3613 results for "*geneti*"

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• Comprehensive Genomic Characterization of Translocation Renal Cell Carcinoma

  Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the TFE3 gene on chromosome Xp11.2 and a partner gene on either chrX or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics uniquely constrains somatic chrX alterations and underlies cancer sex differences.This version of the dbGaP study provides a comprehensive set of whole genome data and tables with clinical information collected for the 16 patients (15 pateints as tRCC and 1 patient as ccRCC) in the study cohort. The data also contains 12 RNA-seq samples used in the study and analyses. We anticipate that this data will considerably advance our molecular and genetic understanding of oncogenic translocations in TFE3-tRCC involving inactive chromosome X and its role in cancer sex bias.

  Study phs003008

• DNA-Sequencing of Baseline and Progression Plasma from the Phase III Alliance A031201 Trial

  Circulating tumor DNA (ctDNA) in plasma cell free DNA (cfDNA) of cancer patients is associated with poor prognosis, but is challenging to detect from low plasma volumes. In metastatic castration-resistant prostate cancer (mCRPC), ctDNA assays are needed to prognosticate outcomes of patients treated with androgen receptor (AR) inhibitors. We developed a custom targeted cfDNA sequencing assay, named AR-ctDETECT, to detect ctDNA in limiting plasma cfDNA available from mCRPC patients in the Alliance A031201 randomized phase 3 trial of enzalutamide with or without abiraterone. For the AR ctDETECT assay, DNA-seq libraries were constructed from cfDNA using Takara ThruPLEX Tag-Seq or Plasma-Seq kits, and subjected to hybridization enrichment using a custom-designed Agilent SureSelect bait panel. Post-capture DNA-seq libraries were pooled and sequenced on an Illumina HiSeq 2500 or an Illumina NovaSeq 6000 SP using 2x150 bp settings. ctDNA positivity was defined by samples harboring high ctDNA aneuploidy as measured by a modified ichorCNA algorithm, or samples harboring low ctDNA aneuploidy but displaying AR gain or genomic structural rearrangement (AR-GSR), MYC/MYCN gain, or a pathogenic mutation. We used the AR-ctDETECT assay to analyze plasma collected at baseline from 776 patients, and found that 59% were ctDNA-positive. Patients who were ctDNA-positive at baseline had significantly worse median overall survival than patients who were ctDNA-negative at baseline. We also used the AR-ctDETECT assay to analyze plasma collected at progression from 431 patients. Relative to baseline cfDNA, progression cfDNA exhibited enrichment of features associated with poor prognosis, including elevated cfDNA concentrations and increased ctDNA positivity. AR alterations were enriched at progression relative to baseline, primarily driven by AR-GSRs, including those predicted to truncate the AR ligand binding domain and originate from AR amplification on extrachromosomal DNA. Stratification by radiographic progression-free survival revealed that patients with rapid progression were enriched for non-AR gene alterations, while patients with initially durable responses showed selective enrichment of AR alterations. These results indicate that non-AR genetic alterations in ctDNA are associated with primary resistance to AR pathway inhibitors in first-line mCRPC, while AR alterations are associated with secondary resistance, even in patients who initially respond. .

  Study phs003325

• Trisomy 21 Dosage Compensation Map (T21DoCoMap)

  Excess gene dosage from human chromosome 21 (HSA21), due to trisomy or translocation of HSA21 material, causes Down syndrome (DS). We derived trisomy 21 (T21) induced pluripotent stem cells (iPSCs) alongside otherwise isogenic euploid controls from mosaic DS fibroblasts (GM00260, first described in Lubiniecki et al., PMID: 225951) of the NIGMS genetic cell repository, to enable analysis of whole-chromosomal and individual gene dosage imbalance in the context of in vitro models of DS development. Virtual karyotyping (by Infinium CytoSNP-850k), and phased genotyping (by linked-read whole-genome sequencing) of the resulting iPSC lines provide a deeply-characterized genomic platform for dissection of HSA21 gene dosage. We apply this highly unique resource to allelic analysis of mRNA sequencing of iPSCs and differentiated neural lineages, and demonstrate its utility in the context of inducible HSA21 dosage compensation. To this end, we equipped one distinct HSA21 copy with a doxycycline-inducible XIST transgene, which endogenously silences one X in 46,XX females. Standard and allele-specific RNA-seq analysis confirms mono-allelic T21 silencing to be virtually complete and irreversible, further supported by DNA methylation data (Infinium methylEPIC). This full-length HSA21 map of phased single-nucleotide and insertion/deletion variants enables allele-specific applications for gene-level dissection T21 dosage effects. Because our XIST remains inducible in post-mitotic T21 neurons and astrocytes, we perform single-nuclei RNA-seq to demonstrate XIST efficiently represses genes even after terminal differentiation.

