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Updated: Jan 9, 2026
Sample Preparation to Bioinformatics Analysis of DNA Methylation: Association Strategy for Obesity and Related Trait Studies
Published on: May 6, 2022
Epigenome-Wide Association Study in Asian Cohort Identifies Novel DNA Methylation Markers for Carotid Intima-Media
Konstanze Tan1, Sarah E Harris2, Jane Maddock3
1Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore.
Background:
Carotid-intima media-thickness predicts cardiovascular events and informs mechanistic research on cardiovascular diseases (CVD). However, CVD research remains Eurocentric despite etiological differences across ancestries. Incorporating Asian populations- who face substantial CVD burden with distinct etiological landscape- can enhance our understanding of cIMT biology and subclinical processes linked to CVD. This study aimed to elucidate methylation-based mechanisms of cIMT through DNA methylation profiling integrated with multi-omics data and clinically informative cIMT thresholds, leveraging an Asian cohort to enhance discovery.
Methods:
We conducted an epigenome-wide association study (EWAS) of cIMT using peripheral blood DNA methylation at ~850,000 CpG sites in the Asian Health for Life in Singapore (HELIOS) cohort (n=1,357), followed by targeted trans-ancestry meta-analysis with European cohorts (overall n=2,765). Causal inference analyses (summary data-based Mendelian Randomisation [SMR] and colocalisation) evaluated methylation-mediated effects on cIMT, CVD and proximal gene expression. We derived a methylation risk score (MRS) and tested its association with cIMT thresholds indicative of elevated cardiovascular risk (≥75th percentile for age, sex and ethnicity).
Results:
Three novel CpG-cIMT associations were identified (P<9.35E-07). Causal analyses supported cg08227773 methylation-mediated effects on both coronary artery disease risk (PSMR=2.91E-05, coloc PP.H4 =0.91) and NBEAL2 (Neurobeachin-like 2) expression (PSMR=9.13E-08, coloc PP.H4=0.69), a gene implicated in immune dysregulation. MRS of cIMT aggregating the three sentinel CpGs was associated with clinically-informative cIMT elevation (Odds Ratio=2.75 for Q4 vs Q1, 95% CI: 1.47-5.13).
Conclusions:
Through Asian-led discovery, this study identifies three novel DNA methylation markers for cIMT that are linked to cIMT elevation above clinically meaningful risk thresholds. Causal inference analyses suggest methylation-mediated CAD risk via NBEAL2 regulation, nominating biologically relevant targets while underscoring the need for larger multi-omics resources to refine mechanisms.
