ATIC, A Potential Drug Target for Constipation: Evidence from Mendelian Randomization Integrating GWAS and eQTL Data

Introduction: Constipation is a prevalent chronic gastrointestinal disorder. Current treatments primarily focus on short-term relief, leaving significant challenges for achieving long-term improvement. Therefore, identifying novel therapeutic targets is crucial. Material and methods: We employed Mendelian randomization (MR) analysis, using cis-expression quantitative trait locus (cis-eQTL) data from the eQTLGen Consortium and summary data for constipation (ncase = 15,902; ncontrol = 395,721). We performed a replication of the MR analysis using data from the FinnGen study (ncase = 44,590; ncontrol = 409,143). Multiple methods, including Bayesian colocalization, Summary-data Mendelian Randomization (SMR) analysis, heterogeneity testing, Heterogeneity in Dependent Instrument (HEIDI), and horizontal pleiotropy testing, were applied to rigorously validate these findings and assess the likelihood of shared causal variants. Results: The primary MR analysis identified eight druggable genes significantly associated with constipation risk (P < 0.05/2534, FDR corrected), with ATIC and PPIL1 demonstrating consistent associations in replication cohorts (P < 0.05). Sensitivity analyses confirmed the robustness of these findings, with no indication of heterogeneity. Co-localization analysis suggested that ATIC is likely to share causal variants with constipation susceptibility (PP.H4 = 0.91). Subsequent SMR analysis further confirmed a significant association between ATIC and constipation (P _SMR = 8.76 × 10 ^-4 ), while passing the HEIDI test (P _HEIDI = 3.46 × 10 ^-1 ). ATIC was linked to a lower risk of constipation (OR = 0.855, 95% CI = 0.811 – 0.902, P _FDR = 1.86 × 10 ^-5 ). Conclusions: Our study identified the ATIC gene as a highly promising drug target for reducing the risk of constipation, laying the groundwork for future drug development.