Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity.

Emmanuel O Adewuyi,Kosuke Yoshihara,Daniel I Chasman,Grant W Montgomery,Asa Auta,International Headache Genetics Consortium (Ihgc) International Headache Genetics Consortium (Ihgc) ,Lyn R Griffiths,International Endogene Consortium (Iec) International Endogene Consortium (Iec) ,Mette Nyegaard,23Andme Research Team 23Andme Research Team ,Dale R Nyholt,Yadav Sapkota

doi:10.3390/genes11030268

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 × 10−25) 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.

Highlights

Endometriosis is one of the leading gynaecological disorders affecting 6%–10% of women of reproductive age and 35%–50% of women with infertility worldwide [1,2]
The most statistically significant concordance test was produced by Single nucleotide polymorphism (SNP) subsets with ‘International Endogene Consortium (IEC) endometriosis’ genome-wide association study (GWAS)
We present a comprehensive assessment of the molecular genetic overlap, causal relationship as well as shared genes and biological pathways between the two disorders

Summary

Introduction

Endometriosis is one of the leading gynaecological disorders affecting 6%–10% of women of reproductive age and 35%–50% of women with infertility worldwide [1,2]. Women in their reproductive and most productive years are more commonly affected with migraine [5,6]. A typical migraine presents with a recurrent, unilateral and episodic headache of moderate to severe intensity [7]. Both endometriosis and migraine portend substantial morbidity with wide-ranging socioeconomic burdens to sufferers, their families, relationships, and the society at large [8,9,10,11]. The aetiology and pathogenesis of endometriosis and migraine remain relatively obscure, and there are currently no known curative treatments for them

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Conclusion