Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 273
Filtrar
2.
Nat Commun ; 10(1): 4274, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537791

RESUMO

Genetic interactions have been reported to underlie phenotypes in a variety of systems, but the extent to which they contribute to complex disease in humans remains unclear. In principle, genome-wide association studies (GWAS) provide a platform for detecting genetic interactions, but existing methods for identifying them from GWAS data tend to focus on testing individual locus pairs, which undermines statistical power. Importantly, a global genetic network mapped for a model eukaryotic organism revealed that genetic interactions often connect genes between compensatory functional modules in a highly coherent manner. Taking advantage of this expected structure, we developed a computational approach called BridGE that identifies pathways connected by genetic interactions from GWAS data. Applying BridGE broadly, we discover significant interactions in Parkinson's disease, schizophrenia, hypertension, prostate cancer, breast cancer, and type 2 diabetes. Our novel approach provides a general framework for mapping complex genetic networks underlying human disease from genome-wide genotype data.

3.
Cell ; 178(6): 1493-1508.e20, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474370

RESUMO

Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n = 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.

4.
Nucleic Acids Res ; 47(20): 10597-10611, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31544924

RESUMO

Identifying functional variants underlying disease risk and adoption of personalized medicine are currently limited by the challenge of interpreting the functional consequences of genetic variants. Predicting the functional effects of disease-associated protein-coding variants is increasingly routine. Yet, the vast majority of risk variants are non-coding, and predicting the functional consequence and prioritizing variants for functional validation remains a major challenge. Here, we develop a deep learning model to accurately predict locus-specific signals from four epigenetic assays using only DNA sequence as input. Given the predicted epigenetic signal from DNA sequence for the reference and alternative alleles at a given locus, we generate a score of the predicted epigenetic consequences for 438 million variants observed in previous sequencing projects. These impact scores are assay-specific, are predictive of allele-specific transcription factor binding and are enriched for variants associated with gene expression and disease risk. Nucleotide-level functional consequence scores for non-coding variants can refine the mechanism of known functional variants, identify novel risk variants and prioritize downstream experiments.

5.
Nat Commun ; 10(1): 3834, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444360

RESUMO

Transcriptome-wide association studies integrate gene expression data with common risk variation to identify gene-trait associations. By incorporating epigenome data to estimate the functional importance of genetic variation on gene expression, we generate a small but significant improvement in the accuracy of transcriptome prediction and increase the power to detect significant expression-trait associations. Joint analysis of 14 large-scale transcriptome datasets and 58 traits identify 13,724 significant expression-trait associations that converge on biological processes and relevant phenotypes in human and mouse phenotype databases. We perform drug repurposing analysis and identify compounds that mimic, or reverse, trait-specific changes. We identify genes that exhibit agonistic pleiotropy for genetically correlated traits that converge on shared biological pathways and elucidate distinct processes in disease etiopathogenesis. Overall, this comprehensive analysis provides insight into the specificity and convergence of gene expression on susceptibility to complex traits.

6.
BMC Med Genomics ; 12(Suppl 6): 108, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345219

RESUMO

BACKGROUND: Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. RESULTS: We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. CONCLUSION: In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.

