The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. ...To characterize molecular systems associated with late-onset Alzheimer’s disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.
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•Systems approach to LOAD based on large-scale human brain-tissue sampling•Molecular networks show strong remodeling effect in LOAD brains•Integrative network-based analysis implicates the immune/microglia network in LOAD•TYROBP implicated as key causal regulator within the immune/microglia module
An integrated systems approach leverages transcriptome data from postmortem brains of late-onset Alzheimer’s disease patients to identify key nodes that drive dysregulated or rewired networks in the disease state.
With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not ...understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.
Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection.
Microarrays from 434 ...patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided.
Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval CI = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients.
Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.
Repeated mild traumatic brain injury (rmTBI) can lead to development of chronic traumatic encephalopathy (CTE), which is characterized by progressive neurodegeneration with presence of white matter ...damage, gliosis and hyper-phosphorylated tau. While animal models of rmTBI have been documented, few characterize the molecular pathogenesis and expression profiles of relevant injured brain regions. Additionally, while the usage of transgenic tau mice in rmTBI is prevalent, the effects of tau on pathological outcomes has not been well studied. Here we characterized a 42-impact closed-head rmTBI paradigm on 3–4 month old male C57BL/6 (WT) and Tau-overexpressing mice (Tau58.4). This injury paradigm resulted in chronic gliosis, T-cell infiltration, and demyelination of the optic nerve and associated white matter tracts at 1-month post-injury. At 3-months post-injury, Tau58.4 mice showed progressive neuroinflammation and neurodegeneration in multiple brain regions compared to WT mice. Corresponding to histopathology, RNAseq of the optic nerve tract at 1-month post-injury showed significant upregulation of inflammatory pathways and downregulation of myelin synthetic pathways in both genotypes. However, Tau58.4 mice showed additional changes in neurite development, protein processing, and cell stress. Comparisons with published transcriptomes of human Alzheimer's Disease and CTE revealed common signatures including neuroinflammation and downregulation of protein phosphatases. We next investigated the demyelination and T-cell infiltration phenotypes to determine whether these offer potential avenues for therapeutic intervention. Tau58.4 mice were treated with the histamine H3 receptor antagonist GSK239512 for 1-month post-injury to promote remyelination of white matter lesions. This restored myelin gene expression to sham levels but failed to repair the histopathologic lesions. Likewise, injured T-cell-deficient Rag2/Il2rg (R2G2) mice also showed evidence for inflammation and loss of myelin. However, unlike immune-competent mice, R2G2 mice had altered myeloid cell gene expression and fewer demyelinated lesions. Together this data shows that rmTBI leads to chronic white matter inflammatory demyelination and axonal loss exacerbated by human tau overexpression but suggests that immune-suppression and remyelination alone are insufficient to reverse damage.
•Repeated mild traumatic brain injuries leads to prominent white matter injury.•Injured white matter shows increased gliosis, T-cells, and demyelination.•Disease associated human tau exacerbates repeated mild traumatic brain injury.•RNAseq shows increased inflammation with decreased myelin and neuronal pathways.•Remyelination agents and immune deficiency show limited efficacy in lesion repair.
Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted ...extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states.
The increasing prevalence of type 2 diabetes poses a major challenge to societies worldwide. Blood-based factors like serum proteins are in contact with every organ in the body to mediate global ...homeostasis and may thus directly regulate complex processes such as aging and the development of common chronic diseases. We applied a data-driven proteomics approach, measuring serum levels of 4,137 proteins in 5,438 elderly Icelanders, and identified 536 proteins associated with prevalent and/or incident type 2 diabetes. We validated a subset of the observed associations in an independent case-control study of type 2 diabetes. These protein associations provide novel biological insights into the molecular mechanisms that are dysregulated prior to and following the onset of type 2 diabetes and can be detected in serum. A bidirectional two-sample Mendelian randomization analysis indicated that serum changes of at least 23 proteins are downstream of the disease or its genetic liability, while 15 proteins were supported as having a causal role in type 2 diabetes.
