3613 results for "*geneti*"

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• Assessment of Epigenetic and Transcriptomic Signatures During Induced Neural Stem Cell Conversion of Human Blood Cells

  Cellular reprogramming by direct cell fate conversion has been shown to be associated with epigenetic de-aging. However, the dynamics of this process still remain elusive. Here, we generated induced neural stem cells (iNSCs) from erythroid progenitors of donors ranging from neonatal to 101 years of age by overexpression of the transcription factors SOX2 and MYC. First, performing DNA methylation analyses, we corroborated our previous finding that iNSCs generated from aged donors show pronounced epigenetic de-aging (data deposited as GSE295849). Studying the dynamic of epigenetic de-aging during iNSC conversion across time, we found that this process is largely protracted. Second, RNA sequencing analysis revealed that transcriptomic differences between young and old donor-derived iNSCs dissipate with extended time in conversion, too (data available through dbGaP). Concordant with this observation, established iNSC lines lack age-associated cellular hallmarks, similar to induced pluripotent stem cells and their derivatives. Finally, time course analyses on epigenome and transcriptome level both revealed that acquisition of a bona fide NSC signature extends greatly beyond the time point when proliferative PAX6-positive iNSCs emerge.

  Study phs004047

• Assessing Molecular GxT Interactions in Neural Progenitors Exposed to Valproic Acid and Lithium

  In this study we aimed to identify context-dependent regulatory functions of common genetic variation after stimulation with clinically relevant molecules, valproate and lithium. Fetal cortical tissue between 14 and 21 weeks gestation was subjected to RNA-Sequencing (232 samples) and ATAC-Sequencing (232 samples) to profile expression and chromatin accessibility, respectively. Considering donor genotypes, we were able to identify eQTLs, caQTLs, as well as response QTLs of both categories. The dataset provided here includes 232 RNA-sequencing files in bam format and 232 ATAC-sequencing files in bam format. We also provide 83 donor genotypes in VCF format (hg38). NOTE: Some sequence data files used in this study were previously submitted for phs003642.v1.p1 NIMH/Wnt_NeuralProgenitors. Investigators requesting access to data from phs004321 should also apply for access to phs003642.

  Study phs004321

• Integrating Contemporary Biospecimens and Immunomethylomics into the study of the Glioma Genetics and Immunity - CIDR

  Gliomas account for 80% of all malignant brain tumors and have an extremely poor prognosis, with a 5-year survival of 5.1%. The etiology of glioma remains poorly understood, with few established modifiable risk factors. Multiple studies have implicated infections in the development of glioma; however, the underlying mechanisms and putative causal pathogens remain unclear. In addition to risk, we have recently shown that reactivity to varicella zoster virus is also associated with a significant survival benefit in patients with glioma. Previous epidemiologic studies have investigated a limited number of pathogens using serological assays that only allowed detection. Recent analyses from our group have also highlighted that glioma subtypes have varying immune cells at diagnosis, and that there may be prognostic value. This CIDR proposal has two parts to add to the parent R01- Discovering Infection-mediated Pathways of Glioma Etiology and Prognosis by Leveraging Multiplex Serology and Immunogenomics (R01 CA266676) that applies multiplex serology and targeted HLA sequencing to understand the interplay between germline genetics, antigen reactivity and glioma risk/survival. In the first part of this application, we seek to expand our current plans to include 447 Immune Profiles Study subjects that have contemporary treatment, and highly detailed longitudinal biospecimens and clinical data measured at every clinic visit across the course of treatment. We plan to genotype these subjects for inclusion in viral antigen measurement and HLA sequencing. We will also include 30 cross-study replicate samples from the UCSF Adult Glioma Study (dbGaP Study Accession: phs001497) in this genotyping project. The second part of this CIDR proposal seeks to analyze whole blood methylation to deconvolute blood cell proportions for 1592 glioma cases and 1147 matched controls from the Adult Glioma Study that do not have existing blood methylation. The derived blood cell proportions will facilitate a deeper understand of the subtype specific risk and prognosis associated with immune cell traits, integrate mediation by germline genetics, and hone the antigen associations by controlling for antigen presenting cells. This proposal will unite two parallel, but independent and complementary studies, and will complete the viral, immunologic and genetic understanding of the association with viral reactivity and immune cells that will pave the way for functional studies. This will allow us to develop comprehensive immunogenomic models for predicting glioma risk and survival. Taken together, the proposed study will contribute new, high-quality data that will significantly advance our understanding of glioma pathogenesis, as well as inform avenues for prevention and improvement of outcomes in glioma patients.

