Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity

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.

Pathophysiological Bases of Comorbidity in Migraine

“…The biological mechanisms underlying this comorbidity remain unknown. Interestingly, a recent genome-wide association study found a positive and highly significant genetic correlation ( p = 2.30 × 10 −25 ) between endometriosis and migraine and suggested a role for genes involved in interleukin-1 receptor binding, focal adhesion-PI3K-Akt-mTOR-signaling, mitogen-activated protein kinase (MAPK), and tumor necrosis factor-alpha (TNF-α) signaling in the association between these two traits (Adewuyi et al, 2020 ).…”

“…Investigations of metaboloendocrine comorbidities of migraine further support the role of shared molecular genetic mechanisms between all these highly prevalent medical conditions. Migraine and diabetes, obesity, and endometriosis are complex genetic traits sharing common genes as well as common metabolic pathways (McCarthy et al, 2001 ; Netzer et al, 2008 ; Adewuyi et al, 2020 ). Further investigating these pathways will allow us to disentangle the biochemical mechanisms of migraine.…”

Shared genetic influences on resting-state functional networks of the brain

“…Interesting significant gene-wide associations also included FHL5 , a gene previously associated with migraine 47,48 , spatial memory 49 , and cerebral blood flow 50 , and SMYD3 , which previously came up in GWASs of cognitive ability 51,52 , suicide attempt 53 , and bipolar disorder 54 . However, the genes retrieved by our gene-wide analyses were not all related to traits exclusively relevant to the brain, but also to cardiovascular 55,56 , metabolic 57,58 , and drug response traits 59,60 .…”

Features of pain syndrome in genital endometriosis and migraine

“…Мигрень и эндометриоз являются генетически детерминированными заболеваниями, что подтверждено крупными полногеномными ассоциативными исследованиями [14][15][16]. Также предполагается, что важную роль в коморбидности мигрени и эндометриоза играет ген рецептора эстрогена 1 (ESR1), который отвечает за восприимчивость к мигрени и эндометриозу [17,18].…”