DNA Methylation-Mediated Downregulation of SDK1 Promotes COPD Progression: A Multi-Omics Mendelian Randomization Study.
To systematically explore the potential causal relationships among gene expression, DNA methylation, and chronic obstructive pulmonary disease (COPD) susceptibility using a multi-omics Mendelian randomization (MR) framework, and to further investigate key regulatory genes and methylation sites potentially involved in COPD pathogenesis.
We integrated genome-wide association study (GWAS) data from 635,145 individuals, expression quantitative trait loci (eQTL) data (N=15,695) from the eQTLGen Consortium, and methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC). Two-sample Mendelian randomization was performed using genome-wide significant, linkage disequilibrium (LD)-independent (P < 5×10-⁸, r² < 0.1) instruments filtered by Steiger analysis. Sensitivity analyses included inverse-variance weighted (IVW), MR-Egger, weighted median, and leave-one-out approaches. Colocalization analysis (posterior probability H₄ ≥ 0.75) and summary data-based Mendelian randomization (SMR) with heterogeneity in dependent instruments (HEIDI) test (P > 0.05) were used to validate shared causal variants. A three-step Mendelian randomization assessed mediation through methylation, gene expression, and COPD risk.
We identified eight putative causal genes for COPD based on Mendelian randomization and colocalization analyses. SDK1 demonstrated consistent statistical significance across all subsequent steps. Increased SDK1 expression was significantly associated with a reduced risk of COPD (β = -0.124, P = 0.002). Methylation at the intronic CpG site cg07526904 within SDK1 was associated with lower SDK1 expression (β = -0.148, P = 0.002) and elevated COPD susceptibility (β = 0.036, P = 0.038). Mediation analysis indicated that SDK1 expression mediated approximately 51.9% of the total effect of cg07526904 on COPD risk (β = 0.018, P = 0.038), supporting a potential epigenetic pathway.
This analysis suggests that SDK1 methylation may affect COPD risk by regulating gene expression, highlighting a potential epigenetic mechanism. These findings offer preliminary insights into COPD pathogenesis and may help identify targets for future biomarker-based interventions.
We integrated genome-wide association study (GWAS) data from 635,145 individuals, expression quantitative trait loci (eQTL) data (N=15,695) from the eQTLGen Consortium, and methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC). Two-sample Mendelian randomization was performed using genome-wide significant, linkage disequilibrium (LD)-independent (P < 5×10-⁸, r² < 0.1) instruments filtered by Steiger analysis. Sensitivity analyses included inverse-variance weighted (IVW), MR-Egger, weighted median, and leave-one-out approaches. Colocalization analysis (posterior probability H₄ ≥ 0.75) and summary data-based Mendelian randomization (SMR) with heterogeneity in dependent instruments (HEIDI) test (P > 0.05) were used to validate shared causal variants. A three-step Mendelian randomization assessed mediation through methylation, gene expression, and COPD risk.
We identified eight putative causal genes for COPD based on Mendelian randomization and colocalization analyses. SDK1 demonstrated consistent statistical significance across all subsequent steps. Increased SDK1 expression was significantly associated with a reduced risk of COPD (β = -0.124, P = 0.002). Methylation at the intronic CpG site cg07526904 within SDK1 was associated with lower SDK1 expression (β = -0.148, P = 0.002) and elevated COPD susceptibility (β = 0.036, P = 0.038). Mediation analysis indicated that SDK1 expression mediated approximately 51.9% of the total effect of cg07526904 on COPD risk (β = 0.018, P = 0.038), supporting a potential epigenetic pathway.
This analysis suggests that SDK1 methylation may affect COPD risk by regulating gene expression, highlighting a potential epigenetic mechanism. These findings offer preliminary insights into COPD pathogenesis and may help identify targets for future biomarker-based interventions.
Authors
Xue Xue, Xue Xue, Deng Deng, Li Li, Liang Liang, Chen Chen, Xue Xue, Fang Fang
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