Dissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indices
Abstract Background Tobacco and alcohol are recognized risk factors for heart disease, yet their causal effects on electrocardiogram (ECG) signaling and mechanisms remain unclear. Previous studies may be susceptible to confounding or bias, and this study dissected the genetic architecture linking to...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-03-01
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| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13148-025-01851-x |
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| Summary: | Abstract Background Tobacco and alcohol are recognized risk factors for heart disease, yet their causal effects on electrocardiogram (ECG) signaling and mechanisms remain unclear. Previous studies may be susceptible to confounding or bias, and this study dissected the genetic architecture linking tobacco and alcohol consumption with P-wave duration, PR interval, and QT interval. Methods Utilizing genetic instruments for tobacco and alcohol consumption, associated methylation quantitative trait locus (mQTL), and summary-level GWAS data for ECG indices, we assessed heritability and genetic causal associations using linkage disequilibrium score regression and Mendelian randomization (MR) analysis. Fine mapping was performed via colocalization analysis and summary-data-based MR (SMR) to identify potential shared genetic variants. Results A positive causal relationship was found between drinks per week (DrnkWk) and QT interval [β (95%CI): 1.06 (0.91, 5.05), P = 0.005], with causality substantiated through multiple robust MR models. Multivariable MR confirmed independence from smoking phenotypes. In epigenetic MR analyses, two alcohol-related CpG loci (cg03345232 and cg04605617) were causally associated with QT interval changes, with cg04605617 mapping to PLA2G2C gene significantly prolonging QT. The mQTL rs10916683 at cg04605617 is a strong eQTL for PLA2G2C. Additionally, cg03345232 shared a causal variant (rs12881206) with QT interval predisposition through colocalization analysis. SMR analysis did not identify shared putative functional genes passing the HEIDI test between DrnkWk and the QT interval. Conclusions There is a causal relationship between DrnkWk and QT interval prolongation, and targeting specific DNA methylation sites like cg04605617 mapped to PLA2G2C may provide novel targets for preventing QT interval prolongation. Graphic abstract |
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| ISSN: | 1868-7083 |