3613 results for "*geneti*"

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• Blood Group Genotypes and Phenotypes in Omani Blood Donors and Its Links With Susceptibility to Malaria

  The Omani population experienced endemic malaria prior to eradication in the late 1990's. Since malaria is known to be a strong selective pressure on the human genome, particularly at blood group associated loci, we aimed to understand how selective pressures from malaria may be affecting genetic variation at blood group loci. Blood samples were collected from 100 healthy, Omani blood donors. Serology testing for 10 clinically relevant blood groups and whole genome sequencing (WGS) to an average coverage of 16X were performed on all samples. Additionally, using the WGS data, genetic variants (SNPs and INDELs) were called for chromosomes 1 - 22 using GRCh38. We find signals of selection at the Plasmodium vivax associated locus, ACKR1 (the Duffy blood group), but not at any Plasmodium falciparum associated loci. We also characterized several previously undescribed blood group alleles in the Omani population affecting antigenic expression, mostly at the RHD, RHCE, and GYPB loci. The data available from this project include BAM files from 100 Omani samples aligned to GRCh38, per chromosome VCF files, and results from the serology tests for all 10 blood groups.

  Study phs003694

• Immunogenetics of BCG Vaccination and Pediatric Tuberculosis

  We examined genetic variation associated with BCG-induced innate immune responses and susceptibility to pediatric tuberculosis (TB) disease. South African study participants were enrolled at the South African Tuberculosis Vaccine Initiative (SATVI) as part of a larger BCG vaccination study. This area has one of the highest rates of TB incidence in the world. Infants were vaccinated with BCG at birth, and a nested case-control study was performed over a 2-year prospective observation period, which resulted in 135 infant TB cases and 521 controls. Whole blood was collected from BCG vaccinated infants at 10 weeks of age. Genotyping was performed with the llumina MegaEx Beadchip, and GWAS was performed against TB disease to assess for associations between genetic variants and susceptibility to TB. In addition, a subset of infants were assessed for BCG-induced innate immune responses (N=198). For these, whole blood was stimulated with BCG or media and flow cytometry was used to measure BCG-induced PDL1, CD40, and cytokine expression in myeloid (mDC) and plasmacytoid (pDC) dendritic cells, monocytes, and neutrophils. Cellular GWAS was then performed to associate genetic variants with BCG-induced immune responses.

  Study phs003406

• Heterogeneity in Lysosomal Storage Disorders

  Gaucher disease (GD) is an inherited lysosomal storage disorder caused by biallelic pathogenic variants in GBA1, which encodes glucocerebrosidase. Additionally, GBA1 variants are a well-established genetic risk factor for Parkinson's disease (PD), leading some PD research centers to incorporate GBA1 screening to identify patients who may benefit from targeted therapeutics. However, detecting GBA1 variants remains challenging due to the gene's high sequence homology with its pseudogene, which can give rise to complex recombinant alleles. This study evaluates the performance of Gauchian, a recently developed software tool for identifying GBA1 variants from whole genome sequencing (WGS) data. The assessment was conducted in a cohort of 90 individuals with GD and five GBA1 heterozygotes, all previously characterized through Sanger sequencing. While Gauchian successfully identified the most common genotypes, it demonstrated limitations in detecting rare or de novo variants due to its restricted internal database and heavy reliance on intergenic structural variants. These limitations led to misclassified homozygosity, incomplete genotyping, and undetected recombination events, ultimately reducing the tool's utility for comprehensive variant screening and precluding its application in diagnostic settings. The study dataset includes WGS from the 90 individuals used in the Gauchian pipeline. This data will be available through dbGaP to facilitate further research on GBA1 variant detection, genotype-phenotype correlations in GD and PD, and the development of improved bioinformatics tools for complex variant identification.

  Study phs003459

• Preclinical In Vitro Studies of Prenatal Treatment of Down Syndrome to Improve Brain Development and Neurocognition

  Down syndrome results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. There are no effective treatments for Down syndrome that improve brain development and neurocognition. Altered brain development occurs before birth in Down syndrome, which suggests that the optimal time to initiate therapeutic treatment is during prenatal development. In this study, neural progenitor cell (NPC) cultures were derived from induced pluripotent stem cells (iPSCs), to provide an in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the ability of pharmacological interventions to alleviate these effects. Gene expression was examined using bulk RNA-Seq in untreated T21 and euploid (control) NPCs and in NPCs treated with the candidate therapeutic molecules fasudil, apigenin, epigallocatechin-3-gallate (EGCG), isoxsuprine, and sphingosine. The results showed that the Rho-associated coiled-coil kinase (ROCK) inhibitor fasudil significantly downregulated expression of inflammatory pathway genes in T21 NPCs, of relevance because elevated inflammatory pathways are present in T21 and may contribute to deleterious phenotypes. Data available through dbGaP include five bulk RNA-Seq datasets from euploid and T21 NPC treated with the five molecules listed above, along with untreated euploid and T21 NPCs. Global protein expression data and phosphoproteomic profile data summary files, generated by tandem mass tag (TMT) mass spectrometry, are also available from untreated euploid and T21 iPSCs and NPCs.

