Succinylation-related gene GLS regulates mannose and glycerophospholipid metabolism to promote irritable bowel syndrome: an integrated study combining Mendelian randomization, SMR, and mediation analysis

Abstract

To investigate whether succinylation-related genes participate in irritable bowel syndrome (IBS) pathogenesis by regulating blood metabolites. Genome-wide association study (GWAS) data for cis-expression Quantitative Trait Loci (cis-eQTLs) were obtained from eQTLGen Consortium. Blood metabolite GWAS data were derived from Chen et al., and IBS datasets originated from FinnGen R12. We identified 19 succinylation-related genes, intersecting with eQTL data to obtain succinylation-related eQTLs. Using these eQTLs as exposures and IBS as outcome, we performed two-sample Mendelian Randomization (MR) analysis with inverse-variance weighting (IVW) as the primary method, selecting results with P < 0.05 without heterogeneity or pleiotropy. Subsequent Summary-data-based Mendelian Randomization (SMR) analysis further evaluated these findings (p_SMR < 0.05 and p_HEIDI > 0.05). Finally, mediation analysis using metabolites as mediators identified results with P < 0.05, mediation proportion > 10%, and consistent direction between mediation and total effects. Expression of succinylation-related genes GLS, LDHA, and PGAM1 showed positive associations with IBS risk (P < 0.05). GLS and LDHA passed SMR validation (p_SMR < 0.05 and p_HEIDI > 0.05), whereas PGAM1 did not (p_SMR = 0.422). Although all retained LDHA instruments had F-statistics > 10, LDHA had fewer valid SNPs than GLS (5 vs. 20); therefore, GLS was selected for mediation analysis. GLS may increase IBS risk through higher mannose levels (mediation proportion 26.27%, P = 0.012) and mannonate levels (mediation proportion 47.15%, P = 0.002), and through lower levels of 1-(1-enyl-palmitoyl)-GPC (p-16:0) (mediation proportion 25.76%, P = 0.031), 1-arachidonoyl-GPE (20:4n6) (mediation proportion 11.73%, P = 0.048), the protective glucose/mannose ratio (mediation proportion 24.64%, P = 0.006), and the protective phosphate/mannose ratio (mediation proportion 30.81%, P = 0.029). These findings suggest that the succinylation-related gene GLS may contribute to IBS risk partly through circulating mannose-related and glycerophospholipid metabolic alterations, providing candidate metabolite-mediated pathways for further mechanistic validation.