The impact of common and rare genetic variants on bradyarrhythmia development.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively.

Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites.

Background: Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear.

Comparison of methods for building polygenic scores for diverse populations.

Polygenic scores (PGSs) are a promising tool for estimating individual-level genetic risk of disease based on the results of genome-wide association studies (GWASs). However, their promise has yet to be fully realized because most currently available PGSs were built with genetic data from predominantly European-ancestry populations, and PGS performance declines when scores are applied to target populations different from the populations from which they were derived. Thus, there is a great need to improve PGS performance in currently under-studied populations.

Inflammatory protein associations with brain MRI measures: Framingham Offspring Cohort.

Introduction: Brain magnetic resonance imaging (MRI) and inflammatory biomarkers are crucial for investigating preclinical neurocognitive disorders. Current investigations focus on a few inflammatory markers. The study aims to investigate the associations between inflammatory biomarkers and MRI measures and to examine sex differences among the associations in the Framingham Heart Study.

Subjective Cognitive Decline Plus and Longitudinal Assessment and Risk for Cognitive Impairment.

Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting.

Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults.

Immune cell phenotypes and mortality in the Framingham Heart Study.

Background: Global life expectancy is rising, with the 60 + age group projected to hit 2 billion by 2050. Aging impacts the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs).

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer's disease in the Framingham Heart Study.

Aim: Endothelial dysfunction has been associated with both cerebrovascular pathology and Alzheimer's disease (AD). However, the connection between circulating endothelial cells and the risk of AD remains uncertain. The objective was to leverage data from the Framingham Heart Study to investigate various circulating endothelial subtypes and their potential correlations with the risk of AD.

MitoH3: Mitochondrial Haplogroup and Homoplasmic/Heteroplasmic Variant Calling Pipeline for Alzheimer's Disease Sequencing Project.

Background: Mitochondrial DNA (mtDNA) is a double-stranded circular DNA and has multiple copies in each cell. Excess heteroplasmy, the coexistence of distinct variants in copies of mtDNA within a cell, may lead to mitochondrial impairments. Accurate determination of heteroplasmy in whole-genome sequencing (WGS) data has posed a significant challenge because mitochondria carrying heteroplasmic variants cannot be distinguished during library preparation.

Correlation-based tests for the formal comparison of polygenic scores in multiple populations.

Polygenic scores (PGS) are measures of genetic risk, derived from the results of genome wide association studies (GWAS). Previous work has proposed the coefficient of determination (R2) as an appropriate measure by which to compare PGS performance in a validation dataset. Here we propose correlation-based methods for evaluating PGS performance by adapting previous work which produced a statistical framework and robust test statistics for the comparison of multiple correlation measures in multiple populations.

Learning Gaussian Graphical Models from Correlated Data.

Gaussian Graphical Models (GGM) have been widely used in biomedical research to explore complex relationships between many variables. There are well established procedures to build GGMs from a sample of independent and identical distributed observations. However, many studies include clustered and longitudinal data that result in correlated observations and ignoring this correlation among observations can lead to inflated Type I error.

APOE genotype-specific methylation patterns are linked to Alzheimer disease pathology and estrogen response.

The joint effects of APOE genotype and DNA methylation on Alzheimer disease (AD) risk is relatively unknown. We conducted genome-wide methylation analyses using 2,021 samples in blood (91 AD cases, 329 mild cognitive impairment, 1,391 controls) and 697 samples in brain (417 AD cases, 280 controls). We identified differentially methylated levels in AD compared to controls in an APOE genotype-specific manner at 25 cytosine-phosphate-guanine (CpG) sites in brain and 36 CpG sites in blood.

Aging-Related Immune Cell Phenotypes and Mortality in the Framingham Heart Study.

Background: The global increase in human life expectancy is evident. The total number of individuals aged 60 or above is anticipated to reach 2 billion by 2050. Aging, an inherently complex process, manifests prominently in the changes observed in the immune system.

Addition of polygenic risk score to a risk calculator for prediction of breast cancer in US Black women.

Background: Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory performance as measured by the AUC (area under the curve). Following publication of the first PRS to perform well in women of African ancestry (AA-PRS), we conducted an external validation of the AA-PRS and then evaluated the addition of the AA-PRS to a risk calculator for incident breast cancer in Black women based on epidemiologic factors (BWHS model).

Methods: Data from the Black Women's Health Study, an ongoing prospective cohort study of 59,000 US Black women followed by biennial questionnaire since 1995, were used to calculate AUCs and 95% confidence intervals (CIs) for discriminatory accuracy of the BWHS model, the AA-PRS alone, and a new model that combined them.

Identification of an ε4-specific blood-based molecular pathway for Alzheimer's disease risk.

Introduction: The precise apolipoprotein E () ε4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear.

Methods: Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by genotype.

The impact of blood MCP-1 levels on Alzheimer's disease with genetic variation of UNC5C and NAV3 loci.

Background: Previous study shows that monocyte chemoattractant protein-1 (MCP-1), which is implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption, modulates the genetic risks of AD in established AD loci.

Methods: In this study, we hypothesized that blood MCP-1 impacts the AD risk of genetic variants beyond known AD loci. We thus performed a genome-wide association study (GWAS) using the logistic regression via generalized estimating equations (GEE) and the Cox proportional-hazards models to examine the interactive effects between single nucleotide polymorphisms (SNPs) and blood MCP-1 level on AD in three cohorts: the Framingham Heart Study (FHS), Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study/Memory and Aging Project (ROSMAP).

Peripheral inflammatory biomarkers are associated with cognitive function and dementia: Framingham Heart Study Offspring cohort.

Inflammatory protein biomarkers induced by immune responses have been associated with cognitive decline and the pathogenesis of Alzheimer's disease (AD). Here, we investigate associations between a panel of inflammatory biomarkers and cognitive function and incident dementia outcomes in the well-characterized Framingham Heart Study Offspring cohort. Participants aged ≥40 years and dementia-free at Exam 7 who had a stored plasma sample were selected for profiling using the OLINK proteomics inflammation panel.

DNA from multiple viral species is associated with Alzheimer's disease risk.

Introduction: Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer's disease (AD) risk by independent lines of evidence. We explored this association by comparing the frequencies of viral species identified in a large sample of AD cases and controls.

Methods: DNA sequence reads that did not align to the human genome in sequences were mapped to viral reference sequences, quantified, and then were tested for association with AD in whole exome sequences (WES) and whole genome sequences (WGS) datasets.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively.