3854 results for "*geneti*"

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• Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

  We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway and re-expression of epigenetically silenced endogenous retrovirus. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.

  Study phs001038

• Autopsy-Confirmed Parkinson Disease GWAS Consortium (APDGC)

  The APDGC was formed to conduct a genome-wide association study in individuals with neuropathologically confirmed Parkinson Disease (PD) and neuropathologically normal controls. The rationale for the study is that including only cases and controls with neuropathologically confirmed disease status will reduce diagnostic misclassification and increase power to detect novel genetic associations.

  Study phs000394

• Xeroderma Pigmentosum, Complementation Group C, (XPC) and Non-XPC Cutaneous Squamous Cell Carcinoma (cSCC) Mutation Rate Study

  Base mutations occur at higher frequencies within heterochromatin and late-replicating DNA. In this study, we show that regional differences in mutation frequency are absent in portions of the genome that are not transcribed within cutaneous squamous cell carcinomas (cSCCs) with an XPC-\- genetic background. The XPC-\- genetic background predicates a loss of global genome nucleotide excision repair (GG-NER), thus our data shows that regional differences in mutation frequency are a result of differential access of DNA repair protein. Unexpectedly, we also note that greater transcription reduces mutations on both strands of genes in heterochromatin, and only to those levels observed in euchromatin, in a XPC-dependent fashion. Therefore, transcription likely reduces mutation prevalence by increasing access to DNA repair proteins. This tripartite relationship between DNA repair, transcription, and chromatin state shows a new cancer risk factor in human populations.

  Study phs000830

• The Genetics of Lung Cancer Susceptibility in Smokers

  Over 85% of all patients diagnosed with lung cancer report a history of tobacco use, though only 10% of tobacco smokers eventually develop lung cancer. Epidemiologic studies have shown that family members of patients with lung cancer have a higher risk of developing lung cancer than controls. In an effort to identify variants associated with tobacco induced lung cancer, we have sequenced germline DNA from affected and unaffected members of families with strong histories of tobacco related lung cancer.

  Study phs000728

• PsychENCODE Consortium: Epigenetic and Transcriptional Dysregulation in Autism Spectrum

  Our current understanding of autism spectrum disorders (ASD) delineates a highly heritable, yet etiologically heterogeneous disease. Forward genetic approaches to find disease associated mutations or common variation have been successful and continue to offer considerable power. Yet, given the accumulating evidence for very significant heterogeneity and environmental influences, complementary approaches to classic forward genetics become necessary. Genetic polymorphism and mutation data to date have identified dozens of causal or contributory variants, yet our preliminary data from autism brain suggest that common molecular pathways are involved in a significant subset of cases. This convergence at the tissue level suggests that other mechanisms, specifically epigenetic changes, combined with genetic background, are contributing to such final common pathways. We further tested this hypothesis by taking a comprehensive and integrative genome-wide approach to assessing brain gene-expression, miRNA levels and the related, causal epigenetic mechanisms in ASD etiology. We performed RNA-seq analyses of four cerebral cortical regions and cerebellum from ASD cases and controls, to assess mRNA, miRNA, and splicing isoform regulation. In parallel, we identified key differences in chromatin state and DNA methylation across multiple brain regions in the same ASD and control individuals used in the expression analyses using ChIP-Seq and MeDIP. We assessed the mechanisms by which changes in DNA methylation, histone modification, and DNA sequence contribute to the observed differences in gene expression. This work, which represents an unprecedented effort to unify these often disparate data (usually produced without integration in mind), delineates potential shared molecular pathways in ASD and the underlying mechanism of these differences at the level of miRNA, the chromatin regulatory apparatus, and DNA methylation. The following substudies are part of the PsychENCODE release at dbGaP and offer additional molecular data: PsychENCODE: RNA-Sequencing - SRRM4 Splicing Study phs000872 PsychENCODE: Global Changes in Patterning, Splicing and lncRNAs phs001061 PsychENCODE: Chromatin Contact Map in Fetal Cortical Laminae phs001190 PsychENCODE: Epigenetic Dysregulation in Autism Spectrum Disorder phs001220

  Study phs001022

• Genetic contributions of lupus nephritis in a multi-ethnic cohort of systemic lupus erythematosus (SLE)

  Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) and it occurs at a much higher rate in patients that are not of European descent. The purpose of this study is to identify genetic variants contributing to the risk of LN in a multi-ethnic cohort of SLE patients. We used a comprehensive genome-wide screen and 1244 SLE patients from 5 different ethnic groups. In genome-wide gene-based and candidate SNP analyses, we found distinct genes and pathways, and established risk SNPs associated with lupus nephritis for each ethnic group. This study represents progress in elucidating the genetic underpinnings driving LN among SLE patients of different ethnic groups.