  Study phs002397

• Temptation Resistance Failures: Transdiagnostic Features and Influences

  Multiple forms of psychopathology involve problems with resisting temptations and urges. This study utilizes experience sampling (ES) methodology to assess temptation resistance across different classes of temptations and urges including both common everyday temptations and more disorder-specific temptation classes. The study tests the hypothesis that the broad ability to successfully resist temptations and urges across temptation classes is a common features of the externalizing superspectrum (factor) of psychopathology, particularly the disinhibition spectra as defined by the Hierarchical Taxonomy of Psychopathology (HiTOP). Additional associations are expected to arise between reduced temptation resistance success for specific temptation classes and narrower symptom domains associated with the externalizing and internalizing spectra (e.g., binge eating, and nonsuicidal self-harm among internalizing symptoms). The study further tests genetic and environmental influences on temptation strength and resistance ability with a focus on polygenic scores, adverse childhood experiences and childhood neighborhood deprivation variables that have previously been related to externalizing. To address these issues, we will study up to 1200 subjects (minimum 1000) selected with enrichment for psychopathology. Subjects will be recruited from a combination of ResearchMatch, and targeted contact with Reddit groups, and targeted social media/online advertisements, with targeted recruitment of at least 150 subjects who indicate problems with SUD, alcohol use disorder (AUD) or nicotine dependence, 70 who indicate problems with gambling or other impulse control problems, 70 subjects with criminal/legal problems, and 70 subjects based on binge eating episodes 70 with self-injurious behavior, and 70 with obsessive-compulsive disorder. Subjects will complete the (Externalizing Spectrum Inventory-BF and HiTOP-SR) to measure externalizing and internalizing spectra. Diagnoses in key categories will be confirmed with structured diagnostic interviews. Subjects also complete information on childhood adversity and geocoding is used to assess environment during development. The two-week ES regimen collects data on the strongest types of temptations and urges experienced by the subject, their subjective strength, the goal of the urge (pleasure/relief from negative feelings), the level of conflict with other goals, whether the person attempted to resist the temptation, the resistance strategy, and resistance success, to allow assessment of the extent to which differences in each of these facets (and calculated temptation resistance efficacy) are related to narrow or broad dimensions of psychopathology. Whole genome sequencing with .5x coverage and imputation will be performed to allow generation of polygenic scores for externalizing and addiction in order to test the hypothesis that externalizing polygenic scores are related to poor temptation resistance efficacy across temptation classes.

