Leveraging DNA methylation quantitative-trait loci to characterize the relationship between metabolic traits and Alzheimer’s disease
Abstract Background: The relationship between DNA methylation, common metabolic risk and Alzheimer’s disease (AD) is not well understood.Methods: Summary statistics integrating DNA methylation quantitative trait loci (mQTLs) and several genome-wide association study data were used. Network with bidirectional mendelian randomization (MR) analysis was performed to examine the causal association among metabolic traits, DNA methylation and AD.Results: Our study showed that cis-mQTLs determined DNA methylation to higher total cholesterol (TC) was associated with higher AD risk (β [95% CI] =0.007 [0.002-0.013], P=0.005). The findings were robust in sensitivity analyses with different instrumental variables. We found no evidence to support causal associations of cis-mQTLs determined obesity and T2D with AD, and vice versa.Conclusion: Overall, our study showed that the cis-mQTLs determined DNA methylation to higher TC was associated with higher AD risk, whereas the relation of cis-mQTLs determined AD and metabolic dysregulation was unlikely to be causal.