1. Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity
- Author
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Adewuyi, Emmanuel O., Sapkota, Yadav, International Endogene Consortium (IEC), 23andMe Research Team, International Headache Genetics Consortium (IHGC), Auta, Asa, Yoshihara, Kosuke, Nyegaard, Mette, Griffiths, Lyn R., Montgomery, Grant W., Chasman, Daniel, and Nyholt, Dale R.
- Subjects
endometriosis ,0301 basic medicine ,Linkage disequilibrium ,Endometriosis ,Genetic overlap ,Genome-wide association study ,Comorbidity ,Bioinformatics ,Linkage Disequilibrium ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Risk Factors ,GWAS ,migraine ,Molecular genetics ,Pathway enrichment study ,Mendelian randomisation ,Genetics (clinical) ,pathway enrichment study ,gwas ,Middle Aged ,mendelian randomisation ,Causality ,comorbidity ,Phenotype ,Female ,genetic overlap ,Adult ,causality ,lcsh:QH426-470 ,Migraine Disorders ,Concordance ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,gene-based association study ,Genetics ,medicine ,Humans ,SNP ,Genetic Predisposition to Disease ,Migraine ,Aged ,Gene‐-based association study ,B230 ,Mendelian Randomization Analysis ,medicine.disease ,lcsh:Genetics ,030104 developmental biology ,molecular genetics ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
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&minus, 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 ×, 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 ×, °, 3) were significantly enriched for biological pathways, including interleukin-1 receptor binding, focal adhesion-PI3K-Akt-mTOR-signaling, MAPK and TNF-&alpha, 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.
- Published
- 2020