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1.
PLoS Genet ; 17(4): e1009482, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33798195

RESUMO

Transcriptome-wide association studies (TWAS) have been widely used to integrate transcriptomic and genetic data to study complex human diseases. Within a test dataset lacking transcriptomic data, traditional two-stage TWAS methods first impute gene expression by creating a weighted sum that aggregates SNPs with their corresponding cis-eQTL effects on reference transcriptome. Traditional TWAS methods then employ a linear regression model to assess the association between imputed gene expression and test phenotype, thereby assuming the effect of a cis-eQTL SNP on test phenotype is a linear function of the eQTL's estimated effect on reference transcriptome. To increase TWAS robustness to this assumption, we propose a novel Variance-Component TWAS procedure (VC-TWAS) that assumes the effects of cis-eQTL SNPs on phenotype are random (with variance proportional to corresponding reference cis-eQTL effects) rather than fixed. VC-TWAS is applicable to both continuous and dichotomous phenotypes, as well as individual-level and summary-level GWAS data. Using simulated data, we show VC-TWAS is more powerful than traditional TWAS methods based on a two-stage Burden test, especially when eQTL genetic effects on test phenotype are no longer a linear function of their eQTL genetic effects on reference transcriptome. We further applied VC-TWAS to both individual-level (N = ~3.4K) and summary-level (N = ~54K) GWAS data to study Alzheimer's dementia (AD). With the individual-level data, we detected 13 significant risk genes including 6 known GWAS risk genes such as TOMM40 that were missed by traditional TWAS methods. With the summary-level data, we detected 57 significant risk genes considering only cis-SNPs and 71 significant genes considering both cis- and trans- SNPs; these findings also validated our findings with the individual-level GWAS data. Our VC-TWAS method is implemented in the TIGAR tool for public use.

2.
Alzheimers Res Ther ; 13(1): 55, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663605

RESUMO

BACKGROUND: Single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies only explain part of the heritability of Alzheimer's disease (AD). Epistasis has been considered as one of the main causes of "missing heritability" in AD. METHODS: We performed genome-wide epistasis screening (N = 10,389) for the clinical diagnosis of AD using three popularly adopted methods. Subsequent analyses were performed to eliminate spurious associations caused by possible confounding factors. Then, candidate genetic interactions were examined for their co-expression in the brains of AD patients and analyzed for their association with intermediate AD phenotypes. Moreover, a new approach was developed to compile the epistasis risk factors into an epistasis risk score (ERS) based on multifactor dimensional reduction. Two independent datasets were used to evaluate the feasibility of ERSs in AD risk prediction. RESULTS: We identified 2 candidate genetic interactions with PFDR <  0.05 (RAMP3-SEMA3A and NSMCE1-DGKE/C17orf67) and another 5 genetic interactions with PFDR <  0.1. Co-expression between the identified interactions supported the existence of possible biological interactions underlying the observed statistical significance. Further association of candidate interactions with intermediate phenotypes helps explain the mechanisms of neuropathological alterations involved in AD. Importantly, we found that ERSs can identify high-risk individuals showing earlier onset of AD. Combined risk scores of SNPs and SNP-SNP interactions showed slightly but steadily increased AUC in predicting the clinical status of AD. CONCLUSIONS: In summary, we performed a genome-wide epistasis analysis to identify novel genetic interactions potentially implicated in AD. We found that ERS can serve as an indicator of the genetic risk of AD.

3.
Neurobiol Dis ; 153: 105331, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33711493

RESUMO

The past 10 years have seen a rapid advance in our ability to profile the epigenome from human pathologic material, opening up new study designs to investigate the role of epigenomic features in human disease. Moderate to large scale studies have now been conducted in the target tissue of neurodegenerative diseases, the brain, and, through the use of rigorous statistical methodologies, have laid a foundation of validated observations and successful study designs that inform our perspective on the role of the epigenome in these diseases, generate new hypotheses, and guide our path forward for a second generation of studies. It is clear that sampling the epigenome is not redundant with other "omic" profiling of the same tissue and that it can serve as an important vehicle for the integration of the effect of multiple environmental exposures on risk of disease. In some cases, change in the epigenome may thus have a causal impact on disease, but we now have evidence that such changes may also mediate some of the effect of tau proteinopathy and that other changes may moderate the impact of genetic risk factors. Thus, the epigenome may be involved at multiple different stages of the sequence of events that leads to human neurodegeneration, and we review the study designs that may begin to guide the development of a more comprehensive perspective on the aging brain's epigenome.

