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Open AccessArticle

Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity

1
School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4000, Australia
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Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
3
23andMe, Inc., 899 W. Evelyn Avenue, Mountain View, California 94041, USA
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School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK
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Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 950-2181, Japan
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Department of Biomedicine – Human Genetics, Aarhus University, DK-8000 Aarhus, Denmark
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iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark
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Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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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; https://doi.org/10.3390/genes11030268
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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