  Study phs001609

• Epigenetic Profiling of Human Colorectal Cancer

  DNA methylation, together with chromatin modifications, constitute the epigenome that functions to regulate gene expression and genome integrity. DNA methylation alterations are ubiquitous in human cancers, as many genes acquire DNA methylation in a cancer-specific manner. DNA methylation at these sites in the genome of cancer cells not only serves as a marker for tumor identification, but together with gene mutation and gene expression data, can also be used to describe subsets of tumors of the same organ source. We have previously shown distinct human colorectal cancer subtypes based on DNA methylation differences. Correlating these DNA methylation differences with clinical co-variates will serve to further understand how these distinct subtypes are generated. We have collected 100 colorectal tumor tissues (for which clinical information is known) and have obtained (unprotected) genome-wide DNA methylation and chromatin modification information for each sample for the purposes of identifying and classifying unique tumor subtypes of colorectal cancers. In addition, we have determined mutations of key genes relevant to colorectal cancer as well as gene expression profiles. We will use the clinical data for each de-identified sample to correlate with the DNA methylation, mutation and gene expression information so as to understand the driving forces behind these distinct colorectal subtypes. We have selected the most promising tumors for whole-genome bisulfite sequencing using next-generation sequencing technology to obtain complete maps of colon cancer methylomes. Researchers will be unable to identify the subjects because the samples and associated information have been de-identified and anonymized by the tissue source site. In addition, upon receipt by the USC Epigenome Center, we have assigned new random identifiers for each sample. The data generated using these new codes are not traceable to the patient identity.

  Study phs000385

• Genome-Wide Pleiotropy Scan Across Multiple Cancers

  A whole-exome sequencing (WES) study was conducted in 3,233 cases diagnosed with multiple primary cancers and 3,229 matched cancer-free controls (90% non-Hispanic white, 3% African-American, 3% East Asian, and 4% Latino) selected from individuals in the Kaiser Permanente Research Bank (KPRB) who were members of the Kaiser Permanente Northern California (KPNC) health plan. Cancer-free controls were matched to cases on age at specimen collection (within 2 years), sex, genotyping array (which matched on self-reported race/ethnicity), closest distance using the first two principal components for genetic ancestry, and reagent kit. Cases and controls were drawn from two prospective KPRB cohorts: the Research Program on Genes, Environment and Health (RPGEH) and the ProHealth study. Participants were sequenced by the Regeneron Genetics Center using the Illumina NovaSeq 6000 platform, and sample preparation and quality control were performed using a high-throughput, fully-automated system [PMID: 33087929]. Reads were aligned to the GRCh38 reference genome, and variants were called using WeCall [PMID: 33087929]. Participants with sex discordance, 20x coverage at less than 80% of targeted sites, and/or contamination greater than 5% were excluded. After quality control, we retained n = 6,247 (3,111 cases, 3,136 controls) individuals for downstream analyses. Among participants selected for this WES study, n = 5,432 (2,299 cases; 3,133 controls) consented to deposition of data to the National Institutes of Health (NIH).Further quality control was applied to filter low quality variants. Genotype calls with low depth of coverage (DP) were updated to missing (DP < 7 for SNPs and DP < 10 for indels), after which sites with low allele balance (AB) - variants without at least one sample having AB ≥ 15% for SNPs or AB ≥ 20% for indels - were removed. Lastly, variants with missingness > 10% and Hardy-Weinberg equilibrium p-value < 10-15 were excluded. Further description of quality control and downstream single-variant and gene-based analyses is available in Cavazos et al, 2022 [medRxiv].

  Study phs002809

• Integration of Genomics and Transcriptomics in unselected Twins and in Major Depression

  Our goals are to develop a comprehensive understanding of the genomics of transcription in a population based unselected sample and to discover DNA and RNA biomarkers for major depressive disorder (MDD). This work is essential to developing a more complete understanding of the biological basis of MDD, a common complex trait associated with considerable morbidity, mortality, and personal/societal cost. All biological samples have been collected from well-defined populations, and are now available. First, we conduct a "genetical genomics" or eQTL study of ~800 MZ and ~800DZ twin pairs. Each subject has been assayed for genome-wide SNPs and CNVs and gene expression from peripheral blood sampled under standardized conditions. We determine the genetic architecture (genetic and non-genetic proportions of variance via twin analyses) for every transcript, and the genome-wide associations (i.e., SNP-transcript eQTL pairs). These analyses will be expanded to consider transcriptional modules. The key deliverable is a detailed catalogue of the general and specific architecture of transcription plus raw intensity files. Second, we seek to discover DNA and RNA biomarkers relevant to MDD, capitalizing on the results of a large MDD study with repeated clinical and biological assessments; we have previously shown that PB is a reasonable proxy for CNS expression and employ an advanced modelling framework: (a) Using baseline data, we identify biomarkers for MDD by comparing ~1000 controls with ~1400 MDD cases via comparisons of SNP, CNV, expression transcripts, and transcriptional modules. (b) Using longitudinal data, we contrast gene expression signatures assessed at baseline and two years later in ~200 controls and ~500 MDD cases.

  Study phs000486

• Whole Exome Sequencing for Familial Intracranial Aneurysm (FIA I-II) Study

  The goal of this study is to identify the genes underlying the risk of intracranial aneurysm (IA). The FIA Study initially recruited families appropriate for linkage analysis. Therefore, the recruitment focus was not only on probands with a family history of IA but also required that biological samples be obtained for at least two affected family members. Family members underwent detailed interviews for medical, social and family history, and provided blood samples for DNA extraction. Over 400 multiplex IA families were recruited and enrolled. The whole exome sequencing project aims to identify novel and rare (in the general population) genetic variants that are enriched in seven extended multiplex families with a strong familial aggregation of intracranial aneurysms.

  Study phs000636