  Study phs004455

• Kids First: Hear-'n-Seq Sequencing for Hearing

  One in 100 children will lose significant hearing by school age with hearing loss of 40 decibels or more, making hearing loss one of the single most common structural defects affecting the pediatric population. Hearing loss can affect a child's ability to develop speech, language, cognitive and social skills. The earlier a child with hearing loss starts receiving appropriate medical and educational services, the more likely they are to reach their full potential. More than half of early hearing loss is due to genetic factors. Approximately 1 in 500 babies is born with hearing loss. While the majority of prelingual hearing loss is nonsyndromic, over 400 syndromes have been described that have hearing impairment as a component. It is critically important to identify the etiology of hearing loss for many reasons, as there may be important health surveillance implications particularly with syndromic causes. Genetic testing is available for congenital hearing loss, but the current standard of care is by no means comprehensive because: 1) many types of genetic variants in known hearing loss genes are not detectable by clinical testing, and 2) it is estimated that more than 100 hearing loss genes are as yet unknown. With this proposal, called Hear-'n-SEQ, we will leverage the resources of the NIH Common Fund's Gabriella Miller Kids First Pediatric Research program to "seek-out" the genetic etiology of childhood hearing loss through comprehensive phenotypic and genomic analyses in an international cohort of hearing impaired patients. By sharing both the clinical and sequence data with the pediatric research community we will be empowered to identify genetic pathways that underlie hearing loss as well as pathways shared with other pediatric conditions. This project will be coordinated through the Harvard Medical School Center for Hereditary Deafness (HMSCHD). The Specific Aims of the project are to: (1) build an international consortium to identify and collect well-curated patient clinical information and DNA samples from children with hearing loss and their parents (trios) or carefully selected multiple affected individuals based on the pedigree structure, (2) submit appropriate DNA samples for whole genome sequencing at an NIH-supported sequencing center, and, (3) identify the genetic etiology of hearing impairment in individuals where possible, and integrate the data collectively into a shared data resource. Because of the tremendous genetic heterogeneity inherent in hearing loss, the proposed international collaboration will produce a maximum yield of diverse genetic causes, as it has been well established that different populations segregate distinct concentrations of hearing loss alleles. Therefore we will sample the hearing impaired pediatric populations of parts of Asia (Hong Kong), the Middle East (Turkey), and the US (individuals of European, African American, Central American and Caribbean descent). In addition to identifying novel etiologies for hearing loss, ultimately this work is designed to help create a pipeline for routinely integrating genomic sequencing into clinical diagnostics, generating more refined diagnostic capabilities, and ultimately more targeted therapies or interventions for children with hearing loss.

  Study phs002115

• The Genetic Landscape of Familial Pulmonary Fibrosis

  This dataset was collected from a study that was designed to identify disease-causing rare genetic variants in individuals with Familial Interstitial Pneumonia (FIP). Subjects were identified from our ongoing FIP Registry (IRB #020343), where FIP is defined as idiopathic interstitial lung disease (ILD) in two or more family members with at least one affected individual diagnosed with idiopathic pulmonary fibrosis (IPF). Whole exome sequencing was performed on ~600 affected members from 525 kindreds using genomic DNA isolated from peripheral blood.

  Study phs003750

• Direct Transposition of Native DNA for Sensitive Multimodal Single-Molecule Sequencing