  Study phs004064

• Cardiovascular Health Study (CHS-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. Related Studies having other CHS data available include:phs003639.v1.p1 Cardiovascular Health Study (CHS) – Imagingphs003637.v1.p1 Sleep Heart Health Study (SHHS-BioLINCC)phs001368.v4.p2 NHLBI TOPMed: Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Project: Cardiovascular Health Studyphs000287.v7.p1 Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults 65 years or olderphs000667.v4.p1 Building on GWAS for NHLBI-Diseases: The U.S. CHARGE Consortium - Sequencing (CHARGE-S): CHSphs000400.v6.p1 NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (CHS)phs000377.v6.p1 NHLBI Cardiovascular Health Study (CHS) Candidate Gene Association Resource (CARe)phs000301.v6.p1 PAGE: CALiCo: Cardiovascular Health Study (CHS)phs000226.v7.p1 STAMPEED: Cardiovascular Health Study (CHS)Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from CHS include EDTA Plasma, Citrated Plasma, Serum, 2 Hour Serum, DNA, and Urine. Please note that use of biospecimens in genetic research is subject to a tiered consent.Available Data: The CHS-BioLINCC data package includes follow-up data through year 35, events data through 6/30/2015, and many ancillary studies.Objectives: The Cardiovascular Health Study (CHS) is a study of risk factors for development and progression of CHD and stroke in people aged 65 years and older. The objectives of the Cardiovascular Health Study are to: 1) quantify associations of conventional and hypothesized risk factors with CHD and stroke; 2) assess the associations of non-invasive measures of subclinical disease with the incidence of CHD and stroke; 3) quantify the associations of risk factors with subclinical disease; 4) characterize the natural history of CHD and stroke, and identify factors associated with clinical course; and 5) describe the prevalence and distributions of risk factors, non-invasive measures of subclinical disease, and clinical CHD and stroke.Background: The study originated in 1988 from the recommendations of an NHLBI workshop on the management of CHD in the elderly. This is the most extensive study undertaken by the NHLBI to study CVD exclusively in an elderly population. Initially funded for six years, CHS was renewed multiple times for additional examinations and continued morbidity and mortality follow-up.Participants: The 5,888 study participants were recruited from four U.S. communities and have undergone extensive clinic examinations for evaluation of markers of subclinical cardiovascular disease. The original cohort totaled 5,201 participants. A new cohort was recruited in 1992. The 687 participants in the new cohort are predominately African-American and were recruited at three of the four field centers.Design: The 2,962 women and 2,239 men were examined yearly from 1989 through 1999. The added minority cohort of 256 men and 431 women was examined from 1992 to 1999. Examination components have included medical history questionnaires, measurement of ankle-brachial index, abdominal and carotid ultrasound studies, echocardiograms, ambulatory electrocardiograms, cerebral magnetic resonance imaging, spirometry and retinal photographs over the past decade. The most extensive evaluations were at study entry (baseline) and again in 1992-1993 to assess change in subclinical disease measures. CHS has undertaken extensive follow-up for ascertainment of cardiovascular events including incident claudication, myocardial infarction, congestive heart failure, stroke and death.

  Study phs004879

• Pharmacogenomics and Pharmacometabolomics of Acamprosate Treatment Outcome

  Design and aims:The overarching goal of the study was to identify genetic markers associated with response to acamprosate treatment of alcohol use disorder (AUD). Specifically, the study aimed to enroll patients with AUD and randomize them to acamprosate or placebo treatment to allow identification of genetic markers associated with treatment outcomes, including acamprosate-specific pharmacogenomic effects. Genome-wide association analyses were completed using the newly collected data; subsequently, meta-analyses were performed to combine the new data with data from a prior genome-wide association study (GWAS) of AUD treatment outcomes that included the Mayo Clinic Center for Individualized Treatment of Addiction (CITA1) study, the COMBINE study and the PREDICT study (Biernacka et al., Neuropsychopharmacology, 2021). Here, the newly collected sample is referred to as CITA2. For CITA2, participants with AUD were recruited from Mayo Clinic sites in Rochester, MN and Albert Lea, MN (Fountain Center Residential Treatment Program), as well as Hazelden-Betty Ford affiliated treatment facilities in Center City, MN and Newberg, OR. Participants with comorbid depression and/or anxiety were treated with escitalopram or other SSRIs. Participants were randomized to acamprosate vs. placebo treatment, using stratified randomization within sites and within antidepressant (vs. no antidepressant) groups. Study participants and clinical personnel remained blinded to acamprosate or placebo assignment. Participants were evaluated by Psychiatric Research Interview for Substance and Mental Disorders (PRISM) at baseline to confirm alcohol use disorder diagnosis, and no secondary diagnosis of active other substance use disorder was present. Additional testing was done to rule out subjects with renal impairment or advanced liver disease. Participants were required to be willing to stop chronic/daily use of prescribed benzodiazepines, opioids, stimulants, cannabis related medication such as CBD or medical marijuana during participation. Review of medications including anti-depressants was done. Alcohol consumption was assessed by Timeline Follow Back (TLFB) at baseline and 1, 2 and 3 months during treatment. Treatment outcomes were derived from TLFB data and included continuous sobriety (yes/no) during 3 months of treatment, as well as the number of days until first alcohol use, the number of days until first relapse (≥ 5 drinks/day for men and ≥ 4 drinks/day for women) , and cumulative abstinence duration proportion, defined as the proportion of days over the length of follow-up during which a participant was completely abstinent from alcohol use.Population information: The total number of subjects that consented for the study was 379, with 288 randomized to acamprosate or placebo.Molecular Technologies: DNA was extracted and genotyping was performed using the Illumina Infinium Global Diversity Array. Principal Findings: Genome-wide association analyses were performed for time until relapse to any drinking ("time until relapse"), and time until relapse to heavy drinking ("time until heavy relapse") across all treatment groups. The analyses of the newly collected (CITA2) data identified no genome-wide significant associations with time until relapse or time until heavy relapse. Meta-analyses with data previously analyzed in Biernacka et al. (Neuropsychopharmacology, 2021) also did not identify significant associations with time until relapse or time until heavy relapse in the primary analyses. Data available: Genome-wide genetic data for participants recruited for this study will be available in dbGaP, along with demographic data and AUD treatment outcomes data.

