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Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.
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Enfermedad de Parkinson , alfa-Sinucleína , Humanos , Enfermedad de Parkinson/metabolismo , Cuerpos de Procesamiento , Estabilidad del ARN , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For a global view of IFN signatures and regulatory pathways, we performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN and revealed underlying changes in chromatin configuration. We combined 1,398 human and mouse datasets to computationally infer ISG modules and their regulators, validated by genetic analysis in both species. Some ISGs are controlled by Stat1/2 and Irf9 and the ISRE DNA motif, but others appeared dependent on non-canonical factors. This regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being affected under tonic or IFN-stimulated conditions, and the IFN signatures previously associated with human diseases, revealing unrecognized subtleties in disease footprints, as affected by human ancestry.
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Redes Reguladoras de Genes , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Animales , Linfocitos T CD4-Positivos/metabolismo , Conjuntos de Datos como Asunto , Humanos , Quinasas Janus/metabolismo , Ratones , Ratones Endogámicos C57BL , Receptor de Interferón alfa y beta/metabolismoRESUMEN
Alzheimer's disease (AD) has recently been associated with diverse cell states1-11, yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-ß proteinopathy while the other mediates the effect of amyloid-ß on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing.
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Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here, we mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The maps yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments. They also reveal global features of the epigenome, related to nuclear architecture, that also vary across cellular phenotypes. Specifically, developmental specification is accompanied by progressive chromatin restriction as the default state transitions from dynamic remodeling to generalized compaction. Exposure to serum in vitro triggers a distinct transition that involves de novo establishment of domains with features of constitutive heterochromatin. We describe how these global chromatin state transitions relate to chromosome and nuclear architecture, and discuss their implications for lineage fidelity, cellular senescence, and reprogramming.
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Ensamble y Desensamble de Cromatina , Cromatina/metabolismo , Epigénesis Genética , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Núcleo Celular , Senescencia Celular , Células Madre Embrionarias/metabolismo , Regulación de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Especificidad de ÓrganosRESUMEN
The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species and recently demonstrated to occur in rare instances from one human generation to the next. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors. Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed.
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Encéfalo , ADN Mitocondrial , Fibroblastos , Humanos , ADN Mitocondrial/genética , Fibroblastos/metabolismo , Encéfalo/metabolismo , Masculino , Femenino , Núcleo Celular/metabolismo , Persona de Mediana Edad , Adulto , Anciano , Longevidad/genética , Envejecimiento/fisiología , Envejecimiento/genéticaRESUMEN
Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these "mind-mitochondria" associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes.
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Encéfalo , Mitocondrias , Fosforilación Oxidativa , Humanos , Mitocondrias/metabolismo , Masculino , Femenino , Encéfalo/metabolismo , Anciano , Estrés Psicológico/metabolismo , Persona de Mediana Edad , Corteza Prefrontal/metabolismo , Neuronas/metabolismo , Proteómica/métodos , Afecto/fisiologíaRESUMEN
Late-Onset Alzheimer's Disease (LOAD) is a heterogeneous neurodegenerative disorder with complex etiology and high heritability. Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified genetic risk factors. Here we describe the "whole person" genetic risk landscape of polygenic risk scores for 2218 traits in 2044 elderly individuals and test if novel eigen-PRSs derived from clustered subnetworks of single-trait PRSs can improve the prediction of LOAD diagnosis, rates of cognitive decline, and canonical LOAD neuropathology. Network analyses revealed distinct clusters of PRSs with clinical and biological interpretability. Novel eigen-PRSs (ePRS) from these clusters significantly improved LOAD-related phenotypes prediction over current state-of-the-art LOAD PRS models. Notably, an ePRS representing clusters of traits related to cholesterol levels was able to improve variance explained in a model of the brain-wide beta-amyloid burden by 1.7% (likelihood ratio test P = 9.02 × 10-7). All associations of ePRS with LOAD phenotypes were eliminated by the removal of APOE-proximal loci. However, our association analysis identified modules characterized by PRSs of high cholesterol and LOAD. We believe this is due to the influence of the APOE region from both PRSs. We found significantly higher mean SNP effects for LOAD in the intersecting APOE region SNPs. Combining genetic risk factors for vascular traits and dementia could improve current single-trait PRS models of LOAD, enhancing the use of PRS in risk stratification. Our results are catalogued for the scientific community, to aid in generating new hypotheses based on our maps of clustered PRSs and associations with LOAD-related phenotypes.
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Enfermedad de Alzheimer , Puntuación de Riesgo Genético , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/genética , Apolipoproteínas E/genética , Disfunción Cognitiva/genética , Estudio de Asociación del Genoma Completo , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer's Disease.
