Alzheimer's disease (AD) involves brain neuropathologies such as amyloid plaque and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms ...underlying disease onset and progression based on quantifiable phenotypes will help understand disease etiology and devise therapies.
Our objective was to identify molecular pathways associated with hallmark AD biomarkers and cognitive status, accounting for variables such as age, sex, education, and APOE genotype.
We introduce a pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of the three phenotypes (amyloid-β, tau, cognition) using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved 634 subjects with data available for all three phenotypes, allowing for the identification of common pathways.
We identified 14 pathways significantly associated with amyloid-β; 5 associated with tau; and 174 associated with cognition, which showed a larger number of pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited associations with all three phenotypes. Mediation analysis showed that among the VEGF-RB family genes, ITGA5 mediates the relationship between cognitive scores and pathological biomarkers.
We presented a new statistical approach linking continuous phenotypes, gene expression across pathways, and covariates like sex, age, and education. Our results reinforced VEGF RB2's role in AD cognition and demonstrated ITGA5's significant role in mediating the AD pathology-cognition connection.
Abstract
Objectives
Genetic risks for cognitive decline are not modifiable; however their relative importance compared to modifiable factors is unclear. We used machine learning to evaluate ...modifiable and genetic risk factors for Alzheimer’s disease (AD), to predict cognitive decline.
Methods
Health and Retirement Study participants, aged 65–90 years, with DNA and >2 cognitive evaluations, were included (n = 7,142). Predictors included age, body mass index, gender, education, APOE ε4, cardiovascular, hypertension, diabetes, stroke, neighborhood socioeconomic status (NSES), and AD risk genes. Latent class trajectory analyses of cognitive scores determined the form and number of classes. Random Forests (RF) classification investigated predictors of cognitive trajectories. Performance metrics (accuracy, sensitivity, and specificity) were reported.
Results
Three classes were identified. Discriminating highest from lowest classes produced the best RF performance: accuracy = 78% (1.0%), sensitivity = 75% (1.0%), and specificity = 81% (1.0%). Top ranked predictors were education, age, gender, stroke, NSES, and diabetes, APOE ε4 carrier status, and body mass index (BMI). When discriminating high from medium classes, top predictors were education, age, gender, stroke, diabetes, NSES, and BMI. When discriminating medium from the low classes, education, NSES, age, diabetes, and stroke were top predictors.
Discussion
The combination of latent trajectories and RF classification techniques suggested that nongenetic factors contribute more to cognitive decline than genetic factors. Education was the most relevant predictor for discrimination.
Diet and host phylogeny drive the taxonomic and functional contents of the gut microbiome in mammals, yet it is unknown whether these patterns hold across all vertebrate lineages. Here, we assessed ...gut microbiomes from ∼900 vertebrate species, including 315 mammals and 491 birds, assessing contributions of diet, phylogeny, and physiology to structuring gut microbiomes. In most nonflying mammals, strong correlations exist between microbial community similarity, host diet, and host phylogenetic distance up to the host order level. In birds, by contrast, gut microbiomes are only very weakly correlated to diet or host phylogeny. Furthermore, while most microbes resident in mammalian guts are present in only a restricted taxonomic range of hosts, most microbes recovered from birds show little evidence of host specificity. Notably, among the mammals, bats host especially bird-like gut microbiomes, with little evidence for correlation to host diet or phylogeny. This suggests that host-gut microbiome phylosymbiosis depends on factors convergently absent in birds and bats, potentially associated with physiological adaptations to flight. Our findings expose major variations in the behavior of these important symbioses in endothermic vertebrates and may signal fundamental evolutionary shifts in the cost/benefit framework of the gut microbiome.
In this comprehensive survey of microbiomes of >900 species, including 315 mammals and 491 birds, we find a striking convergence of the microbiomes of birds and animals that fly. In nonflying mammals, diet and short-term evolutionary relatedness drive the microbiome, and many microbial species are specific to a particular kind of mammal, but flying mammals and birds break this pattern with many microbes shared across different species, with little correlation either with diet or with relatedness of the hosts. This finding suggests that adaptation to flight breaks long-held relationships between hosts and their microbes.
Patients with late-onset Alzheimer's disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms with depression and anxiety being most frequent, and individuals with major depressive ...disorder (MDD) have an increased prevalence of LOAD. This suggests shared etiologies and intersecting pathways between LOAD and MDD. We performed pleiotropy analyses using LOAD and MDD GWAS data sets from the International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium (PGC), respectively. We found a moderate enrichment for SNPs associated with LOAD across increasingly stringent levels of significance with the MDD GWAS association (LOAD|MDD), of maximum four and eightfolds, including and excluding the APOE-region, respectively. Association analysis excluding the APOE-region identified numerous SNPs corresponding to 40 genes, 9 of which are known LOAD-risk loci primarily in chromosome 11 regions that contain the SPI1 gene and MS4A genes cluster, and others were novel pleiotropic risk-loci for LOAD conditional with MDD. The most significant associated SNPs on chromosome 11 overlapped with eQTLs found in whole-blood and monocytes, suggesting functional roles in gene regulation. The reverse conditional association analysis (MDD|LOAD) showed a moderate level, ~sevenfold, of polygenic overlap, however, no SNP showed significant association. Pathway analyses replicated previously reported LOAD biological pathways related to immune response and regulation of endocytosis. In conclusion, we provide insights into the overlapping genetic signatures underpinning the common phenotypic manifestations and inter-relationship between LOAD and MDD. This knowledge is crucial to the development of actionable targets for novel therapies to treat depression preceding dementia, in an effort to delay or ultimately prevent the onset of LOAD.
