Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity

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 (r_G = 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 (P_gene < 0.05) with both traits (P_{binomial-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 P_gene < 0.1 for both endometriosis and migraine (P_{binomial-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.