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ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer's disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis using data from human autopsy tissue (consisting of males and females) and female human cell lines. Co-immunoprecipitation (co-IP) of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA-splicing proteins. ZCCHC17 knockdown results in widespread RNA-splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4-dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, a majority of ZCCHC17 interactors also co-IP with known tau interactors, and we find a significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17's role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that the maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology.
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Enfermedad de Alzheimer , Resiliencia Psicológica , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/metabolismo , Cognición , Neuronas/metabolismo , ARN , Empalme del ARN/genética , Proteínas tau/metabolismoRESUMEN
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.
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Encéfalo/metabolismo , Proteoma/genética , Sitios de Carácter Cuantitativo/genética , Transcriptoma/genética , Autopsia , Femenino , Regulación de la Expresión Génica/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Proteómica , ARN Mensajero/genéticaRESUMEN
OBJECTIVE: VGF is proposed as a potential therapeutic target for Alzheimer's (AD) and other neurodegenerative conditions. The cell-type specific and, separately, peptide specific associations of VGF with pathologic and cognitive outcomes remain largely unknown. We leveraged gene expression and protein data from the human neocortex and investigated the VGF associations with common neuropathologies and late-life cognitive decline. METHODS: Community-dwelling older adults were followed every year, died, and underwent brain autopsy. Cognitive decline was captured via annual cognitive testing. Common neurodegenerative and cerebrovascular conditions were assessed during neuropathologic evaluations. Bulk brain RNASeq and targeted proteomics analyses were conducted using frozen tissues from dorsolateral prefrontal cortex of 1,020 individuals. Cell-type specific gene expressions were quantified in a subsample (N = 424) following single nuclei RNASeq analysis from the same cortex. RESULTS: The bulk brain VGF gene expression was primarily associated with AD and Lewy bodies. The VGF gene association with cognitive decline was in part accounted for by neuropathologies. Similar associations were observed for the VGF protein. Cell-type specific analyses revealed that, while VGF was differentially expressed in most major cell types in the cortex, its association with neuropathologies and cognitive decline was restricted to the neuronal cells. Further, the peptide fragments across the VGF polypeptide resembled each other in relation to neuropathologies and cognitive decline. INTERPRETATION: Multiple pathways link VGF to cognitive health in older age, including neurodegeneration. The VGF gene functions primarily in neuronal cells and its protein associations with pathologic and cognitive outcomes do not map to a specific peptide. ANN NEUROL 2023;94:232-244.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedades del Sistema Nervioso , Humanos , Anciano , Encéfalo/patología , Disfunción Cognitiva/patología , Neuropatología , Enfermedades del Sistema Nervioso/patología , Cognición , Enfermedad de Alzheimer/patología , Factores de Crecimiento Nervioso/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia, and disease mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying the familial AD APPV717I mutation after cell injection into the mouse forebrain. APPV717I mutant iPSCs and isogenic controls were differentiated into neurons revealing enhanced Aß42 production, elevated phospho-tau, and impaired neurite outgrowth in APPV717I neurons. Two months after transplantation, APPV717I and control neural cells showed robust engraftment but at 12 months post-injection, APPV717I grafts were smaller and demonstrated impaired neurite outgrowth compared to controls, while plaque and tangle pathology were not seen. Single-nucleus RNA-sequencing of micro-dissected grafts, performed 2 months after cell injection, identified significantly altered transcriptome signatures in APPV717I iPSC-derived neurons pointing towards dysregulated synaptic function and axon guidance. Interestingly, APPV717I neurons showed an increased expression of genes, many of which are also upregulated in postmortem neurons of AD patients including the transmembrane protein LINGO2. Downregulation of LINGO2 in cultured APPV717I neurons rescued neurite outgrowth deficits and reversed key AD-associated transcriptional changes related but not limited to synaptic function, apoptosis and cellular senescence. These results provide important insights into transcriptional dysregulation in xenografted APPV717I neurons linked to synaptic function, and they indicate that LINGO2 may represent a potential therapeutic target in AD.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Células Madre Pluripotentes Inducidas , Neuronas , Transcriptoma , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Neuronas/metabolismo , Neuronas/patología , Animales , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Mutación , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Sinapsis/patología , Sinapsis/metabolismo , Péptidos beta-Amiloides/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (ß = -0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; ßfemale = 0.8289, P = 3.52 × 10-8), the other in males (rs698805; ßmale = -1.5395, P = 4.35 × 10-8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in CNS compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and G-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.
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Esclerosis Múltiple , Masculino , Femenino , Humanos , Esclerosis Múltiple/genética , Estudio de Asociación del Genoma Completo , Recurrencia Local de Neoplasia , Pronóstico , Sistema InmunológicoRESUMEN
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, which also validated our findings with the individual-level GWAS data. Our VC-TWAS method is implemented in the TIGAR tool for public use.
