Genome-wide genetic analyses highlight mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis

Abstract

STUDY QUESTIONDo genome-wide association study (GWAS) data for endometriosis provide insight into novel biological pathways associated with its pathogenesis?SUMMARY ANSWERGWAS analysis uncovered multiple pathways that are statistically enriched for genetic association signals, analysis of Stage A disease highlighted a novel variant in MAP3K4, while top pathways significantly associated with all endometriosis and Stage A disease included several mitogen-activated protein kinase (MAPK)-related pathways.WHAT IS KNOWN ALREADYEndometriosis is a complex disease with an estimated heritability of 50%. To date, GWAS revealed 10 genomic regions associated with endometriosis, explaining <4% of heritability, while half of the heritability is estimated to be due to common risk variants. Pathway analyses combine the evidence of single variants into gene-based measures, leveraging the aggregate effect of variants in genes and uncovering biological pathways involved in disease pathogenesis.STUDY DESIGN, SIZE, DURATIONPathway analysis was conducted utilizing the International Endogene Consortium GWAS data, comprising 3194 surgically confirmed endometriosis cases and 7060 controls of European ancestry with genotype data imputed up to 1000 Genomes Phase three reference panel. GWAS was performed for all endometriosis cases and for Stage A (revised American Fertility Society (rAFS) I/II, n = 1686) and B (rAFS III/IV, n = 1364) cases separately. The identified significant pathways were compared with pathways previously investigated in the literature through candidate association studies.PARTICIPANTS/MATERIALS, SETTING, METHODSThe most comprehensive biological pathway databases, MSigDB (including BioCarta, KEGG, PID, SA, SIG, ST and GO) and PANTHER were utilized to test for enrichment of genetic variants associated with endometriosis. Statistical enrichment analysis was performed using the MAGENTA (Meta-Analysis Gene-set Enrichment of variaNT Associations) software.MAIN RESULTS AND THE ROLE OF CHANCEThe first genome-wide association analysis for Stage A endometriosis revealed a novel locus, rs144240142 (P = 6.45 × 10−8, OR = 1.71, 95% CI = 1.23–2.37), an intronic single-nucleotide polymorphism (SNP) within MAP3K4. This SNP was not associated with Stage B disease (P = 0.086). MAP3K4 was also shown to be differentially expressed in eutopic endometrium between Stage A endometriosis cases and controls (P = 3.8 × 10−4), but not with Stage B disease (P = 0.26). A total of 14 pathways enriched with genetic endometriosis associations were identified (false discovery rate (FDR)-P < 0.05). The pathways associated with any endometriosis were Grb2-Sos provides linkage to MAPK signaling for integrins pathway (P = 2.8 × 10−5, FDR-P = 3.0 × 10−3), Wnt signaling (P = 0.026, FDR-P = 0.026) and p130Cas linkage to MAPK signaling for integrins pathway (P = 6.0 × 10−4, FDR-P = 0.029); with Stage A endometriosis: extracellular signal-regulated kinase (ERK)1 ERK2 MAPK (P = 5.0 × 10−4, FDR-P = 5.0 × 10−4) and with Stage B endometriosis: two overlappin...

Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why

“…These genes included RON, SOS, 14-3-3 protein eta, and uPAR in epithelial cells and KSR and PI3K p85 regulatory subunit alpha in stromal cells. A recent GWAS analysis of Stage A endometriosis revealed a total of 14 pathways were enriched, including the Grb2-Sos, Wnt signaling p130Cas, and extracellular signal-regulated kinase (ERK)1/ERK2/MAPK pathways (134). Wu et al, (135) conducted a comprehensive profiling of gene expression differences between the ectopic and eutopic endometrium taken from women with endometriosis adjusted for menstrual phase and the location of the lesions.…”

Pathogenesis of deep endometriosis

“…The many observations in women with endometriosis can be interpreted as the expression of predisposition and/or as the consequence of endometriosis instead of being the cause. These comprise abundant retrograde menstruation (194) and the recent observations on cellular pathways (195), cytokines (196)(197)(198)(199), dentritic cells (200), vitamin D (201), mast cells (202,203), hypoxia-inducible factor (204), high Mobility Group Box-1 and Toll-Like Receptor 4 (205), matrix metalloproteinase promoter polymorphisms (206), galectin-3 expression (207), promoter polymorphisms of matrix metalloproteinase genes (208), P receptor (PR) expression (209), acylcarnitines, phosphatidylcholines, and sphingomyelins in PF (210), uterine leukocytes (96), vascular epithelial growth factor (211,212), and other angiogenic factors (213) such as the TGF-b superfamily (214), vezatin expression (215), lymphocytes in blood (216), prostaglandins (217), insulin-like growth factor I (IGF-I) (218), repeated micro-trauma (219) or macro-trauma (63), transcription-3 signaling (220), genetic variants expression (221), and the Hoxa10/HOXA10 gene (222).…”

Associations of genetic variants in endocytic trafficking of epidermal growth factor receptor super pathway with risk of nonsyndromic cleft lip with or without cleft palate

“…So the pathway-based or gene set enrichment analyses were introduced as a supplement to GWAS in recent years. The pathway-based association analysis has been increasingly utilized as one of the effective complements to GWAS (Pan et al, 2017;Wang, Li, & Hakonarson, 2010;Weng et al, 2011;Zhong, Yang, Kaplan, Molony, & Schadt, 2010) by investigating genetic variants of some aggregate genes in given pathways (Ramanan, Shen, Moore, & Saykin, 2012;Uimari et al, 2017). This measure makes it possible to better understand the genetic variants and provides clues to biological processes in complex disease research.…”