Promoter DNA Methylation in GWAS-Identified Genes as Potential Functional Elements for Blood Pressure: An Observational and Mendelian Randomization Study.
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ABSTRACT:
SUBMITTER: Zhang H
PROVIDER: S-EPMC8787193 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The pathogenesis of Alzheimer's disease (AD) remains largely unclear. Exploring the genetic/epigenetic loci showing pleiotropic association with the neuropathologies of AD may greatly enhance understanding of the mechanisms underlying the development of AD. In this study, using data from the Religious Orders Study and the Rush Memory and Aging Project, we undertook a Mendelian randomization approach integrating genome-wide association studies (GWASs) and DNA methylation quantitative trait locus data to explore pleiotropic epigenetic loci for AD neuropathologies, including amyloid-β (Aβ) load and tau-containing neurofibrillary tangle density. We performed GWASs of DNA methylation in brain tissues from 592 participants and mapped 60,595 cis-SNP-CpG pairs after correction for multiple testing. By linking cis-DNA methylation quantitative trait locus with GWAS results for Aβ load and tau tangles, we identified 47 CpGs showing pleiotropic association with Aβ load by the Mendelian randomization analysis. We then used gene expression data from 537 individuals and performed quantitative trait methylation analysis. We found that 18 of the 47 CpGs were in cis associated with 25 mRNAs/genes, comprising 41 unique CpG-mRNA/gene pairs. Our findings shed light on the role of DNA methylation in the pathogenesis of Aβ.
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Project description:PurposeTo test for causality with regard to the association between blood pressure (BP) and intraocular pressure (IOP) and glaucoma.MethodsSingle nucleotide polymorphisms (SNPs) associated with BP were identified in a genome-wide association study (GWAS) meta-analysis of 526,001 participants of European ancestry. These SNPs were used to assess the BP versus IOP relationship in a distinct sample (n = 70,832) whose corneal-compensated IOP (IOPcc) was measured. To evaluate the BP versus primary open-angle glaucoma (POAG) relationship, additional Mendelian randomization (MR) analyses were conducted using published GWAS summary statistics.ResultsObservational analysis revealed a linear relationship between BP traits and IOPcc, with a +0.28 mm Hg increase in IOPcc per 10-mm Hg increase in systolic BP (95% confidence interval [CI], 0.26-0.29); for diastolic blood pressure (DBP) and pulse pressure (PP), these estimates were +0.41 mm Hg and +0.36 mm Hg, respectively. An inverse-variance weighted MR analysis did not support a causal relationship, as the estimated causal effect was +0.01 mm Hg IOPcc per 10-mm Hg increase in systolic blood pressure (SBP); +0.13 mm Hg IOPcc per 10-mm Hg increase in DBP; and +0.02 mm Hg IOPcc per 10-mm Hg increase in PP (all P > 0.05). With regard to the risk of POAG, MR analyse yielded causal effect estimate of odds ratio = 0.98 (95% CI, 0.92-1.04) per 10-mm Hg increase in SBP. Neither DBP nor PP demonstrated evidence of a causal effect on POAG.ConclusionsA range of different MR analysis methods provided evidence, in general, that the causal effect of BP on IOP (and POAG) was modest, or even zero. However, interpretation was complicated by SNPs associated with BP potentially having pleiotropic effects on IOP.
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Project description:BACKGROUND:High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension. METHODS:We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ?750?000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP. RESULTS:A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm?Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm?Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm?Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm?Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio. CONCLUSIONS:Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.
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Project description:BackgroundPrevious large observational cohort studies showed higher blood pressure (BP) positively associated with cancer. We used Mendelian randomization (MR) to obtain less confounded estimates of BP on total and site-specific cancers.MethodsWe applied replicated genetic instruments for systolic and diastolic BP to summary genetic associations with total cancer (37387 cases, 367856 non-cases) from the UK Biobank, and 17 site-specific cancers (663-17881 cases) from a meta-analysis of the UK Biobank and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging. We used inverse-variance weighting with multiplicative random effects as the main analysis, and sensitivity analyses including the weighted median, MR-Egger and multivariable MR adjusted for body mass index and for smoking. For validation, we included breast (Breast Cancer Association Consortium: 133384 cases, 113789 non-cases), prostate (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium: 79194 cases, 61112 non-cases) and lung (International Lung and Cancer Consortium: 10246 cases, 38295 non-cases) cancer from large consortia. We used asthma as a negative control outcome.ResultsSystolic and diastolic BP were unrelated to total cancer (OR 0.98 per standard deviation higher [95% confidence interval (CI) 0.89, 1.07] and OR 1.00 [95% CI 0.92, 1.08]) and to site-specific cancers after accounting for multiple testing, with consistent findings from consortia. BP was nominally associated with melanoma and possibly kidney cancer, and as expected, not associated with asthma. Sensitivity analyses using other MR methods gave similar results.ConclusionsIn contrast to previous observational evidence, BP does not appear to be a risk factor for cancer, although an effect on melanoma and kidney cancer cannot be excluded. Other targets for cancer prevention might be more relevant.