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Enfermedad de Alzheimer/genética , Demencia/genética , Proteínas de Transporte de Membrana/genética , Transcriptoma/genética , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/patología , Demencia/epidemiología , Demencia/patología , Femenino , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The majority of genetic variants detected in genome wide association studies (GWAS) exert their effects on phenotypes through gene regulation. Motivated by this observation, we propose a multi-omic integration method that models the cascading effects of genetic variants from epigenome to transcriptome and eventually to the phenome in identifying target genes influenced by risk alleles. This cascading epigenomic analysis for GWAS, which we refer to as CEWAS, comprises two types of models: one for linking cis genetic effects to epigenomic variation and another for linking cis epigenomic variation to gene expression. Applying these models in cascade to GWAS summary statistics generates gene level statistics that reflect genetically-driven epigenomic effects. We show on sixteen brain-related GWAS that CEWAS provides higher gene detection rate than related methods, and finds disease relevant genes and gene sets that point toward less explored biological processes. CEWAS thus presents a novel means for exploring the regulatory landscape of GWAS variants in uncovering disease mechanisms.
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Enfermedades Genéticas Congénitas/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo/genética , Alelos , Epigenoma/genética , Enfermedades Genéticas Congénitas/patología , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Transcriptoma/genéticaRESUMEN
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.
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Enfermedad de Alzheimer/genética , Descubrimiento de Drogas , Predisposición Genética a la Enfermedad , Transcriptoma/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Trastorno Bipolar/patología , Encéfalo/metabolismo , Encéfalo/patología , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Terapia Molecular Dirigida , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo/genética , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/patologíaRESUMEN
INTRODUCTION: Dietary patterns are associated with dementia risk, but the underlying molecular mechanisms are largely unknown. METHODS: We used RNA sequencing data from post mortem prefrontal cortex tissue and annual cognitive evaluations from 1204 participants in the Religious Orders Study and Memory and Aging Project. We identified a transcriptomic profile correlated with the MIND diet (Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay) among 482 individuals who completed ante mortem food frequency questionnaires; and examined its associations with cognitive health in the remaining 722 participants. RESULTS: We identified a transcriptomic profile, consisting of 50 genes, correlated with the MIND diet score (p = 0.001). Each standard deviation increase in the transcriptomic profile score was associated with a slower annual rate of decline in global cognition (ß = 0.011, p = 0.003) and lower odds of dementia (odds ratio = 0.76, p = 0.0002). Expressions of several genes (including TCIM and IGSF5) appeared to mediate the association between MIND diet and dementia. DISCUSSION: A brain transcriptomic profile for healthy diets revealed novel genes potentially associated with cognitive health. HIGHLIGHTS: Why healthy dietary patterns are associated with lower dementia risk are unknown. We integrated dietary, brain transcriptomic, and cognitive data in older adults. Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet intake is correlated with a specific brain transcriptomic profile. This brain transcriptomic profile score is associated with better cognitive health. More data are needed to elucidate the causality and functionality of identified genes.
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INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.
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Enfermedad de Alzheimer , Estudio de Asociación del Genoma Completo , Secuenciación Completa del Genoma , Humanos , Enfermedad de Alzheimer/genética , Femenino , Masculino , Predisposición Genética a la Enfermedad/genética , Anciano , Polimorfismo de Nucleótido Simple/genética , Variación Genética/genéticaRESUMEN
BACKGROUND: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment. METHODS: Induced pluripotent stem cell (iPSC)-derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation. RESULTS: Neurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits. DISCUSSION: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation-prone proteins such as tau. HIGHLIGHTS: Polygenic risk score for AD is associated with the ubiquitin-proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation-prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge.
Asunto(s)
Complejo de la Endopetidasa Proteasomal , Ubiquitina , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Proteostasis , Proteómica , Neuronas/metabolismoRESUMEN
Identifying ancestry-specific molecular profiles of late-onset Alzheimer's Disease (LOAD) in brain tissue is crucial to understand novel mechanisms and develop effective interventions in non-European, high-risk populations. We performed gene differential expression (DE) and consensus network-based analyses in RNA-sequencing data of postmortem brain tissue from 39 Caribbean Hispanics (CH). To identify ancestry-concordant and -discordant expression profiles, we compared our results to those from two independent non-Hispanic White (NHW) samples (n = 731). In CH, we identified 2802 significant DE genes, including several LOAD known-loci. DE effects were highly concordant across ethnicities, with 373 genes transcriptome-wide significant in all three cohorts. Cross-ancestry meta-analysis found NPNT to be the top DE gene. We replicated over 82% of meta-analyses genome-wide signals in single-nucleus RNA-seq data (including NPNT and LOAD known-genes SORL1, FBXL7, CLU, ABCA7). Increasing representation in genetic studies will allow for deeper understanding of ancestry-specific mechanisms and improving precision treatment options in understudied groups.