It’s in Our Blood: A Glimpse of Personalized Medicine Lamb, John R.; Jennings, Lori L.; Gudmundsdottir, Valborg ...
Trends in molecular medicine,
January 2021, 2021-01-00, 20210101, Letnik:
27, Številka:
1
Journal Article
Recenzirano
Recent advances in protein profiling technology has facilitated simultaneous measurement of thousands of proteins in large population studies, exposing the depth and complexity of the plasma and ...serum proteomes. This revealed that proteins in circulation were organized into regulatory modules under genetic control and closely associated with current and future common diseases. Unlike networks in solid tissues, serum protein networks comprise members synthesized across different tissues of the body. Genetic analysis reveals that this cross-tissue regulation of the serum proteome participates in systemic homeostasis and mirrors the global disease state of individuals. Here, we discuss how application of this information in routine clinical evaluations may transform the future practice of medicine.
Parallel measurements of thousands of plasma and serum proteins in populations give an unprecedented view of the complexity of the protein content of blood.Serum proteins exist in coregulated modules that are genetically controlled and to which all tissues contribute. Modules are closely associated with past, current, and future diseases of diverse etiologies.Measurements of serum proteins en masse can facilitate the yet largely unrealized promise of personalized medicine and, where additional treatment-specific biomarkers of response or adverse events can be derived. This offers numeric classification of individuals.With routine use in clinical practice, measurement of serum proteins could change the focus of medicine from treating illness to preventing its onset.
Treating messenger RNA transcript abundances as quantitative traits and mapping gene expression quantitative trait loci for these traits has been pursued in gene-specific ways. Transcript abundances ...often serve as a surrogate for classical quantitative traits in that the levels of expression are significantly correlated with the classical traits across members of a segregating population. The correlation structure between transcript abundances and classical traits has been used to identify susceptibility loci for complex diseases such as diabetes and allergic asthma. One study recently completed the first comprehensive dissection of transcriptional regulation in budding yeast, giving a detailed glimpse of a genome-wide survey of the genetics of gene expression. Unlike classical quantitative traits, which often represent gross clinical measurements that may be far removed from the biological processes giving rise to them, the genetic linkages associated with transcript abundance affords a closer look at cellular biochemical processes. Here we describe comprehensive genetic screens of mouse, plant and human transcriptomes by considering gene expression values as quantitative traits. We identify a gene expression pattern strongly associated with obesity in a murine cross, and observe two distinct obesity subtypes. Furthermore, we find that these obesity subtypes are under the control of different loci.
Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. ...In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases.
Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non‐demented controls, we investigated global disruptions in the co‐regulation of genes in two ...neurodegenerative diseases, late‐onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co‐expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242‐gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter‐connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter‐connection of these two processes and our key regulator prediction, we generated two brain‐specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10−12), while Dnmt3a KO signature does not (P = 0.017).
Synopsis
Network analysis of changes in gene co‐regulation, between large sets of Alzheimer's (AD) or Huntington's (HD) disease versus control brains, reveals that opposing dysregulation of two interacting processes, chromatin organization and neural differentiation, underlies both AD and HD.
Postmortem prefrontal cortex samples of over 600 dementia patients (late‐onset AD or HD) and non‐demented controls were expression profiled.
Pronounced global changes were observed in the gene–gene co‐expression patterns in AD or HD patients relative to the control group and revealed novel neurodegeneration‐associated genes.
Network alignment uncovered shared dysregulation of two inter‐connected processes, chromatin organization and neural differentiation, as a common pathology of AD and HD.
DNA methyltransferase, DNMT1, was validated as a key regulator of the inter‐connection between these two processes, using RNAseq data from brain‐specific knockout mice.
Network analysis of changes in gene co‐regulation, between large sets of Alzheimer's (AD) or Huntington's (HD) disease versus control brains, reveals that opposing dysregulation of two interacting processes, chromatin organization and neural differentiation, underlies both AD and HD.
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