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Project description:Background: Atrial fibrillation (AF) is the most common arrhythmia. Genome-wide association studies (GWAS) have identified more than 100 loci associated with AF, but the underlying biological interpretation remains largely unknown. The goal of this study is to identify gene expression and DNA methylation (DNAm) that are pleiotropically or potentially causally associated with AF, and to integrate results from transcriptome and methylome. Methods: We used the summary data-based Mendelian randomization (SMR) to integrate GWAS with expression quantitative trait loci (eQTL) studies and methylation quantitative trait loci (mQTL) studies. The HEIDI (heterogeneity in dependent instruments) test was introduced to test against the null hypothesis that there is a single causal variant underlying the association. Results: We prioritized 22 genes by eQTL analysis and 50 genes by mQTL analysis that passed the SMR & HEIDI test. Among them, 6 genes were overlapped. By incorporating consistent SMR associations between DNAm and AF, between gene expression and AF, and between DNAm and gene expression, we identified several mediation models at which a genetic variant exerted an effect on AF by altering the DNAm level, which regulated the expression level of a functional gene. One example was the genetic variant-cg18693985-CPEB4-AF axis. Conclusion: In conclusion, our integrative analysis identified multiple genes and DNAm sites that had potentially causal effects on AF. We also pinpointed plausible mechanisms in which the effect of a genetic variant on AF was mediated by genetic regulation of transcription through DNAm. Further experimental validation is necessary to translate the identified genes and possible mechanisms into clinical practice.
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Project description:Breast cancer (BC) remains a major disease posing a threat to women's health, but the underlying biological interpretation remains largely unknown. Here, we aimed to identify genes associated with breast cancer and analyze their pathophysiological mechanisms based on multi-omics Mendelian randomization (MR). Summary-data-based MR (SMR) was performed to estimate the causal effects of blood and breast mammary tissue expression quantitative trait loci (eQTLs) on BC. External validation analysis was used to validate the identified genes. Integration analyses BC GWAS summaries with eQTLs and DNA methylation QTLs (mQTLs) from the blood were conducted using SMR to prioritize putative blood genes and their regulatory elements associated with BC risk. Finally, two prior genes (ATG10 and RCCD1) from blood tissue reached significant levels in both BCAC (ATG10: ORBRCR = 0.91, PBRCR = 1.29 × 10-11; RCCD1: ORBRCR = 0.90, PBRCR = 3.72 × 10-15) and FinnGen cohorts (ATG10: ORFinnGen = 0.89, PFinnGen = 8.55 × 10-5; RCCD1: ORFinnGen = 0.89, PFinnGen = 2.38 × 10-8). Additionally, those two genes from breast tissues also replicated in both BCAC (ATG10: ORBRCR = 0.95, PBRCR = 1.02 × 10-9; RCCD1: ORBRCR = 0.87, PBRCR = 4.70 × 10-10) and FinnGen cohorts (ATG10: ORFinnGen = 0.93, PFinnGen = 2.38 × 10-4; RCCD1: ORFinnGen = 0.85, PFinnGen = 3.81 × 10-6). Sensitive analysis and external validation analysis validated those two identified genes. Multi-omics MR analysis showed that the SNP signals associated with ATG10 and RCCD1 were significant across the data from BC Genome-wide association study (GWAS), eQTL, and mQTL studies. In conclusion, we identified two priority genes that are potentially associated with BC. These findings improve our limited understanding of the mechanism of BC and shed light on the development of therapeutic agents for treating BC.