4.
Acta Neuropathol ; 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33646358

RESUMO

Age-related neuropathologies progressively impair cognitive abilities by damaging synaptic function. We aimed to identify key components within the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) machinery associated with cognitive performance and estimate their potential contribution to brain reserve in old age. We used targeted SRM proteomics to quantify amounts of 60 peptides, encoded in 30 different genes, in postmortem specimens of the prefrontal cortex from 1209 participants of two aging studies, with available antemortem cognitive evaluations and postmortem neuropathologic assessments. We found that select (but not all) proteoforms are strongly associated with cognitive function and the burden of Alzheimer's disease (AD) pathology. Specifically, greater abundance of STX1A (but not other syntaxins), SYT12, full-length SNAP25, and the GABAergic STXBP1 variant were robustly associated with better cognitive performance. By contrast, greater abundance of other presynaptic proteins (e.g., STXBP5 or tomosyn, STX7, or SYN2) showed a negative influence on cognition. Regression models adjusting for demographic and pathologic variables showed that altered levels of these protein species explained 7.7% additional between-subject variance in cognition (more than any individual age-related neuropathology in the model), suggesting that these molecules constitute key elements of brain reserve. Network analyses indicated that those peptides associated with brain reserve, and closest to the SNARE fusogenic activity, showed greater centrality measures and were better connected in the network. Validation assays confirmed the selective loss of the STX1A (but not STX1B) isoform in cognitively impaired cases. In rodent and human brains, STX1A was selectively located at glutamatergic terminals. However, in AD brains, STX1A was redistributed adjacent to neuritic pathology, and markedly expressed in astrocytes. Our study provides strong evidence, indicating that select presynaptic proteins are key in maintaining brain reserve. Compromised ability to sustain expression levels of these proteins may trigger synaptic dysfunction and concomitant cognitive impairment.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33616290

RESUMO

OBJECTIVE: To report initial results of a planned multicenter year-long prospective study examining the risk and impact of COVID-19 among persons with neuroinflammatory disorders (NID), particularly multiple sclerosis (MS). METHODS: In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of suspected COVID-19 in persons with NID (PwNID) and change in their neurological care. RESULTS: Our cohort included 1115 participants (630 NID, 98% MS; 485 reference) as of 30 April 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. PwNID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of PwNID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (ORadj  = 1.45, 1.17-1.84). INTERPRETATIONS: Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries which capture an excess of severe cases. Overall, PwNID seem to have a risk of suspected COVID-19 similar to the reference population.

6.
Am J Hum Genet ; 108(3): 400-410, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33571421

RESUMO

We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects' tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.


Assuntos
Encéfalo/metabolismo , Proteoma/genética , Locos de Características Quantitativas/genética , Transcriptoma/genética , Autopsia , Feminino , Regulação da Expressão Gênica/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Proteômica , RNA Mensageiro/genética
7.
PLoS Genet ; 17(1): e1009224, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33417599

RESUMO

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.

8.
J Neurol ; 2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33392637

RESUMO

OBJECTIVE: To investigate associations of social support to psychological well-being, cognition, and motor functioning in patients with multiple sclerosis (MS). Secondarily, we were interested in exploring sex differences in these relationships, based on a bioevolutionary theoretical justification. METHODS: Social support was assessed in 185 recently diagnosed patients (RADIEMS cohort), and in an independent validation sample (MEMCONNECT cohort, n = 62). Patients also completed a comprehensive neurobehavioral evaluation including measures of mental health, fatigue, quality of life, cognition, and motor function. Correlations tested links between social support and these variables, along with potential gender differences. RESULTS: In both samples, higher social support was associated with better mental health, quality of life, subjective cognitive function, and less fatigue. In the RADIEMS cohort, higher social support was associated with better motor functions, particularly grip strength and gait endurance in women. CONCLUSIONS: These findings highlight associations of social support to overall psychological health and motor functioning in persons with MS, underlining the potential opportunity of evaluating and promoting social engagement in novel treatment strategies.

9.
Transl Psychiatry ; 11(1): 50, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446646

RESUMO

Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs-modules 113 and 114-relate to the accumulation of ß-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes (ACADVL, TRABD, and VASP) encode proteins that are upregulated in activated microglia in AD.

10.
Nat Commun ; 12(1): 654, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510174

RESUMO

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Debilidade Muscular/genética , Sarcopenia/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Estudos de Coortes , Europa (Continente) , Feminino , Fator 5 de Diferenciação de Crescimento/genética , Cadeias alfa de HLA-DQ/genética , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/genética , Força Muscular/fisiologia , Debilidade Muscular/fisiopatologia , Polimorfismo de Nucleotídeo Único , Sarcopenia/fisiopatologia
11.
Nat Genet ; 53(2): 143-146, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33510477

RESUMO

Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD)1,2, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.


Assuntos
Doença de Alzheimer/genética , Encéfalo/metabolismo , Proteoma/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas E/genética , Epóxido Hidrolases/genética , Estudo de Associação Genômica Ampla , Humanos , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Virais/genética , Análise de Sequência de RNA , Análise de Célula Única
13.
Nat Commun ; 11(1): 6129, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257666

RESUMO

The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer's disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD.

