Search Results - EGA European Genome-Phenome Archive

De novo mutations in cell-free foetal DNA (cffDNA)

This project is to develop and validate a method to detect de novo mutations in a foetal genome through deep sequencing of cell-free DNA from the plasma of pregnant women. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Dataset EGAD00001000596

Cooperative activity of BRAF F595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling

Mutations that activate the RAF-MEK-ERK signaling pathway, in particular BRAFV600E, occur in many cancers, and mutant BRAF-selective inhibitors have clinical activity in these diseases. Activating BRAF alleles are usually considered to be mutually exclusive with mutant RAS, whereas inactivating mutations in the D594F595G596 motif of the BRAF activation segment can coexist with oncogenic RAS and cooperate via paradoxical MEK/ERK activation. We determined the functional consequences of a largely uncharacterized BRAF mutation, F595L, which was detected along with an HRASQ61R allele by clinical exome sequencing in a patient with histiocytic sarcoma and also occurs in epithelial cancers, melanoma, and neuroblastoma, and investigated its interaction with mutant RAS. We demonstrate that, unlike previously described DFG motif mutants, BRAFF595L is a gain-of-function variant with intermediate activity towards MEK that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling. Of immediate clinical relevance, BRAFF595L shows divergent responses to different mutant BRAF-selective inhibitors, whereas signaling driven by BRAFF595L with and without mutant RAS is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from primary patient samples and cell lines show that BRAFF595L, as well as other BRAF mutations with intermediate activity, frequently coincide with mutant RAS in a broad spectrum of cancers. These data define a novel class of activating BRAF mutations that cooperate with oncogenic RAS in a non-paradoxical fashion to achieve an optimal level of MEK-ERK signaling, extend the spectrum of patients with systemic histiocytic disorders and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway, and underscore the value of comprehensive genetic profiling for understanding the signaling requirements of individual cancers.

Dataset EGAD00001001384

Combined MEK and BCL-2/XL inhibition is effective in high-grade serous ovarian cancer patient-derived xenograft models and BIM levels are predictive of responsiveness

Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, thus making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft (PDX) models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the pro-apoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/XL inhibitor (ABT-263) significantly reduced cell number, increased cell death and displayed synergy in vitro in most models. In vivo, the GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive models – those with high BIM at baseline that was increased with MEK inhibition and those with low basal Bim and high pERK levels. Models with low BIM and low pERK were non-responsive. Our findings demonstrate that combined MEK and BCL-2/XL inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.

Dataset EGAD00001005111

MutWP1: CRUK Grand Challenge Mutographs of Cancer: Colorectal_LCM (2020-02-20)

The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development. . This dataset contains all the data available for this study on 2020-02-20.

Dataset EGAD00001005994

Longitudinal profiling of the immune response to Plasmodium vivax in naive hosts by RNA-sequencing

Plasmodium vivax offers unique challenges for control and elimination, and may prove a tougher hurdle to overcome than Plasmodium falciparum. And yet compared to P. falciparum we know very little about the innate and adaptive immune responses that need to be harnessed to reduce disease and transmission. We recently generated a blood bank of a new clonal field isolate of P. vivax (PvW1) for human challenge studies and used systems immunology tools to track the host response throughout infection and convalescence. As part of this study, RNA-sequencing was used to resolve changes in whole blood gene expression through time in 6 volunteers (7-9 time-points per volunteer). In summary, these data show that P. vivax induces two distinct transcriptional programmes in whole blood during and after infection. During infection, transcriptional profiling reveals the rapid mobilisation of an emergency myeloid response, which leads to systemic inflammation and the recruitment of all major T cell subsets into lymphoid tissues. Six days after infection, this innate response subsides and a transcriptional signature of proliferation is revealed. This most likely represents widespread activation of lymphocytes, which return to the circulation after parasite clearance - transcriptional profiling of T cells at this time-point could therefore reveal the outcomes of critical cell-cell interactions that take place within the spleen during infection. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ .

