Alzheimer's Disease Sequencing Project Release 4 Whole Genome Sequencing Dataset.

The Alzheimer's Disease Sequencing Project (ADSP) is a national initiative to understand the genetic architecture of Alzheimer's Disease and Related Dementias (AD/ADRD) by sequencing whole genomes of affected participants and age-matched cognitive controls from diverse populations. The Genome Center for Alzheimer's Disease (GCAD) processed whole-genome sequencing data from 36,361 ADSP participants, including 35,014 genetically unique participants of which 45% are from non-European ancestry, across 17 cohorts in 14 countries in this fourth release (R4). This sequencing effort identified 387 million bi-allelic variants, 42 million short insertions/deletions, and 2.

Diverse ancestry GWAS for advanced age-related macular degeneration in TOPMed-imputed and Ophthalmologically-confirmed 16,108 cases and 18,038 controls.

Age-related macular degeneration (AMD) is a leading cause of blindness with $344 billion dollars global costs. In 2016, the International Age-related Macular Degeneration Genomics Consortium devised genomic data on ∼50,000 individuals (IAMDGC 1.0) and identified 52 variants across 34 loci associated with advanced AMD in European ancestry.

HORNET: Tools to find genes with causal evidence and their regulatory networks using eQTLs.

Motivation: Nearly two decades of genome-wide association studies (GWAS) have identify thousands of disease-associated genetic variants, but very few genes with evidence of causality. Recent methodological advances demonstrate that Mendelian Randomization (MR) using expression quantitative loci (eQTLs) as instrumental variables can detect potential causal genes. However, existing MR approaches are not well suited to handle the complexity of eQTL GWAS data structure and so they are subject to bias, inflation, and incorrect inference.

Constructing phylogenetic trees for microbiome data analysis: A mini-review.

As next-generation sequencing technologies advance rapidly and the cost of metagenomic sequencing continues to decrease, researchers now face an unprecedented volume of microbiome data. This surge has stimulated the development of scalable microbiome data analysis methods and necessitated the incorporation of phylogenetic information into microbiome analysis for improved accuracy. Tools for constructing phylogenetic trees from 16S rRNA sequencing data are well-established, as the highly conserved regions of the 16S gene are limited, simplifying the identification of marker genes.

Identification and characterization of ADAR1 mutations and changes in gene expression in human cancers.

ADAR1 (Adenosine deaminase action on RNA1) is involved in post-transcriptional RNA editing. ADAR1 mutations have been identified in many cancers but its role in tumor formation is still not well understood. Here we used available cancer genomes deposited on CSOMIC and cBioPortal to identify and characterize mutations and changes in ADAR1 expression in cancer cells.

Blood pressure variability compromises vascular function in middle-aged mice.

Blood pressure variability (BPV) has emerged as a novel risk factor for cognitive decline and dementia, independent of alterations in average blood pressure (BP). However, the underlying consequences of large BP fluctuations on the neurovascular complex are unknown. We developed a novel mouse model of BPV in middle-aged mice based on intermittent Angiotensin II infusions.

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.

NIAGADS: A Comprehensive National Data Repository for Alzheimer's Disease and Related Dementia Genetics and Genomics Research.

NIAGADS is the National Institute on Aging (NIA) designated national data repository for human genetics research on Alzheimer's Disease and related dementia (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis. NIAGADS hosts whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project (ADSP) and other genotype/phenotype data, encompassing 209,000 samples.

Country Level Incidence of Alzheimer Disease and Related Dementias is Associated with Increased Omega6 PUFA Consumption.

Introduction: Clinical and genetic studies have implicated lipid dysfunction in Alzheimer Disease (AD) pathogenesis. However, lipid consumption at the individual-level does not vary greatly within most cohorts, and multiple lipids are rarely measured in any one study.

Methods: Mean country-level lipid intakes were compared to Age-Standardized Alzheimer-Disease-Incidence-Rates(ASAIR) in 183 countries across all inhabited continents.

Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry.

Introduction: Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts.

Methods: Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses.

KDM4B mutations in human cancers.

Homologous recombination (HR) is essential for repair of DNA double-strand breaks (DSBs) and restart of stalled or collapsed replication forks. Most cancers are characterized by mutations in components of the DSB repair pathways. Redundant DSB repair pathways exist in eukaryotes from yeast to humans and recent evidence has shown that complete loss of HR function appears to be lethal.

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.

Brain and Blood Transcriptome-Wide Association Studies Identify Five Novel Genes Associated with Alzheimer's Disease.

Introduction: Transcriptome-wide Association Studies (TWAS) extend genome-wide association studies (GWAS) by integrating genetically-regulated gene expression models. We performed the most powerful AD-TWAS to date, using summary statistics from -eQTL meta-analyses and the largest clinically-adjudicated Alzheimer's Disease (AD) GWAS.

Methods: We implemented the OTTERS TWAS pipeline, leveraging -eQTL data from cortical brain tissue (MetaBrain; N=2,683) and blood (eQTLGen; N=31,684) to predict gene expression, then applied these models to AD-GWAS data (Cases=21,982; Controls=44,944).

Generalizability of Tau and Amyloid Plasma Biomarkers in Alzheimer's Disease Cohorts of Diverse Genetic Ancestries.

Introduction: Plasma phosphorylated threonine-181 of Tau and amyloid beta are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). Given differences in AD risk across diverse populations, generalizability of existing biomarker data is not assured.

Methods: In 2,086 individuals of diverse genetic ancestries (African American, Caribbean Hispanic, and Peruvians) we measured plasma pTau-181 and Aβ42/Aβ40.

magpie: A power evaluation method for differential RNA methylation analysis in N6-methyladenosine sequencing.

Recently, novel biotechnologies to quantify RNA modifications became an increasingly popular choice for researchers who study epitranscriptome. When studying RNA methylations such as N6-methyladenosine (m6A), researchers need to make several decisions in its experimental design, especially the sample size and a proper statistical power. Due to the complexity and high-throughput nature of m6A sequencing measurements, methods for power calculation and study design are still currently unavailable.

NaHCO3 loading causes increased arterial pressure and kidney damage in rats with chronic kidney disease.

Sodium bicarbonate (NaHCO3) is commonly utilized as a therapeutic to treat metabolic acidosis in people with chronic kidney disease (CKD). While increased dietary sodium chloride (NaCl) is known to promote volume retention and increase blood pressure, the effects of NaHCO3 loading on blood pressure and volume retention in CKD remain unclear. In the present study, we compared the effects of NaCl and NaHCO3 loading on volume retention, blood pressure, and kidney injury in both 2/3 and 5/6 nephrectomy remnant kidney rats, a well-established rodent model of CKD.

Human whole-exome genotype data for Alzheimer's disease.

The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits.

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.

Introduction: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline.

Methods: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts.

Results: We found high heritability for two ancestry backgrounds.

Sex-specific genetic architecture of late-life memory performance.

Background: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear.

Methods: We conducted the largest sex-aware genetic study on late-life memory to date (N  = 11,942; N  = 15,641).