Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity

Genes (Basel). 2020 Feb 29;11(3):268. 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.

Keywords: GWAS; Mendelian randomisation; causality; comorbidity; endometriosis; gene-based association study; genetic overlap; migraine; molecular genetics; pathway enrichment study.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Comorbidity
  • Endometriosis / complications
  • Endometriosis / genetics*
  • Endometriosis / pathology
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium / genetics
  • Mendelian Randomization Analysis
  • Middle Aged
  • Migraine Disorders / complications
  • Migraine Disorders / genetics*
  • Migraine Disorders / pathology
  • Phenotype
  • Phosphatidylinositol 3-Kinases / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors