Investigating causality in the association between DNA methylation and type 2 diabetes using bidirectional two-sample Mendelian randomisation
Authors' conclusion
We identified one CpG mapping to a gene related to the metabolism of lipids (DHCR24) as a novel causal biomarker for risk of type 2 diabetes. CpGs within the same gene region have previously been associated with type 2 diabetes-related traits in observational studies (BMI, waist circumference, HDL-cholesterol, insulin) and in Mendelian randomisation analyses (LDL-cholesterol). Thus, we hypothesise that our candidate CpG in DHCR24 may be a causal mediator of the association between known modifiable risk factors and type 2 diabetes. Formal causal mediation analysis should be implemented to further validate this assumption.
Study context
- Population
- 58 CpG sites from a meta-analysis of epigenome-wide association studies (meta-EWAS) of prevalent T2D in European populations; genetic proxies from the largest genome-wide association study (GWAS) available, plus Avon Longitudinal Study of Parents and Children (ALSPAC) (UK) data58 CpG sites
- Outcome
- Causal relationship between DNAm and T2D (both directions)
Methodological detailsBonferroni correction, 62 independent SNPs as proxies for T2D; 39 methylation quantitative trait loci as proxies for 30 of the 58 CpGs
- Bonferroni correction
- 62 independent SNPs as proxies for T2D; 39 methylation quantitative trait loci as proxies for 30 of the 58 CpGs
Main finding
As reported in the abstract
OR for T2D per increase in DNAm at cg25536676 (DHCR24), 95% CI 1.15, 1.78, p=0.001
1.43
Further findings
In silico analyses
- CpGs analysed enriched for expression quantitative trait methylation sites (eQTMs) and for specific traits, dependent on the predicted direction of causality
Original publication
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