7.
Hum Mutat ; 40(11): e37-e51, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31260137

RESUMO

The human CYP2C locus harbors the polymorphic CYP2C18, CYP2C19, CYP2C9, and CYP2C8 genes, and of these, CYP2C19 and CYP2C9 are directly involved in the metabolism of ~15% of all medications. All variant CYP2C19 and CYP2C9 star (*) allele haplotypes currently cataloged by the Pharmacogene Variation (PharmVar) Consortium are defined by sequence variants. To determine if structural variation also occurs at the CYP2C locus, the 10q23.33 region was interrogated across deidentified clinical chromosomal microarray (CMA) data from 20,642 patients tested at two academic medical centers. Fourteen copy number variants that affected the coding region of CYP2C genes were detected in the clinical CMA cohorts, which ranged in size from 39.2 to 1,043.3 kb. Selected deletions and duplications were confirmed by MLPA or ddPCR. Analysis of the clinical CMA and an additional 78,839 cases from the Database of Genomic Variants (DGV) and ClinGen (total n = 99,481) indicated that the carrier frequency of a CYP2C structural variant is ~1 in 1,000, with ~1 in 2,000 being a CYP2C19 full gene or partial-gene deletion carrier, designated by PharmVar as CYP2C19*36 and *37, respectively. Although these structural variants are rare in the general population, their detection will likely improve metabolizer phenotype prediction when interrogated for research and/or clinical testing.

8.
Sci Rep ; 9(1): 8350, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171808

RESUMO

Subcellular RNAseq promises to dissect transcriptional dynamics but is not well characterized. Furthermore, FACS may introduce bias but has not been benchmarked genome-wide. Finally, D1 and D2 dopamine receptor-expressing medium spiny neurons (MSNs) of the nucleus accumbens (NAc) are fundamental to neuropsychiatric traits but have only a short list of canonical surface markers. We address these gaps by systematically comparing nuclear-FACS, whole cell-FACS, and RiboTag affinity purification from D1- and D2-MSNs. Using differential expression, variance partitioning, and co-expression, we identify the following trade-offs for each method. RiboTag-seq best distinguishes D1- and D2-MSNs but has the lowest transcriptome coverage. Nuclear-FACS-seq generates the most differentially expressed genes and overlaps significantly with neuropsychiatric genetic risk loci, but un-annotated genes hamper interpretation. Whole cell-FACS is more similar to nuclear-FACS than RiboTag, but captures aspects of both. Using pan-method approaches, we discover that transcriptional regulation is predominant in D1-MSNs, while D2-MSNs tend towards cytosolic regulation. We are also the first to find evidence for moderate sexual dimorphism in these cell types at baseline. As these results are from 49 mice (nmale = 39, nfemale = 10), they represent generalizable ground-truths. Together, these results guide RNAseq methods selection, define MSN transcriptomes, highlight neuronal sex differences, and provide a baseline for D1- and D2-MSNs.

9.
J Am Coll Cardiol ; 73(23): 2946-2957, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31196451

RESUMO

BACKGROUND: Genetic variants currently known to affect coronary artery disease (CAD) risk explain less than one-quarter of disease heritability. The heritability contribution of gene regulatory networks (GRNs) in CAD, which are modulated by both genetic and environmental factors, is unknown. OBJECTIVES: This study sought to determine the heritability contributions of single nucleotide polymorphisms affecting gene expression (eSNPs) in GRNs causally linked to CAD. METHODS: Seven vascular and metabolic tissues collected in 2 independent genetics-of-gene-expression studies of patients with CAD were used to identify eSNPs and to infer coexpression networks. To construct GRNs with causal relations to CAD, the prior information of eSNPs in the coexpression networks was used in a Bayesian algorithm. Narrow-sense CAD heritability conferred by the GRNs was calculated from individual-level genotype data from 9 European genome-wide association studies (GWAS) (13,612 cases, 13,758 control cases). RESULTS: The authors identified and replicated 28 independent GRNs active in CAD. The genetic variation in these networks contributed to 10.0% of CAD heritability beyond the 22% attributable to risk loci identified by GWAS. GRNs in the atherosclerotic arterial wall (n = 7) and subcutaneous or visceral abdominal fat (n = 9) were most strongly implicated, jointly explaining 8.2% of CAD heritability. In all, these 28 GRNs (each contributing to >0.2% of CAD heritability) comprised 24 to 841 genes, whereof 1 to 28 genes had strong regulatory effects (key disease drivers) and harbored many relevant functions previously associated with CAD. The gene activity in these 28 GRNs also displayed strong associations with genetic and phenotypic cardiometabolic disease variations both in humans and mice, indicative of their pivotal roles as mediators of gene-environmental interactions in CAD. CONCLUSIONS: GRNs capture a major portion of genetic variance and contribute to heritability beyond that of genetic loci currently known to affect CAD risk. These networks provide a framework to identify novel risk genes/pathways and study molecular interactions within and across disease-relevant tissues leading to CAD.

