Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity

• Published in: Genes Vol. 11; no. 3; p. 268
• Main Authors: Adewuyi, Emmanuel O., Sapkota, Yadav, Auta, Asa, Yoshihara, Kosuke, Nyegaard, Mette, Griffiths, Lyn R., Montgomery, Grant W., Chasman, Daniel I., Nyholt, Dale R.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 29.02.2020
• Subjects: Adult; Aged; Comorbidity; endometriosis; Endometriosis - complications; Endometriosis - genetics; Endometriosis - pathology; etiology; Female; genes; genetic correlation; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; interleukin-1; linkage disequilibrium; Linkage Disequilibrium - genetics; loci; Mendelian Randomization Analysis; meta-analysis; Middle Aged; migraine; Migraine Disorders - complications; Migraine Disorders - genetics; Migraine Disorders - pathology; mitogen-activated protein kinase; observational studies; Phenotype; Phosphatidylinositol 3-Kinases - genetics; Polymorphism, Single Nucleotide - genetics; regression analysis; risk; Risk Factors; single nucleotide polymorphism; tumor necrosis factor-alpha; molecular genetics; GWAS; comorbidity; migraine; endometriosis; gene-based association study; genetic overlap; pathway enrichment study; Mendelian randomisation; causality
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes11030268

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.