14.
Nat Commun ; 11(1): 5781, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188183

RESUMO

The temporal molecular changes that lead to disease onset and progression in Alzheimer's disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage-or disease pseudotime-for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0 × 10-5), Aß (CERAD score, P = 1.8 × 10-5), and cognitive diagnosis (P = 3.5 × 10-7) of late-onset (LO) AD. Early stage disease pseudotime samples are enriched for controls and show changes in basic cellular functions. Late stage disease pseudotime samples are enriched for late stage AD cases and show changes in neuroinflammation and amyloid pathologic processes. We also identify a set of late stage pseudotime samples that are controls and show changes in genes enriched for protein trafficking, splicing, regulation of apoptosis, and prevention of amyloid cleavage pathways. In summary, we present a method for ordering patients along a trajectory of LOAD disease progression from brain transcriptomic data.


Assuntos
Encéfalo/patologia , Degeneração Neural/patologia , Algoritmos , Doença de Alzheimer/patologia , Progressão da Doença , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Degeneração Neural/genética , Córtex Pré-Frontal/patologia , Fatores de Tempo , Aprendizado de Máquina não Supervisionado
16.
Mult Scler ; : 1352458520958362, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33146069

RESUMO

OBJECTIVE: To build a model to predict cognitive status reflecting structural, functional, and white matter integrity changes in early multiple sclerosis (MS). METHODS: Based on Symbol Digit Modalities Test (SDMT) performance, 183 early MS patients were assigned "lower" or "higher" performance groups. Three-dimensional (3D)-T2, T1, diffusion weighted, and resting-state magnetic resonance imaging (MRI) data were acquired in 3T. Using Random Forest, five models were trained to classify patients into two groups based on 1-demographic/clinical, 2-lesion volume/location, 3-local/global tissue volume, 4-local/global diffusion tensor imaging, and 5-whole-brain resting-state-functional-connectivity measures. In a final model, all important features from previous models were concatenated. Area under the receiver operating characteristic curve (AUC) values were calculated to evaluate classifier performance. RESULTS: The highest AUC value (0.90) was achieved by concatenating all important features from neuroimaging models. The top 10 contributing variables included volumes of bilateral nucleus accumbens and right thalamus, mean diffusivity of left cingulum-angular bundle, and functional connectivity among hubs of seven large-scale networks. CONCLUSION: These results provide an indication of a non-random brain pattern mostly compromising areas involved in attentional processes specific to patients who perform worse in SDMT. High accuracy of the final model supports this pattern as a potential neuroimaging biomarker of subtle cognitive changes in early MS.

17.
Sci Rep ; 10(1): 16902, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037294

RESUMO

Epidemiological studies have suggested differences in the rate of multiple sclerosis (MS) in individuals of European ancestry compared to African ancestry, motivating genetic scans to identify variants that could contribute to such patterns. In a whole-genome scan in 899 African-American cases and 1155 African-American controls, we confirm that African-Americans who inherit segments of the genome of European ancestry at a chromosome 1 locus are at increased risk for MS [logarithm of odds (LOD) = 9.8], although the signal weakens when adding an additional 406 cases, reflecting heterogeneity in the two sets of cases [logarithm of odds (LOD) = 2.7]. The association in the 899 individuals can be fully explained by two variants previously associated with MS in European ancestry individuals. These variants tag a MS susceptibility haplotype associated with decreased CD58 gene expression (odds ratio of 1.37; frequency of 84% in Europeans and 22% in West Africans for the tagging variant) as well as another haplotype near the FCRL3 gene (odds ratio of 1.07; frequency of 49% in Europeans and 8% in West Africans). Controlling for all other genetic and environmental factors, the two variants predict a 1.44-fold higher rate of MS in European-Americans compared to African-Americans.

18.
Sci Data ; 7(1): 340, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046718

RESUMO

The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis-eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying >4.1 million significant eQTL for >18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for >10,000 genes). We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. Additionally, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a resource for use by the research community. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalization with lncRNA RP11-677M14.2 (posterior probability of colocalization 0.975).

19.
Am J Hum Genet ; 107(4): 714-726, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961112

RESUMO

Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that leverages both cis- and trans-eQTL information for a TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans-eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWASs achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N = ∼3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of ZC3H12B and Alzheimer dementia (AD) (p value = 5.42 × 10-13), neurofibrillary tangle density (p value = 1.89 × 10-6), and global measure of AD pathology (p value = 9.59 × 10-7). These associations for ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of KCTD12 was found to be significantly associated with ß-amyloid (p value = 3.44 × 10-8) which was driven by both cis- and trans-eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N = ∼54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína C-I/genética , Genoma Humano , Modelos Estatísticos , Proteínas/genética , Locos de Características Quantitativas , Ribonucleases/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína C-I/metabolismo , Teorema de Bayes , Estudos de Casos e Controles , Simulação por Computador , Feminino , Expressão Gênica , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/metabolismo , Humanos , Masculino , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Proteínas/metabolismo , Ribonucleases/metabolismo , Transcriptoma
20.
Mol Neurodegener ; 15(1): 56, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993812

RESUMO

BACKGROUND: Tau neurofibrillary tangle pathology characterizes Alzheimer's disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. METHODS: Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutant form causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. RESULTS: TauWT induced 1514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a ~ 70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. CONCLUSIONS: Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.

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