Dataset EGAD00001006924

Tracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing

Intratumoral heterogeneity (ITH) has been linked to decreased efficacy of clinical treatments. However, although genomic ITH has been characterized in genetic, transcriptomic and epigenetic alterations are hallmarks of esophageal squamous cell carcinoma (ESCC), the extent to which these are heterogeneous in ESCC has not been explored in a unified framework. Further, the extent to which tumor-infiltrated T lymphocytes (TILs) are directed against cancer cells, but how the immune infiltration acts as a selective force to shape the clonal evolution of ESCC is unclear. In this study, we perform multi-omic sequencing on 186 samples from 36 primary ESCC patients. Through multi-omics analyses, it is discovered that genomic, epigenomic, and transcriptomic ITH are underpinned by ongoing chromosomal instability. Based on the RNA-seq data, we observe diverse levels of immune infiltrate across different tumor sites from the same tumor. We reveal genetic mechanisms of neoantigen evasion under distinct selection pressure from the diverse immune microenvironment. Overall, our work offers an avenue of dissecting the complex contribution of the multi-omics level to the ITH in ESCC and thereby enhances the development of clinical therapy.

Dataset EGAD00001009482

The long term effects of chemotherapy on normal blood - Nanoseq dataset

In developed countries, ~10% of individuals are exposed to systemic chemotherapy for cancer and other diseases. Many chemotherapeutic agents act by increasing DNA damage in cancer cells, hence triggering cell death. However, there is limited understanding of the extent and consequences of collateral DNA damage to normal tissues. To investigate the impact of chemotherapy on mutation burdens and cell population structure of a normal tissue we sequenced blood cell genomes from 23 individuals, aged 3-80 years, treated with a range of chemotherapy regimens. Substantial additional mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but there were differences in burden between different classes of agent, different agents of the same class and different blood cell types. Chemotherapy also induced premature changes in the cell population structure of normal blood, similar to those of normal ageing. The results constitute an initial survey of the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed during the course of their disease management, raising mechanistic questions and highlighting opportunities for mitigation of adverse effects.

Dataset EGAD00001015340

Adipose transcriptome and plasma metabolome responses after a 6-day very-low energy fast in obesity: a single-arm feeding trial (FASTOMICS-6)

Background: Fasting and ketogenic diets have gained popularity due to potential health benefits, in part via autophagy and other protective processes. However, although the basic physiology of fasting is well-established, we lack a deeper understanding of mechanisms on the tissue level and associated metabolome changes, particularly in humans. Method: 4 males and 9 females with severe obesity underwent a very-low-energy in-hospital feeding study (600 kcal/day). Plasma (n=13) and subcutaneous adipose tissue (sAT) samples (n=12) were collected in the morning before and after 6 days and analysed by GC-MS/MS and RNA-sequencing, respectively. Gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis were used to identify biological pathways and modules of affected genes and their correlation with plasma ketones and metabolites.

Study EGAS50000001015

Genome-wide cell-free DNA biological patterns in patients with cancer

The structure of cell-free DNA (cfDNA) is altered in the blood of cancer patients. From whole genome sequencing we retrieved the cfDNA fragment-end composition using a new software (FrEIA), as well as the cfDNA size and tumor fraction in three independent cohorts (n=925 cancer from >10 types and 321 control samples). At 95% specificity, we detect 72% of cancer samples using at least one cfDNA measure, including 64% of early-stage cancer (n=220). cfDNA detection correlates with a shorter overall (p=0.018) and recurrence-free (p=0.006) survival in patients with resectable esophageal adenocarcinoma. Integrating cfDNA measures with machine learning in an independent test set (n=396 cancer, 90 controls) achieve a detection accuracy of 82% and AUROC of 96%. In conclusion, harnessing the biological features of cfDNA can improve at no-extra cost the diagnostic performance of liquid biopsies.

Study EGAS00001007400

RNA sequencing in primary inflammatory (TPP) macrophages following deletion of a disease-associated gene desert at chr21q22, disruption of ETS2, or treatment of ETS2-edited macrophages with a HIF1α stabiliser.

GWAS studies in five different inflammatory diseases have identified a strong genetic association at a gene desert at the chr21q22 locus. We have shown that this locus contains a monocyte/macrophage-specific enhancer that regulates ETS2 - a gene whose role in primary human monocytes/macrophages is incompletely understood. We therefore used a CRISPR-Cas9-based approach to delete the enhancer region or to disrupt ETS2, and performed RNA-sequencing to examine the transcriptional consequences. One effect of ETS2 disruption was upregulation of genes involved in aerobic respiration and oxidative phosphorylation. We therefore treated ETS2-edited inflammatory macrophages with roxadustat, a HIF1α stabiliser that can promote glycolysis via HIF1α-mediated metabolic reprogramming, and performed RNA-sequencing to determine whether this drug might rescue the transcriptional effects of ETS2 disruption.