  Study phs003990

• Clonal Heterogeneity in Human Pancreatic Ductal Adenocarcinoma and Its Impact on Tumor Progression

  This study of primary human pancreatic ductal adenocarcinoma (PDAC) tumors (n=62) aims to characterize intratumoral clonal diversity, transcriptional plasticity, tumor–microenvironment interactions, and spatial patterns associated with progression and metastasis. Combined single-cell RNA sequencing and spatial transcriptomics enabled reconstruction of tumor phylogenies and mapping of clone-specific transcriptional states. Extensive intratumoral heterogeneity was observed, with multiple genetically distinct neoplastic clones coexisting within tumors. Distinct clones exhibited unique interactions with stromal and immune cells, and dispersed clones enriched for epithelial-to-mesenchymal transition (EMT) programs and immune-suppressive microenvironments correlated with metastatic potential and lymph node colonization. A recurrent classical-to-basal clonal transition associated with MYC amplification and reduced immune response was identified and experimentally validated, implicating clonal evolution in emergence of more aggressive phenotypes. Controlled-access dbGaP deposits will include raw sequencing data from single-cell RNA sequencing and spatial transcriptomics experiments and de-identified clinical/sample metadata.

  Study phs004079

• The Genetics of Obesity, Diabetes, and Heart Disease in African Diaspora Populations

  African Americans have one of the highest rates of type 2 diabetes in the United States, and often have other medical problems related to obesity and cardiovascular disease. These conditions have various risk factors, including high blood sugar levels, high cholesterol levels, and insulin resistance. However, these risk factors need further study in individuals with African ancestry, including Afro-Caribbean and sub-Saharan Africa migrant populations. Genetic study of obesity, adult-onset diabetes, heart disease, and other common health conditions in African ancestry individuals across the Diaspora could be particularly informative. Therefore, this study is designed to collect genetic and non-genetic information from individuals with African ancestry to study common health conditions related to obesity, adult-onset diabetes, and heart disease. This ongoing study includes individuals at least 18 years of age who self-identify as African American, Afro-Caribbean, or migrants from sub Saharan Africa. Participants undergo physical examination and provide a blood sample for study. Participants also answer questions about personal and family medical history and current lifestyle behaviors. No treatment is provided as part of this protocol.

  Study phs004382

• Multi-omic Characterization of Genetic Variants in IBD Risk Loci

  This study aims to identify potential target genes of GWAS loci for inflammatory bowel diseases (IBD) by mapping expression quantitative trait loci (eQTL) using colon tissue from a cohort of 252 IBD patients. Results were compared to non-IBD colon eQTL from GTEx and BarcUVa-seq (GTEx Consortium, Science 2020 / Díez-Obrero V et al., Cell Mol Gastroenterol Hepatol. 2021). Statistical colocalization of eQTL and GWAS loci revealed novel colocalizations and target genes using diseased tissue. These eQTL also had regulatory and functional characteristics which were distinct from non-IBD eQTL. Available data includes typed and imputed genotypes, raw total RNA-seq, and association results.

  Study phs003881

• The National Myelodysplastic Syndromes (MDS) Study- Digital Histopathological Slide Images

  The goal of the National MDS Study was to establish a publicly available resource to facilitate the study of MDS natural history. This was accomplished through: 1) Creation of a multi-institutional, rich clinical database with genetic sequencing, longitudinal biorepository of consistently processed and clinically well-annotated blood and tissue specimens collected prospectively from participants with MDS and participants with idiopathic cytopenia of undetermined significance (ICUS); and 2) Support for investigator-initiated studies of MDS that will have high-impact for MDS patients, including basic science, clinical, health outcomes and epidemiological research. The study has assembled a comprehensive worldclass clinical database from over 2,100 participants with suspected or newly diagnosed MDS or MDS/MPN overlap disorders including extensive quality of life assessments, laboratory data, exposure history, histopathology slides and images, targeted and whole genome sequencing data, and hematopoietic and germline tissues representing high-quality biospecimens and data from diverse centers across the United States. These resources are now made available to the scientific community to support investigator-initiated research. The Digital Histopathological Slide Image data set further enhances the characterization of the MDS study cohort. The image library contains a total of 3,988 digital histopathology slides (H&E and Wright stained) of bone marrow aspirate and biopsy samples as well as peripheral blood smears collected from 1,652 MDS participants at baseline and follow-up visits. Clinical data associated with these images includes basic demographics, the central pathologist's WHO classification, and other slide review comments. Additional characterization of the MDS participants is available for further evaluation. The slide image library provides an extensive and unique resource to the research community offering a platform to evaluate new techniques that could potentially lead to improvements in diagnostic screening procedures and classification of patients with MDS.

