Epigenome-wide Association Analysis of Mitochondrial Heteroplasmy Provides Insight into Molecular Mechanisms of Disease.

The relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA (nDNA) methylation (CpGs) remains to be studied. We conducted an epigenome-wide association analysis of heteroplasmy burden scores across 10,986 participants (mean age 77, 63% women, and 54% non-White races/ethnicities) from seven population-based observational cohorts. We identified 412 CpGs (FDR p < 0.

Integrating Whole Genome and Transcriptome Sequencing to Characterize the Genetic Architecture of Isoform Variation and its Implications for Health and Disease.

We created a comprehensive whole blood splice variation quantitative trait locus (sQTL) resource by analyzing isoform expression ratio (isoform-to-gene) in Framingham Heart Study (FHS) participants (discovery: n=2,622; validation: n=1,094) with whole genome (WGS) and transcriptome sequencing (RNA-seq) data. External replication was conducted using WGS and RNA-seq from the Jackson Heart Study (JHS, n=1,020). We identified over 3.

Associations of plasma extracellular microRNAs with new-onset breast cancer in the Framingham heart study.

Breast cancer is the second leading cause of cancer deaths among women. Multiple microRNAs (miRNAs) have been reported to be associated with breast cancer progression or metastasis. The purpose of the current study was to identify plasma extracellular miRNAs associated with incident breast cancer.

DNA Methylation Signatures of Cardiovascular Health Provide Insights into Diseases.

Background: The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.

Methods: We calculated the American Heart Association's Life's Essential 8 (LE8) score to reflect CVH in five cohorts with diverse ancestry backgrounds. Epigenome-wide association studies (EWAS) for LE8 score were conducted, followed by bioinformatic analyses.

Plasma Protein Biomarkers of Spirometry Measures of Impaired Lung Function.

Background: Impaired pulmonary function carries significant risks for lung, cardiovascular, and metabolic disorders.

Research Question: Can circulating protein biomarkers of pulmonary function provide insight into the pathophysiologic features of lung function impairment and links to comorbidities?.

Study Design And Methods: We analyzed plasma levels of 2,922 proteins in 32,493 UK Biobank participants (53% female; mean [SD] age, 57 [8] years) to investigate their associations with spirometry measures of lung function (FEV, FVC, FEV to FVC ratio), and with obstructive (n = 4,713) and restrictive (n = 3,886) spirometry patterns.

Expression quantitative trait locus mapping of extracellular microRNAs in human plasma.

MicroRNAs, crucial in regulating protein-coding gene expression, are implicated in various diseases. We performed a genome-wide association study of plasma miRNAs (ex-miRNAs) in 3,743 Framingham Heart Study (FHS) participants and identified 1,027 ex-miRNA-eQTLs (exQTLs) for 37 ex-miRNAs, with 55% replication in an independent study. Colocalization analyses suggested potential genetic coregulation of ex-miRNAs with whole blood mRNAs.

Epigenome-wide DNA Methylation Association Study of CHIP Provides Insight into Perturbed Gene Regulation.

With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed "clonal hematopoiesis of indeterminate potential" (CHIP). How these mutations confer a proliferative advantage and result in increased risk for numerous age-related diseases remains poorly understood. We conducted a multiracial meta-analysis of epigenome-wide association studies (EWAS) of CHIP and its subtypes in four cohorts (N=8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk.

Plasma Extracellular MicroRNAs Associated With Cardiovascular Disease Risk Factors in Middle-Aged and Older Adults.

Background: Extracellular microRNAs (miRNAs) are a class of noncoding RNAs that remain stable in the extracellular milieu, where they contribute to various physiological and pathological processes by facilitating intercellular signaling. Previous studies have reported associations between miRNAs and cardiovascular diseases (CVDs); however, the plasma miRNA signatures of CVD and its risk factors have not been fully elucidated at the population level.

Methods And Results: Plasma miRNA levels were measured in 4440 FHS (Framingham Heart Study) participants.

Enhancing selection of alcohol consumption-associated genes by random forest.

Machine learning methods have been used in identifying omics markers for a variety of phenotypes. We aimed to examine whether a supervised machine learning algorithm can improve identification of alcohol-associated transcriptomic markers. In this study, we analysed array-based, whole-blood derived expression data for 17 873 gene transcripts in 5508 Framingham Heart Study participants.

Circulating metabolites may illustrate relationship of alcohol consumption with cardiovascular disease.

Background: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD.

Methods: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women).

Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer's disease at CPT1A locus.

Background: Insulin resistance (IR) is a major risk factor for Alzheimer's disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD.

Alcohol consumption and epigenetic age acceleration across human adulthood.

The alcohol-associated biological aging remains to be studied across adulthood. We conducted linear regression analyses to investigate the associations between alcohol consumption and two DNA methylation-based biological age acceleration metrics in 3823 Framingham Heart Study participants (24-92 years and 53.8% women) adjusting for covariates.

Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma.

Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases.

Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs).

Expression quantitative trait methylation analysis elucidates gene regulatory effects of DNA methylation: the Framingham Heart Study.

Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p < 1E-7 where the top most significant eGenes (i.

Circulating Metabolites May Illustrate Relationship of Alcohol Consumption with Cardiovascular Disease.

Background: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD.

Methods: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine and liquor on average of 19 years in 2,428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women).

Rare Dysfunctional Genetic Variants and Progression to Advanced Age-Related Macular Degeneration.

Purpose: To evaluate associations between rare dysfunctional () genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV).

Design: Prospective, longitudinal study.

Participants: Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included.

Transcriptome-wide association study of circulating IgE levels identifies novel targets for asthma and allergic diseases.

Measurement of circulating immunoglobulin E (IgE) concentration is helpful for diagnosing and treating asthma and allergic diseases. Identifying gene expression signatures associated with IgE might elucidate novel pathways for IgE regulation. To this end, we performed a discovery transcriptome-wide association study to identify differentially expressed genes associated with circulating IgE levels in whole-blood derived RNA from 5,345 participants in the Framingham Heart Study across 17,873 mRNA gene-level transcripts.

Opioid medication use and blood DNA methylation: epigenome-wide association meta-analysis.

To identify differential methylation related to prescribed opioid use. This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting.

Systemic Inflammation is Associated with Cardiometabolic Risk Factors and Clinical Outcomes.

Purpose: Assessing an individual's systemic inflammatory state is vital to understand inflammation's role in cardiometabolic diseases and identify those at the greatest risk of disease. We generated global inflammation scores and investigated their associations with cardiometabolic risk factors and adverse outcomes.

Patients And Methods: Aggregate Inflammation Scores (AIS) and Principal Component Analysis (PCA) scores were generated for 7287 Framingham Heart Study participants using up to 26 inflammation-related proteins, with higher scores reflecting a pro-inflammatory milieu.