Study EGAS00001007553

Impact of Respiratory Virus Infections and Bacterial Microbiome Shifts on Lymphocyte and Respiratory Function in Infants Born Prematurely or Full Term

Public health importance: Babies born preterm, approximately 1 out of every 9 live births in the United States, have significant respiratory morbidity over the first two years of life, exacerbated by respiratory viral infections. Many (<50%) return to pediatricians, emergency rooms and pulmonologists with symptoms of respiratory dysfunction (SRD): intermittent or chronic wheezing, poor growth and an excess of upper and lower respiratory tract infections (LRTI). SRD correlate inversely with gestational age and weight at birth and is more common in those with chronic lung disease of prematurity, yet its incidence and severity varies widely among both the prematurely born and those born at term. There is evidence from clinical studies and animal models that risks of LRTI and recurrent wheezing is influenced by gut and respiratory flora and by T cell responses to infection. Information gained from this study will be used to identify characteristics, risk factors and potential mechanisms for early and persistent lung disease in children born at term and born preterm. This Clinical Research Study will investigate the relationships between sequential respiratory viral infections, patterns of intestinal and respiratory bacterial colonization, and adaptive cellular immune phenotypes which are associated with increased susceptibility to respiratory infections and long term respiratory morbidity in preterm and full term infants. We hypothesize that the timing and acquisition of specific viral infections and bacterial species are directly related to respiratory morbidity in the first year of life as defined by SRD and by measures of pulmonary function. We hypothesize that cellular and molecular immuno-maturity are altered due to factors presented by premature birth in such a way as to promote chronic inflammatory and cytotoxic damage to the lung, with subsequent enhanced, damaging responses to infectious agents and environmental irritants. Our preliminary studies demonstrate both feasibility and expertise in mutiparameter immunophenotyping of small volume peripheral blood samples obtained from premature infants including gene expression arrays of flow cytometry sorted cells. We will use new technologies for known viral identification, as well as high-throughput metagenome sequencing of RNA and DNA virus like particles (VLP) to be used for viral discovery in infant respiratory sample and use of high-throughput pyrosequencing (454T) of bacterial 16S rRNA to determine shifts in bacterial community structure, occurring in pre-term (PT) as compared to full term (FT) infants, over the first year of life. Finally, we present statistical approaches to stratify disease risk predictors using multivariate logistic regression modeling approaches. We propose to evaluate T cell phenotypic and functional profiles relative to viral and predominant bacterial exposures according to highly complementary, but independent, Specific Objectives. Objective 1: To determine if viral respiratory infections and patterns of respiratory and gut bacterial community structure (microbiome) in prematurely born babies predict the rate and degree of immunologic maturation, and pulmonary dysfunction, measured from birth to 36 weeks corrected gestational age (CGA). Objective 2: To determine the relationship between respiratory viral infections and disease severity up to one year CGA, and the lymphocyte (Lc) phenotypes documented at term gestation (birth for term infants and 36 wks/NICU discharge in preterm infants) and at one year CGA. Three secondary outcomes of this objective will be to a) relate the quantity, type and severity of viral infections with pulmonary function at one and three years of life, b) relate the viral community structure to severity of viral infections and c) to seek evidence of modulation of viral susceptibility by bacterial respiratory and gut community structure (microbiome). The relationship of colonization with known and non-identified bacterial species in both the respiratory tract and the gut will be evaluated. Flow cytometry data corresponding to this study can be found within Immport study SDY1302. Positive and negative controls for microbiome samples are uploaded under SRA bioproject PRJNA474485. Microbiome samples corresponding to PRISM2 are distinguished from PRISM1 via "_PRISM2" appended to the sample name. Within the positive and negative controls, PRISM1 controls are uploaded as bam files and PRISM2 controls are uploaded as paired fastq. Samples ending in -08 correspond to TLDA qPCR results for a given sample. There is a column for each pathogen tested and a column to indicate where that pathogen was bacteria or virus.