10.
Sci Adv ; 5(5): eaav6528, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31131321

RESUMO

Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor's genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease's genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.

11.
Genome Med ; 11(1): 10, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30808425

RESUMO

BACKGROUND: Increasing numbers of healthy individuals are undergoing predispositional personal genome sequencing. Here we describe the design and early outcomes of the PeopleSeq Consortium, a multi-cohort collaboration of predispositional genome sequencing projects, which is examining the medical, behavioral, and economic outcomes of returning genomic sequencing information to healthy individuals. METHODS: Apparently healthy adults who participated in four of the sequencing projects in the Consortium were included. Web-based surveys were administered before and after genomic results disclosure, or in some cases only after results disclosure. Surveys inquired about sociodemographic characteristics, motivations and concerns, behavioral and medical responses to sequencing results, and perceived utility. RESULTS: Among 1395 eligible individuals, 658 enrolled in the Consortium when contacted and 543 have completed a survey after receiving their genomic results thus far (mean age 53.0 years, 61.4% male, 91.7% white, 95.5% college graduates). Most participants (98.1%) were motivated to undergo sequencing because of curiosity about their genetic make-up. The most commonly reported concerns prior to pursuing sequencing included how well the results would predict future risk (59.2%) and the complexity of genetic variant interpretation (56.8%), while 47.8% of participants were concerned about the privacy of their genetic information. Half of participants reported discussing their genomic results with a healthcare provider during a median of 8.0 months after receiving the results; 13.5% reported making an additional appointment with a healthcare provider specifically because of their results. Few participants (< 10%) reported making changes to their diet, exercise habits, or insurance coverage because of their results. Many participants (39.5%) reported learning something new to improve their health that they did not know before. Reporting regret or harm from the decision to undergo sequencing was rare (< 3.0%). CONCLUSIONS: Healthy individuals who underwent predispositional sequencing expressed some concern around privacy prior to pursuing sequencing, but were enthusiastic about their experience and not distressed by their results. While reporting value in their health-related results, few participants reported making medical or lifestyle changes.


Assuntos
Predisposição Genética para Doença/psicologia , Testes Genéticos , Conhecimentos, Atitudes e Prática em Saúde , Medicina de Precisão/psicologia , Sequenciamento Completo do Genoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Inquéritos e Questionários
12.
Nat Rev Genet ; 20(3): 157-172, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30546107

RESUMO

Prokaryotic DNA contains three types of methylation: N6-methyladenine, N4-methylcytosine and 5-methylcytosine. The lack of tools to analyse the frequency and distribution of methylated residues in bacterial genomes has prevented a full understanding of their functions. Now, advances in DNA sequencing technology, including single-molecule, real-time sequencing and nanopore-based sequencing, have provided new opportunities for systematic detection of all three forms of methylated DNA at a genome-wide scale and offer unprecedented opportunities for achieving a more complete understanding of bacterial epigenomes. Indeed, as the number of mapped bacterial methylomes approaches 2,000, increasing evidence supports roles for methylation in regulation of gene expression, virulence and pathogen-host interactions.


