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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2025-03-01
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| author | Zequn Zheng Yongfei Song Xinhan Li Tao Luo Xuerui Tan |
| author_facet | Zequn Zheng Yongfei Song Xinhan Li Tao Luo Xuerui Tan |
| author_sort | Zequn Zheng |
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| description | 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 |
| format | Article |
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| publishDate | 2025-03-01 |
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| series | Clinical Epigenetics |
| spelling | doaj-art-ba958cd1300944c8a573b1894b038af12025-08-20T01:57:27ZengBMCClinical Epigenetics1868-70832025-03-0117111610.1186/s13148-025-01851-xDissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indicesZequn Zheng0Yongfei Song1Xinhan Li2Tao Luo3Xuerui Tan4Department of Cardiology, First Affiliated Hospital of Shantou University Medical CollegeInstitute of Innovation for Combined Medicine and Engineering, Ningbo Medical Center Lihuili Hospital, Ningbo UniversityDepartment of Cardiology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical UniversityCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Cardiology, First Affiliated Hospital of Shantou University Medical CollegeAbstract 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 abstracthttps://doi.org/10.1186/s13148-025-01851-xAlcohol consumptionQT intervalGenetic architectureDNA methylationMendelian randomization |
| spellingShingle | Zequn Zheng Yongfei Song Xinhan Li Tao Luo Xuerui Tan Dissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indices Clinical Epigenetics Alcohol consumption QT interval Genetic architecture DNA methylation Mendelian randomization |
| title | Dissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indices |
| title_full | Dissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indices |
| title_fullStr | Dissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indices |
| title_full_unstemmed | Dissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indices |
| title_short | Dissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indices |
| title_sort | dissecting the causal effects of smoking alcohol consumption and related dna methylation markers on electrocardiographic indices |
| topic | Alcohol consumption QT interval Genetic architecture DNA methylation Mendelian randomization |
| url | https://doi.org/10.1186/s13148-025-01851-x |
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