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Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk.

ABSTRACT: The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction. Bivariate fine mapping provided evidence that the individual variants responsible for the observed effects on cardiovascular traits at the ADCY3 and ADIPOQ loci were potentially mediated through changes in DNA methylation, although we highlight that we are unable to reliably separate causality from horizontal pleiotropy. Estimates of causal effects were replicated with results from large-scale consortia. Genetic variants and CpG sites identified in this study were enriched for histone mark peaks in relevant tissue types and gene promoter regions. Integrating our results with expression quantitative trait loci data, we provide evidence that variation at these regulatory regions is likely to also influence gene expression levels at these loci.

SUBMITTER: Richardson TG

PROVIDER: S-EPMC5630190 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk.

Richardson Tom G TG Zheng Jie J Davey Smith George G Timpson Nicholas J NJ Gaunt Tom R TR Relton Caroline L CL Hemani Gibran G

American journal of human genetics 20171001 4

The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associa ...[more]

PMID: 28985495

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Project description:BACKGROUND:The extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analysis pipeline that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from a genetic variant to a complex trait. METHODS:We undertook an expression quantitative trait loci-wide association study to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Fine-mapping was performed to prioritize possible causal variants for detected associations. Two-sample Mendelian randomization (MR) was then applied using findings from genome-wide association studies (GWAS) to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently used Bayesian multiple-trait colocalization to further interrogate the findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility. Finally, we applied our analysis pipeline genome-wide using summary statistics from large-scale GWAS. RESULTS:Eight genetic loci were associated with changes in gene expression and measures of cardiovascular function. Our MR analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol, respectively, were particularly insightful. Multiple-trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream of FADS1/TMEM258 may also affect cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses uncovered evidence of tissue specificity between gene expression in liver tissue and cholesterol levels. Applying our pipeline genome-wide using summary statistics from GWAS uncovered 233 association signals at loci which represent promising candidates for further evaluation. CONCLUSIONS:Disease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. The approach undertaken in our study can be used to elucidate mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell types will further improve our capability to understand and prevent disease.

Project description:BACKGROUND:Evidence from randomized trials has shown that therapies that lower LDL (low-density lipoprotein)-cholesterol and triglycerides reduce coronary artery disease (CAD) risk. However, there is still uncertainty about their effects on other cardiovascular outcomes. We therefore performed a systematic investigation of causal relationships between circulating lipids and cardiovascular outcomes using a Mendelian randomization approach. METHODS:In the primary analysis, we performed 2-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188?577 participants, and genetic associations with cardiovascular outcomes from 367?703 participants in UK Biobank. RESULTS:For LDL-cholesterol, in addition to the expected positive associations with CAD risk (odds ratio [OR] per 1 SD increase, 1.45 [95% CI, 1.35-1.57]) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically predicted LDL-cholesterol with abdominal aortic aneurysm (OR, 1.75 [95% CI, 1.40-2.17]) and aortic valve stenosis (OR, 1.46 [95% CI, 1.25-1.70]). Genetically predicted triglyceride levels were positively associated with CAD (OR, 1.25 [95% CI, 1.12-1.40]), aortic valve stenosis (OR, 1.29 [95% CI, 1.04-1.61]), and hypertension (OR, 1.17 [95% CI, 1.07-1.27]), but inversely associated with venous thromboembolism (OR, 0.79 [95% CI, 0.67-0.93]) and hemorrhagic stroke (OR, 0.78 [95% CI, 0.62-0.98]). We also found positive associations of genetically predicted LDL-cholesterol and triglycerides with heart failure that appeared to be mediated by CAD. CONCLUSIONS:Lowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis but may increase thromboembolic risk.

Project description:BACKGROUND: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. METHODS: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. RESULTS: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. CONCLUSION: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.

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Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk.

Publications

Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk.

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