  Study phs004068

• Epigenetic Control of Topoisomerase 1 by MacroH2A1.1

  DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic single-stranded DNA lesions (SSLs). What protects the genome from aberrant TOP1 activity remains unknown. Using a combination of CUT&RUN and TOP1 Covalent Adduct Detection (CAD) Seq in MDA-MB-231 breast cancer cells (American Type Culture Collection, ATCC), we identified chromatin context as an essential means to ensure TOP1cc resolution at TOP1 hot spots. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. MacroH2A1 isoform-specific analyses were based on reconstitution of macroH2A1.1 knockout cells with wild-type or PAR binding-deficient FLAG-tagged macroH2A1.1 in human breast cancer cells. Mechanistically, we find that macroH2A1.1 facilitates the recruitment of the TOP1cc repair factor XRCC1 in response to both endogenous and drug-induced topological stress. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect in breast and ovarian cancer cells. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors (TOP1i). We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

  Study phs003729

• Genomic Landscape of Apical Periodontitis

  We undertook the first genome-wide association (GWAS) study of apical periodontitis, enrolling 932 patients with deep carious lesions at UTHealth School of Dentistry and the University of Pittsburgh School of Dental Medicine. We used a case-control design to compare those with apical periodontitis to those without. Genotype data was generated for all participants and imputed using the TOPMed reference panel. We performed a single-variant association testing, a subphenotype analysis, and a genetically regulated expression association analysis, and generated a polygenic risk score and performed phenome-wide association analysis. We identified eight near-genome-wide significant loci for our primary outcome, eight genes where genetically regulated expression was associated with apical periodontitis status, and 33 phecodes that were associated with the generated polygenic risk score. We also replicated three loci previously reported in the literature. Genotype, phenotype, and results from the primary association analysis will be available via dbGaP.

  Study phs003252

• Combined Genomic and Phenotypic Classification of Inherited and Acquired Genetic Disease with Long-Read Sequencing

  This study investigates the use of paired long read genetic and epigenetic sequencing in cell type deconvolution and the identification of cellular pathologies with absent or expanded populations. The data submitted to dbGaP contains sequencing read data generated by the pooling of samples from healthy individuals, sorting by flow cytometry into the key leukocyte populations of monocytes, CD4 T cells, CD8 T cells, NK cells, B cells, in addition to primary neutrophils acquired commercially, and sequencing by a PromethION sequencer (Oxford Nanopore Technologies). This allowed for the generation of data for both purified cell populations, as well as in silico synthetic mixture of defined compositions for evaluating epigenetic methods for cell type deconvolution.

  Study phs004480

• Pilot Study of Genetic Alterations and Clonal Evolution of Relapsed Refractory Adult ALL in Patients Receiving KTE-X19 CAR-T in ZUMA-3 (ZUMA3 Sequencing)

  This study is from the ZUMA-3 Phase 1/2 study of adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Patients were treated with KTE-X19, an autologous anti-CD19 CAR T-cell therapy under investigation.

  Study phs002721