Assuntos
Bactérias , Metilação de DNA , DNA Bacteriano , Genoma Bacteriano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Bactérias/genética , Bactérias/metabolismo , DNA Bacteriano/genética , DNA Bacteriano/metabolismo
13.
PLoS Genet ; 14(11): e1007755, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30444878

RESUMO

Recent genome-wide association studies (GWAS) have identified multiple new loci which appear to alter coronary artery disease (CAD) risk via arterial wall-specific mechanisms. One of the annotated genes encodes LMOD1 (Leiomodin 1), a member of the actin filament nucleator family that is highly enriched in smooth muscle-containing tissues such as the artery wall. However, it is still unknown whether LMOD1 is the causal gene at this locus and also how the associated variants alter LMOD1 expression/function and CAD risk. Using epigenomic profiling we recently identified a non-coding regulatory variant, rs34091558, which is in tight linkage disequilibrium (LD) with the lead CAD GWAS variant, rs2820315. Herein we demonstrate through expression quantitative trait loci (eQTL) and statistical fine-mapping in GTEx, STARNET, and human coronary artery smooth muscle cell (HCASMC) datasets, rs34091558 is the top regulatory variant for LMOD1 in vascular tissues. Position weight matrix (PWM) analyses identify the protective allele rs34091558-TA to form a conserved Forkhead box O3 (FOXO3) binding motif, which is disrupted by the risk allele rs34091558-A. FOXO3 chromatin immunoprecipitation and reporter assays show reduced FOXO3 binding and LMOD1 transcriptional activity by the risk allele, consistent with effects of FOXO3 downregulation on LMOD1. LMOD1 knockdown results in increased proliferation and migration and decreased cell contraction in HCASMC, and immunostaining in atherosclerotic lesions in the SMC lineage tracing reporter mouse support a key role for LMOD1 in maintaining the differentiated SMC phenotype. These results provide compelling functional evidence that genetic variation is associated with dysregulated LMOD1 expression/function in SMCs, together contributing to the heritable risk for CAD.

14.
J Crohns Colitis ; 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445421

RESUMO

Background: The molecular etiology of inflammatory bowel disease (IBD) and its two subtypes, ulcerative colitis (UC) and Crohn's disease (CD), have been carefully investigated at genome and transcriptome levels. Recent advances in high throughput proteome quantification has enabled comprehensive large scale plasma proteomics studies of IBD. Methods: The study used two cohorts: (1) CERTIFI-cohort: 42 sample from the CERTIFI trial of anti TNFα refractory CD patients; (2) PROgECT-UNITI-HC cohort: 46 UC samples PROgECT study, 84 CD samples of UNITI I and UNITI II, and 72 healthy controls recruited in Mount Sinai Hospital, New York, USA. Plasma proteome for these two cohorts was quantified using high throughput platforms. Results: On PROgECT-UNITI-HC cohort, we measured a total of 1,310 proteins. 493 proteins showed different plasma levels in IBD patients versus controls at 10% FDR, among which 11, proteins had a fold change greater than 2. Proteins up-regulated in IBD were enriched for immunity functionality while the proteins down-regulated in IBD were enriched for nutrition and metabolism. Proteomic profiles were very similar between UC and CD. On CERTIFI cohort, 1,014 proteins were measured, and found plasma protein level had little correlation with blood or intestine transcriptome. Conclusions: We report the largest proteomics study to date on IBD and controls. A large proportion of plasma proteins are altered in IBD, revealing insights on the disease etiology indicating a potential for biomarker discovery.

15.
Nat Commun ; 9(1): 4926, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30451900

RESUMO

In the originally published version of this Article, the affiliation details for Eric E. Schadt and Radoslav Savic incorrectly omitted 'Sema4, a Mount Sinai venture, Stamford, Connecticut, USA'. This has been corrected in both the PDF and HTML versions of the Article.

17.
Nat Commun ; 9(1): 4412, 2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30356048

RESUMO

A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from 12 individuals with SZ and 12 controls across 135 drugs, generating 4320 unique drug-response transcriptional signatures. We identify those drugs that reverse post-mortem SZ-associated transcriptomic signatures, several of which also differentially regulate neuropsychiatric disease-associated genes in a cell type (hiPSC NPC vs. CCL) and/or a diagnosis (SZ vs. control)-dependent manner. Overall, we describe a proof-of-concept application of transcriptomic drug screening to hiPSC-based models, demonstrating that the drug-induced gene expression differences observed with patient-derived hiPSC NPCs are enriched for SZ biology, thereby revealing a major advantage of incorporating cell type and patient-specific platforms in drug discovery.