  STUDY GOALS: This study focuses on elucidating the epigenetic modulators of prostate cancer progression and metastasis at high resolution. This is achieved by applying a novel, high-sensitivity single molecule sequencing assay that measures chromatin state on single DNA molecules (SMRT-Tag) to matched primary and metastatic tumor samples from the same patient. Samples are obtained from patient derived xenograft (PDX) models. STUDY DESIGN: Individuals diagnosed with primary and metastatic prostate cancer in the course of routine care were consented and enrolled, and biopsies of primary and/or metastatic lesions performed to obtain sample material used for generating PDX models. Samples collected from these models were processed with a novel strategy developed for highly-sensitive multimodal profiling of single chromatin fibers using the third generation long-read sequencing. The resulting data indicates genetic variants, chromatin organization, and m5dCpG methylation status across the genome. PRINCIPLE FINDINGS: We determined characteristic single-molecule patterns of chromatin organization (spacing of nucleosomes, presence and absence of m5dCpG marks, etc.) that were altered in the transition from primary malignancy to metastasis. Broadly, global chromatin organization was severely disrupted in metastatic samples, resulting in increased accessibility at CTCF motifs, which may be relevant for disease progression. We further identified specific genomic domains including constitutive heterochromatin significantly enriched for irregular or hyper-accessible chromatin. Together, these findings suggest the involvement of ATP-dependent chromatin remodelers in evicting nucleosomes as a facet of metastatic prostate cancer. DATA AVAILABILITY: SAMOSA-Tag, the assay used in this study, is a sequencing assay that uses the third generation long read sequencing, specifically the SMRT sequencing platform from Pacific Biosciences. Demultiplexed raw SMRT sequencing BAM files generated in this study are deposited. Individual raw subread BAM files correspond to replicate sequencing assays performed on either primary or metastatic PDX prostate tumors.

  Study phs003511

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Prevent Pulmonary Fibrosis (PrePF)

  Cohort Description Prevent Pulmonary Fibrosis (PrePF) has been investigating the clinical, physiologic and genetic phenotypes of interstitial lung disease (ILD) by focusing on families with two or more cases of ILD and individuals with sporadic IPF. It has recruited over 1,200 families with two or more cases of pulmonary fibrosis. These families with pulmonary fibrosis include 2,837 individuals with probable or definite idiopathic interstitial pneumonia (IIP) and 2,404 unaffected FDRs. In addition, PrePF recruited over 10,000 individuals with sporadic idiopathic pulmonary fibrosis (IPF). Data Being Submitted Wave 1 questionnaire data includes 397 variables for up to 585 PrePF participants in C4R Wave 2 questionnaire data includes 448 variables for up to 370 PrePF participants in C4R Dried Blood Spot/Serosurvey data includes 7 variables for up to 206 PrePF participants in C4R Derived data includes 43 variables for up to 585 PrePF participants in C4R Phenotype data includes 113 variables for up to 585 PrePF participants in C4R

  Study phs002975

• The Effects of Long-Term Heavy Metal Exposure on Transcriptome Landscape in Human Peripheral Blood Cells

  The present study investigates the impact of long-term residence in a mining area on transcriptome changes induced by heavy metal exposure in human peripheral blood mononuclear cells (PBMCs) from 65 healthy subjects selected from the general population. This study includes the same participants which were recruited in our previous investigation on heavy metal long-term environmental exposure-related gene-specific methylation changes (phs003392.v1.p1). We performed a differential expression analysis to compare the mRNA transcriptome of 31 residents from the mining region (MRR) - individuals living in the Kapan mining area with reported environmental exposures to heavy metals - with that of 34 residents from non-mining regions (NMR) - individuals residing at a considerable distance from mining locations. We also evaluated the potential association of gene expression profiles with the blood metallome, including levels of Ca, Mg, Co, Fe, Mn, Cu, Mo, Se, Zn, As, Sb, Tl, Be, V, Ni. Poly-A selected strand-specific mRNA library was prepared with Illumina Stranded mRNA Prep kit. The sequencing was performed on the Illumina NovaSeq-6000 platform with 38.5 million single-end 100 bp reads on average generated per sample. Quality checking of the sequencing data was performed using Illumina Basespace reports and the program FastQC (V0.10.1). Reads were aligned against the Human Genome Hg38 using STAR (version 2.7.1a). According to our findings, long-term residence in a mining area is correlated with alterations in the blood transcriptome, with responses varying by sex. Pathway analysis revealed upregulation of immune response related pathways, and downregulation of translation and ribosome biogenesis in the PBMCs of the MRR. Pathways related to metal ion transmembrane transport, epigenetic modifications (histone deacetylases (HDACs) and DNA methylation) were upregulated in males, while in females mostly transcripts involved in inflammation and cytokine mediated signaling were upregulated. Additionally, among the dysregulated pathways, the TNF-α signaling via NF-κB showed opposite changes in females and males.

  Study phs003657

• Understanding Determinants of Racial Disparities in Lung Cancer Incidence

  This is a nested case-control study designed to evaluate the association between common genetic variants and the risk of lung cancer. The study included 1258 cases and 1252 controls selected from the Southern Community Cohort Study (SCCS), a large, prospective observational cohort. Cases were identified from cancer registries across the catchment area of the SCCS. Cases and controls were frequency matched on age, sex, race, and enrollment site (community health center vs general population).

  Study phs003789