Study phs001347

Prevention and Early Treatment of Acute Lung Injury (PETAL) Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) (PETAL CLOVERS-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 PETAL CLOVERS include plasma, and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Available Data: The data available for request now include Long Term Outcome data.Objectives: To compare the effects of a restrictive fluid strategy (with early use of vasopressors) to a liberal fluid strategy in participants with sepsis-induced hypotension.Background: Intravenous fluid resuscitation is a common therapy used in the initial treatment of participants with septic shock and sepsis-induced hypotension. The goal of initial fluid therapy is to increase depleted or functionally reduced intravascular volume that occurs in sepsis due to a vasodilated vascular network. However, intravenous fluid resuscitation can create dilutional coagulopathy, fluid overload, and pathogenic edema in the lungs and other organs. Vasopressor agents are also commonly used to treat hypoperfusion by inducing constriction of arterioles and venules and increasing cardiac contractility. Vasopressor therapy also comes with risks that include vasoconstriction resulting in tissue ischemia, increased cardiac workload, and arrhythmias. Clinicians have used these strategies, typically in combination, to provide supportive care for participants with sepsis-induced hypoperfusion. However, at the time of the CLOVERS study, there was limited data to guide specific use of these therapies, including fluid volumes, in the early care of participants with sepsis-induced hypotension. The CLOVERS study hypothesized that a restrictive fluid strategy used during the first 24-hours of resuscitation for sepsis-induced hypotension would lead to lower mortality before discharge home by day 90 than a liberal fluid strategy.Participants: A total of 1,563 participants, from 60 medical centers, of the planned 2,230 participants were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Enrollment in the trial was ended after the second interim analysis due to a lack of significant difference observed between the two 24-hour strategies.Design: This study was a multi-center, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for participants with sepsis-induced hypotension. Participants were randomly assigned in a 1:1 ratio to either a restrictive fluid strategy (with early vasopressor use) or a liberal fluid strategy. In each group, the assigned protocol was followed for a period of 24 hours. The restrictive fluid protocol prioritized vasopressors as the primary treatment for sepsis-induced hypotension, with 'rescue fluids' being permitted for prespecified indications that suggested severe intravascular volume depletion. The liberal fluid protocol consisted of a recommended initial 2000-ml intravenous infusion of isotonic crystalloid, followed by fluid boluses administered on the basis of clinical triggers (e.g., tachycardia) with 'rescue vasopressors' permitted for prespecified indications. A protocol amendment implemented in October, 2019, allowed for limiting the initial infusion to 1,000 ml if the participant's blood pressure and heart rate had stabilized and the clinical assessment was that the participant was unlikely to benefit from additional intravenous fluid administration. The clinical team could override the protocol-specified care instructions at any time if it was judged to be in the best interest of the participant.The primary outcome was death from any cause before discharge home by day 90. Secondary outcomes included 28-day measures of the number of days free from ventilator use, days free from renal-replacement therapy, days free from vasopressor use, days out of the ICU, and days out of the hospital. Conclusions: Among participants with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality, or other measures of recovery such as length of hospital stay, before discharge home by day 90 than the liberal fluid strategy.