18.
Front Pharmacol ; 9: 1093, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30337873

RESUMO

For almost two decades, pioglitazone has been prescribed primarily to prevent and treat insulin resistance in some type 2 diabetic patients. In this review, we trace the path to discovery of pioglitazone as a thiazolidinedione compound, the glitazone tracks through the regulatory agencies, the trek to molecular agonism in the nucleus and the binding of pioglitazone to the nuclear receptor PPAR gamma. Given the rise in consumption of pioglitazone in T2D patients worldwide and the increased number of clinical trials currently testing alternate medical uses for this drug, there is also merit to some reflection on the reported adverse effects. Going forward, it is imperative to continue investigations into the mechanisms of actions of pioglitazone, the potential of glitazone drugs to contribute to unmet needs in complex diseases associated with the dynamics of adaptive homeostasis, and also the routes to minimizing adverse effects in every-day patients throughout the world.

19.
Mol Psychiatry ; 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30283031

RESUMO

TYROBP/DAP12 forms complexes with ectodomains of immune receptors (TREM2, SIRPß1, CR3) associated with Alzheimer's disease (AD) and is a network hub and driver in the complement subnetwork identified by multi-scale gene network studies of postmortem human AD brain. Using transgenic or viral approaches, we characterized in mice the effects of TYROBP deficiency on the phenotypic and pathological evolution of tauopathy. Biomarkers usually associated with worsening clinical phenotype (i.e., hyperphosphorylation and increased tauopathy spreading) were unexpectedly increased in MAPTP301S;Tyrobp-/- mice despite the improved learning behavior and synaptic function relative to controls with normal levels of TYROBP. Notably, levels of complement cascade initiator C1q were reduced in MAPTP301S;Tyrobp-/- mice, consistent with the prediction that C1q reduction exerts a neuroprotective effect. These observations suggest a model wherein TYROBP-KO-(knock-out)-associated reduction in C1q is associated with normalized learning behavior and electrophysiological properties in tauopathy model mice despite a paradoxical evolution of biomarker signatures usually associated with neurological decline.

20.
Mol Psychiatry ; 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30283032

RESUMO

Integrative gene network approaches enable new avenues of exploration that implicate causal genes in sporadic late-onset Alzheimer's disease (LOAD) pathogenesis, thereby offering novel insights for drug-discovery programs. We previously constructed a probabilistic causal network model of sporadic LOAD and identified TYROBP/DAP12, encoding a microglial transmembrane signaling polypeptide and direct adapter of TREM2, as the most robust key driver gene in the network. Here, we show that absence of TYROBP/DAP12 in a mouse model of AD-type cerebral Aß amyloidosis (APPKM670/671NL/PSEN1Δexon9) recapitulates the expected network characteristics by normalizing the transcriptome of APP/PSEN1 mice and repressing the induction of genes involved in the switch from homeostatic microglia to disease-associated microglia (DAM), including Trem2, complement (C1qa, C1qb, C1qc, and Itgax), Clec7a and Cst7. Importantly, we show that constitutive absence of TYROBP/DAP12 in the amyloidosis mouse model prevented appearance of the electrophysiological and learning behavior alterations associated with the phenotype of APPKM670/671NL/PSEN1Δexon9 mice. Our results suggest that TYROBP/DAP12 could represent a novel therapeutic target to slow, arrest, or prevent the development of sporadic LOAD. These data establish that the network pathology observed in postmortem human LOAD brain can be faithfully recapitulated in the brain of a genetically manipulated mouse. These data also validate our multiscale gene networks by demonstrating how the networks intersect with the standard neuropathological features of LOAD.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA