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Open AccessArticle

Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity

School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4000, Australia
Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
23andMe, Inc., 899 W. Evelyn Avenue, Mountain View, California 94041, USA
School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK
Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 950-2181, Japan
Department of Biomedicine – Human Genetics, Aarhus University, DK-8000 Aarhus, Denmark
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
Divisions of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Authors to whom correspondence should be addressed.
Full lists of consortia members appear at the end of the paper.
Genes 2020, 11(3), 268;
Received: 8 February 2020 / Revised: 28 February 2020 / Accepted: 28 February 2020 / Published: 29 February 2020
(This article belongs to the Special Issue Genes at Ten)
Observational epidemiological studies indicate that endometriosis and migraine co-occur within individuals more than expected by chance. However, the aetiology and biological mechanisms underlying their comorbidity remain unknown. Here we examined the relationship between endometriosis and migraine using genome-wide association study (GWAS) data. Single nucleotide polymorphism (SNP) effect concordance analysis found a significant concordance of SNP risk effects across endometriosis and migraine GWAS. Linkage disequilibrium score regression analysis found a positive and highly significant genetic correlation (rG = 0.38, P = 2.30 × 10−25) between endometriosis and migraine. A meta-analysis of endometriosis and migraine GWAS data did not reveal novel genome-wide significant SNPs, and Mendelian randomisation analysis found no evidence for a causal relationship between the two traits. However, gene-based analyses identified two novel loci for migraine. Also, we found significant enrichment of genes nominally associated (Pgene < 0.05) with both traits (Pbinomial-test = 9.83 × 10−6). Combining gene-based p-values across endometriosis and migraine, three genes, two (TRIM32 and SLC35G6) of which are at novel loci, were genome-wide significant. Genes having Pgene < 0.1 for both endometriosis and migraine (Pbinomial-test = 1.85 ×10°3) were significantly enriched for biological pathways, including interleukin-1 receptor binding, focal adhesion-PI3K-Akt-mTOR-signaling, MAPK and TNF-α signalling. Our findings further confirm the comorbidity of endometriosis and migraine and indicate a non-causal relationship between the two traits, with shared genetically-controlled biological mechanisms underlying the co-occurrence of the two disorders. View Full-Text
Keywords: causality; comorbidity; endometriosis; gene-based association study; genetic overlap; GWAS; Mendelian randomisation; migraine; molecular genetics; pathway enrichment study causality; comorbidity; endometriosis; gene-based association study; genetic overlap; GWAS; Mendelian randomisation; migraine; molecular genetics; pathway enrichment study
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Adewuyi, E.O.; Sapkota, Y.; International Endogene Consortium (IEC); 23andMe Research Team; International Headache Genetics Consortium (IHGC); Auta, A.; Yoshihara, K.; Nyegaard, M.; Griffiths, L.R.; Montgomery, G.W.; Chasman, D.I.; Nyholt, D.R. Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity. Genes 2020, 11, 268.

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