  Study phs004357

• Collagen XVII Promotes Pancreatic Cancer Through Regulation of PIK3R5

  Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that promotes the aggressive biology of this disease. While the varied mechanisms by which fibrillar collagens contribute to PDAC have been defined, little is known about the contribution of transmembrane collagens. Among this class of collagens, Collagen XVII uniquely contains an extensive intracellular domain that connects intracellular cytoplasmic components with the extracellular matrix. Collagen XVII is best characterized as the defining component of the type I hemidesmosome, an anchoring complex that attaches epithelial cells to the underlying basement membrane. In this study, we characterize the expression of collagen XVII in PDAC and the mechanisms by which it contributes to PDAC biology. We demonstrate that crosstalk between PDAC cells and cancer associated fibroblasts drive collagen XVII expression in vitro and xenograft tumor models in vivo. Genetic depletion of collagen XVII in low-passage patient derived cell lines diminishes their metastatic potential and ability to form tumors in mice. Whole transcriptome sequencing of tumors formed by cells with diminished collagen XVII levels revealed dramatically lower levels of PIK3R5, a regulatory subunit of class IB phosphatidylinositol-3-kinase (PI3K) that interacts with G protein-coupled receptors. Consistent with this, collagen XVII-deficient tumors exhibited lower levels of phosphorylated AKT, a downstream effector of PI3K. The studies highlight the importance of collagen XVII signaling in PDAC and define a novel mechanism by which collagen XVII mediates activation of PI3K.

  Study phs003641

• Retinal Contributions to Vision Loss in Albinism

  The human fovea supports some of our most important visual functions, such as color discrimination and high acuity vision, but there remain significant gaps in our understanding of foveal development and the exact causal relationships between structural pathology and specific visual deficits. This study employs human albinism (a hereditary condition in which the fovea is grossly underdeveloped) as a natural model to examine these and other key issues. Using advanced non-invasive imaging approaches together with genetic testing, we seek to reveal the physiological and anatomical basis for visual deficits in albinism on a personalized basis and to refine the anatomical outcome measures for use in correlative studies and emerging therapeutic trials in albinism. Specifically, given the central role of the fovea in our visual function, this study seeks to elucidate the genetic factors affecting normal foveal development, to advance our understanding of a wide range of conditions associated with altered foveal morphology. Around 300 people will be recruited for this study, with an anticipated ~250 consenting to sharing their data in dbGaP. Next generation sequencing of participant samples will be done to analyze over 100 genes (list below) with links to albinism. Information collected for each sample for inclusion in this study will include: Sequencing-derived raw genetic data of study participants,Demographic data, including age, sex, race, Hispanic ethnicity, and gender identity (in some cases)Albinism phenotypeOther related phenotypic data if/when collected: premature birth, AOSLO retinal imaging, ancillary retinal imaging, visual field & fixation evaluation, color vision testing, and macular pigment optical densityClinical data when possible/available, such as: stereoacuity, BCVA, foveal pit morphology, NIR autofluorescence signal

  Study phs003573

• A Case Controlled Etiologic Study of Sarcoidosis (ACCESS-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from (ACCESS) include Bronchial Lavage, DNA, Peripheral Blood Mononuclear Cells, and Plasma. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: To determine the etiology of sarcoidosis by establishing a case control, multi-center study. In addition to etiology, this study also sought to examine socioeconomic variables and the clinical course of patients with sarcoidosis, including quality of life.Background: Sarcoidosis is a chronic granulomatous disorder of unknown cause that is characterized by activation of T-lymphocytes and macrophages. For many years, sarcoidosis was presumed to be an atypical manifestation of tuberculosis because of the similarity between the inflammatory responses of the two diseases. However, as culture techniques became more widely employed to diagnose tuberculosis and it became less common, it became clear that sarcoidosis was not simply a variation of tuberculosis. Data on the etiology of sarcoidosis have come from diverse sources: in clinical investigations, alveolitis has been found to precede granulomatous inflammation; in case control studies, familial aggregation has been identified; and in case reports, recurrence of granulomatous inflammation has been observed after lung transplantation. The cause may not prove to be a single, known exposure. Interactions of exposures with genetic dispositions could have important implications for our understanding of immune responses as well as the pathogenesis of sarcoidosis.Participants: 736 participants with sarcoidosis enrolled within 6 months of diagnosis from 10 clinical centers in the U.S. Using the ACCESS sarcoidosis assessment system, organ involvement was determined for the whole group and for subgroups differentiated by sex, race, and age (Conclusions: The initial presentation of sarcoidosis is related to sex, race and age, and it tends to remain stable over two years in the majority of patients. The etiology is probably multifactoral with both genetic and environmental factors contributing.Specimen Details: The PBMC for this study are pelleted and suspended in guanidinium-based solution and are nonviable.

  Study phs004276