A systems-based model of Alzheimer's disease Tang, Yi; Lutz, Michael W.; Xing, Yi
Alzheimer's & dementia,
January 2019, 2019-01-00, 20190101, Letnik:
15, Številka:
1
Journal Article
Recenzirano
The new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease has been developed to accelerate drug discovery and offer a common structure and ...language to construct new Alzheimer's disease conceptual models. However, as a “complex” disease, a model based on systems-level understanding is needed to accommodate the complex, interacting etiologic pathways and the system-level changes associated with Alzheimer's disease pathogenesis and interventions that are currently known and which will be identified in the future. To accomplish this, the evolution of the structure of the research framework itself should be encouraged.
Alzheimer's disease (AD) is a common neurodegenerative disease and mild cognitive impairment (MCI) is considered as the prodromal stage of AD. Previous studies showed that changes in the neurotrophin ...signaling pathway could lead to cognitive decline in AD. However, the association of single nucleotide polymorphisms (SNPs) in genes that are involved in this pathway with AD progression from MCI remains unclear.
We investigated the associations between SNPs involved in the neurotrophin signaling pathway with AD progression.
We performed single-locus analysis to identify neurotrophin-signaling-related SNPs associated with the AD progression using 767 patients from the Alzheimer's Disease Neuroimaging Initiative study and 1,373 patients from the National Alzheimer's Coordinating Center study. We constructed polygenic risk scores (PRSs) using the identified independent non-APOE SNPs and evaluated its prediction performance on AD progression.
We identified 25 SNPs significantly associated with AD progression with Bayesian false-discovery probability ≤0.8. Based on the linkage disequilibrium clumping and expression quantitative trait loci analysis, we found 6 potentially functional SNPs that were associated with AD progression independently. The PRS analysis quantified the combined effects of these SNPs on longitudinal cognitive assessments and biomarkers from cerebrospinal fluid and neuroimaging. The addition of PRSs to the prediction model for 3-year progression to AD from MCI significantly increased the predictive accuracy.
Genetic variants in the specific genes of the neurotrophin signaling pathway are predictors of AD progression. eQTL analysis supports that these SNPs regulate expression of key genes involved in the neurotrophin signaling pathway.
A viral etiology of sea star wasting syndrome (SSWS) was originally explored with virus-sized material challenge experiments, field surveys, and metagenomics, leading to the conclusion that a ...densovirus is the predominant DNA virus associated with this syndrome and, thus, the most promising viral candidate pathogen. Single-stranded DNA viruses are, however, highly diverse and pervasive among eukaryotic organisms, which we hypothesize may confound the association between densoviruses and SSWS. To test this hypothesis and assess the association of densoviruses with SSWS, we compiled past metagenomic data with new metagenomic-derived viral genomes from sea stars collected from Antarctica, California, Washington, and Alaska. We used 179 publicly available sea star transcriptomes to complement our approaches for densovirus discovery. Lastly, we focus the study on sea star-associated densovirus (SSaDV), the first sea star densovirus discovered, by documenting its biogeography and putative tissue tropism. Transcriptomes contained only endogenized densovirus elements similar to the NS1 gene, while numerous extant densoviral genomes were recovered from viral metagenomes. SSaDV was associated with nearly all tested species from southern California to Alaska, and in contrast to previous work, we show that SSaDV is one genotype among a high diversity of densoviruses present in sea stars across the West Coast of the United States and globally that are commonly associated with grossly normal (i.e., healthy or asymptomatic) animals. The diversity and ubiquity of these viruses in sea stars confound the original hypothesis that one densovirus is the etiological agent of SSWS.
The primary interest in sea star densoviruses, specifically SSaDV, has been their association with sea star wasting syndrome (SSWS), a disease that has decimated sea star populations across the West Coast of the United States since 2013. The association of SSaDV with SSWS was originally drawn from metagenomic analysis, which was further studied through field surveys using quantitative PCR (qPCR), with the conclusion that it was the most likely viral candidate in the metagenomic data based on its representation in symptomatic sea stars compared to asymptomatic sea stars. We reexamined the original metagenomic data with additional genomic data sets and found that SSaDV was 1 of 10 densoviruses present in the original data set and was no more represented in symptomatic sea stars than in asymptomatic sea stars. Instead, SSaDV appears to be a widespread, generalist virus that exists among a large diversity of densoviruses present in sea star populations.
Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary ...pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined.
To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni's correction for multiple testing.
Tissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH.
We report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.
Background
Short structural variants (SSVs), including insertions/deletions (indels), are common in the human genome and impact disease risk. The role of SSVs in late‐onset Alzheimer's disease (LOAD) ...has been understudied. In this study, we developed a bioinformatics pipeline of SSVs within LOAD–genome‐wide association study (GWAS) regions to prioritize regulatory SSVs based on the strength of their predicted effect on transcription factor (TF) binding sites.
Methods
The pipeline utilized publicly available functional genomics data sources including candidate cis‐regulatory elements (cCREs) from ENCODE and single‐nucleus (sn)RNA‐seq data from LOAD patient samples.
Results
We catalogued 1581 SSVs in candidate cCREs in LOAD GWAS regions that disrupted 737 TF sites. That included SSVs that disrupted the binding of RUNX3, SPI1, and SMAD3, within the APOE‐TOMM40, SPI1, and MS4A6A LOAD regions.
Conclusions
The pipeline developed here prioritized non‐coding SSVs in cCREs and characterized their putative effects on TF binding. The approach integrates multiomics datasets for validation experiments using disease models.
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