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Project description:Observational studies suggest that early onset of menopause is associated with increased risk of hypertension. Whether this association is causal or due to residual confounding and/or reverse causation remains undetermined. We aimed to evaluate the observational and causal association between age at natural menopause (ANM) and blood pressure traits in Caucasian women. A cross-sectional and one-sample Mendelian randomization (MR) study was conducted in 4451 postmenopausal women from the CoLaus and Rotterdam studies. Regression models were built with observational data to study the associations of ANM with systolic and diastolic blood pressure (SBP/DBP) and hypertension. One-sample MR analysis was performed by calculating a genetic risk score of 54 ANM-related variants, previously identified in a genome-wide association study (GWAS) on ANM. In the two-sample MR analysis we used the estimates from the ANM-GWAS and association estimates from 168,575 women of the UK Biobank to evaluate ANM-related variants and their causal association with SBP and DBP. Pooled analysis from both cohorts showed that a one-year delay in menopause onset was associated with 2% (95% CI 0; 4) increased odds of having hypertension, and that early menopause was associated with lower DBP (β = -1.31, 95% CI -2.43; -0.18). While one-sample MR did not show a causal association between ANM and blood pressure traits, the two-sample MR showed a positive causal association of ANM with SBP; the last was driven by genes related to DNA damage repair. The present study does not support the hypothesis that early onset of menopause is associated with higher blood pressure. Our results suggest different ANM-related genetic pathways could differently impact blood pressure.
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Project description:Objective To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.Design Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.Setting CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Participants Data from 22 studies with 171?213 participants, and an additional 10 published prospective studies with 26?119 participants included in the observational analysis.Main outcome measures The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.Results Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (?=1.35, 95% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: ?=-0.21, 95% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11).Conclusion The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.
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Project description:Abnormal QRS duration and amplitudes on the electrocardiogram are indicative of cardiac pathology and are associated with adverse outcomes. The causal nature of these associations remains uncertain and could be due to QRS abnormalities being a symptom of cardiac damage rather than a factor on the causal pathway. By performing Mendelian randomization (MR) analyses using summary statistics of genome wide association study consortia with sample sizes between 20,687 and 339,224 individuals, we aimed to determine which cardiovascular risk factors causally lead to changes in QRS duration and amplitude (Sokolow-Lyon, Cornell and 12-leadsum products). Additionally, we aimed to determine whether QRS traits have a causal relationship with mortality and longevity. We performed inverse-variance weighted MR as main analyses and MR-Egger regression and weighted median estimation as sensitivity analyses. We found evidence for a causal relationship between higher blood pressure and larger QRS amplitudes (systolic blood pressure on Cornell: 55SNPs, causal effect estimate per 1?mmHg?=?9.77 millimeters·milliseconds (SE?=?1.38,P?=?1.20?×?10-12) and diastolic blood pressure on Cornell: 57SNPs, causal effect estimate per 1?mmHg?=?14.89 millimeters·milliseconds (SE?=?1.82,P?=?3.08?×?10-16), but not QRS duration. Genetically predicted QRS traits were not associated with longevity, suggesting a more prominent role of acquired factors in explaining the well-known link between QRS abnormalities and outcome.
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Project description:Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper- or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study. Single nucleotide polymorphisms (SNPs) associated with thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), hyper- and hypothyroidism, and anti-thyroid peroxidase antibodies (TPOAb), from genome-wide association studies (GWAS), were selected as MR instrumental variables. SNPs-outcome (BP, CVD) associations were evaluated in a large-scale cohort, the Malmö Diet and Cancer Study (n = 29,298). Causal estimates were computed by inverse-variance weighted (IVW), weighted median, and MR-Egger approaches. Genetically increased levels of TSH were associated with decreased systolic BP and with a lower risk of atrial fibrillation. Hyperthyroidism and TPOAb were associated with a lower risk of atrial fibrillation. Our data support a causal association between genetically decreased levels of TSH and both atrial fibrillation and systolic BP. The lack of significance after Bonferroni correction and the sensitivity analyses suggesting pleiotropy, should prompt us to be cautious in their interpretation. Nevertheless, these findings offer mechanistic insight into the etiology of CVD. Further work into the genes involved in thyroid functions and their relation to cardiovascular outcomes may highlight pathways for targeted intervention.
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