title: Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci.
abstract: 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.
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Rahmioglu
authors.affiliation: Statistical Genetics.
authors.forename: Stuart
authors.initials: S
authors.lastname: Macgregor
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Drong
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Åsa K
authors.initials: ÅK
authors.lastname: Hedman
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA, Unit of Nutritional Epidemiology, Institute for Environmental Medicine, Karolinska Institutet, PO Box 210, SE-171 77 Stockholm, Sweden.
authors.forename: Holly R
authors.initials: HR
authors.lastname: Harris
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Randall
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.affiliation: Neurogenetics.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Department of Biostatistics, University of Liverpool, Duncan Building, Daulby Street, Liverpool L69 3GA, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.affiliation: Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Missmer
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge 02142 MA, USA and.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, Nuffield Department of Obstetrics and Gynaecology & Endometriosis CaRe Centre, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK krinaz@well.ox.ac.uk.
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
mesh_terms: D050154:Adiposity / Q000235:genetics; D000328:Adult; D000483:Alleles; D002897:Chromosomes, Human, Pair 7; D004715:Endometriosis / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009765:Obesity / Q000150:complications* / Q000235:genetics*; D016017:Odds Ratio; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D015398:Signal Transduction