham and Women's Hospital
- Universitetet i Tromsø
- University of Dundee
- Norges Teknisk-Naturvitenskapelige Universitet
- Wellcome Trust (098017, 085475, 085235, 086596/Z/08/Z, 084766, WT085235/Z/08/Z, WT084766, WTCCC2, 090532, WT084766/Z/08/Z, 076113)
- Università degli Studi di Milano
- Cedars-Sinai Medical Center
- QIMR Berghofer Medical Research Institute
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- Universitätsklinikum Essen
- Cancer Research UK (14136)
- National Institute for Health and Care Research (NF-SI-0611-10170, NF-SI-0512-10114)
- British Heart Foundation
- University College London
- Universität Heidelberg
- Universiteit Leiden
- Università degli Studi di Milano-Bicocca
- Lunds Universitet
- Queen's University
- Karolinska Institutet
- Kuopion Yliopistollinen Sairaala
- Leids Universitair Medisch Centrum
- Akademiska Sjukhuset
- Medizinischen Hochschule Hannover
- Uppsala Universitet
- Rheinische Friedrich-Wilhelms-Universität Bonn
- Universität Ulm
- Harokopio University
- School of Medicine, Stanford University
- Medical Research Council (MR/K011480/1)
- NHLBI Division of Intramural Research
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- endometriosis, obesity, waist-to-hip ratio, body mass index, genetic susceptibility loci, pleiotropy, Wnt signalling pathway, Wnt4, Grb14, intergenic variants, endometriosis severity, body fat distribution
- MeSH terms
- Adult, Alleles, Chromosomes, Human, Pair 7, Endometriosis, Female, Humans, Obesity, Signal Transduction, Odds Ratio, Quantitative Trait, Heritable, Genetic Predisposition to Disease, Quantitative Trait Loci, Adiposity, Genome-Wide Association Study
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