Eight putative causal genes for COPD were identified, with increased gene expression significantly associated with a reduced risk of COPD (β = -0.124, P = 0.002).
Methylation at the intronic CpG site cg07526904 is associated with lower gene expression (β = -0.148, P = 0.002) and elevated COPD susceptibility (β = 0.036, P = 0.038).
Expression is suggested to mediate approximately 51.9% of the total effect of cg07526904 on COPD risk (β = 0.018, P = 0.038).
The findings indicate a potential epigenetic pathway influencing COPD risk through gene expression regulation.
Simplified
PURPOSE: To systematically explore the potential causal relationships among gene expression, , and chronic obstructive pulmonary disease (COPD) susceptibility using a multi-omics (MR) framework, and to further investigate key regulatory genes and methylation sites potentially involved in COPD pathogenesis.
PATIENTS AND METHODS: 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 < 5×10⁸,< 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. -r²
RESULTS: We identified eight putative causal genes for COPD based on Mendelian randomization and colocalization analyses.demonstrated consistent statistical significance across all subsequent steps. Increasedexpression was significantly associated with a reduced risk of COPD (β = -0.124, P = 0.002). Methylation at the intronic CpG site cg07526904 withinwas associated with lowerexpression (β = -0.148, P = 0.002) and elevated COPD susceptibility (β = 0.036, P = 0.038). Mediation analysis indicated thatexpression mediated approximately 51.9% of the total effect of cg07526904 on COPD risk (β = 0.018, P = 0.038), supporting a potential epigenetic pathway. SDK1SDK1SDK1SDK1SDK1
CONCLUSION: This analysis suggests thatmethylation 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. SDK1
Key numbers
0.036
Increase in COPD Risk
Effect size for the association between cg07526904 methylation and COPD risk
51.9%
Mediation Proportion
Proportion of total effect mediated by SDK1 expression
-0.148
Gene Expression Decrease
Effect size for the association between cg07526904 methylation and SDK1 expression
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The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this study.