Study phs004080

Sickle Cell Disease Implementation Consortium Registry (SCDIC Registry-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.Objectives: To understand the barriers to care and other factors related to reduced healthcare utilization after the transition from pediatric to adult SCD care which may contribute to increased morbidity and mortality.Background: Fifty years ago, it was rare for individuals with SCD to live beyond childhood. Advances in care delivery and treatment have more than doubled the life expectancy of individuals with sickle cell disease (SCD) since 1972. Beginning in the 1970s, measures such as newborn screening, prophylactic administration of penicillin, and immunization against bacterial infections decreased complications and morbidity, increasing the length and quality of life of children with SCD. Blood transfusions are currently the only proven way to prevent some of the major complications of SCD, especially recurrent stroke. They are also used frequently to help manage some of the acute complications of SCD. More recently, the use of hydroxyurea (HU) as a therapeutic agent to increase fetal hemoglobin has been shown to further reduce the debilitating symptoms of and improve survival in SCD. L-glutamine and crizanlizumab are additional treatments to reduce pain crises and voxelotor is approved to lower the risk of anemia and improve blood flow. In the absence of a widely accessible cure, treatment for SCD is usually aimed at avoiding crises, relieving symptoms, and preventing complications. Many of the advances in treatment have not translated into an increase in longevity or quality of life for adolescents and adults because of disparities in access to routine primary health care.Individuals with SCD experience a markedly increased mortality beginning in the second decade of life. The third and later decades of life are frequently associated with severe chronic pain progressive organ damage and frequent hospitalizations. The provision of evidence-based and expert opinion-based care in SCD is complicated by the difficulties that many patients experience in obtaining access to the health care system and in receiving long-term care from knowledgeable providers. A registry of 2,400 people with SCD was established to provide a rich resource to study the natural history of SCD and to understand barriers to care during the transition from pediatric to adult care. Participants: 2,438 participants with a confirmed diagnosis of SCD were enrolled into the registry over an 18-month period. At the time of enrollment, all participants were 15-45 years of age, English speaking, and without a bone marrow transplant.Design: The SCDIC Registry is a longitudinal observational cohort study. At enrollment, data collection included a medical record abstraction of clinical history, the most recent lab results, and a participant survey which included several patient reported outcomes from PROMIS, ASCQ-Me and NeuroQoL. Similar surveys were administered at annual follow-up. Four to five years after enrollment, a second record abstraction was completed with all clinical events that occurred since enrollment and another set of recent labs. There were many research questions proposed to be answered with the study data thus there was no primary outcome.Conclusions: As noted previously, there were no primary outcomes determined at the start of the study. Research questions included examination of co-morbidities, healthcare utilization, and patient reported outcomes. Key findings from the Registry include:Executive dysfunction, learning difficulties, and poor comprehension significantly associated with poor activities of daily living skills. Executive dysfunction also associated with HU non-adherence. Continuing HU after conception increased odds of miscarriage or stillbirth compared to women who were not using HU. Continuing HU after conception increased odds of low birth weight in infants. Compared to adolescents, young adults had significantly more severe pain, organ dysfunction, mental health disorders, sleep problems, and barriers to medical care. Young adults were significantly less likely to see a sickle cell specialist in the past 2 years. Females had higher pain frequency and severity, more pain episodes, anxiety, depression, hospitalizations, and higher fetal hemoglobin levels. Males had more respiratory, musculoskeletal, genitourinary, and cardiovascular complications, more skin ulcers, and more use of HU. Among 128 subjects that died during the study period, iron overload, pulmonary hypertension, and depression, were significant predictors of the risk of death in multivariate analyses.

Study phs004203

University of Miami Study on Genetics of Autism and Related Disorders (AutismDisorders)

Autism spectrum disorders (ASD) are neurodevelopmental in origin and characterized by impairments in reciprocal social interaction and communication accompanied by restricted and repetitive patterns of interest or behavior. With improved surveillance and a broadening of the diagnostic criteria, the most recent prevalence studies suggest that ASD may affect as many as 1/166 children in the US. Treatments are limited resulting in little impact on the profound morbidity. Little is known about the etiology of ASD, but there is a strong genetic component. Genetic studies over the past decade have failed to identify definitive ASD genes, but have clearly shown that the underlying genetics are more complex than anticipated with the likelihood that multiple genes are acting independently and/or interactively. With this realization the field of ASD genetics is at a critical juncture. To move forward we must embrace new and creative paradigms to successfully dissect the genetic etiology of this disease. Specifically the current study will: Extend our ascertainment to the full range of ASD. We will increase our ASD dataset by collecting 600 families who meet clinical diagnostic criteria for the three most common ASDs: autism (AUT), Asperger disorder (ASP) and Pervasive Developmental Disorder-NOS (PDD-NOS). Phenotype assessment will be expanded to include the Social Responsiveness Scale (SRS) and detailed seizure data. Ascertainment will focus on parent-child trios. Further characterize the ASD-associated variations in the Gamma-Aminobutyric Acid (GABA) receptor (GABR) subunits. We will complete our GABR subunit variant analysis, including coding, UTR, regulatory, and conserved intronic sequence, concentrating on GABRA4 and GABRB1. We will also investigate the role of variation in other GABR subunits. All AUT specific findings will be examined in the entire ASD dataset. Identify the chromosome 19p ASD gene. Multiple genome-wide screens have provided significant evidence for linkage to Chromosome 19p and we have found evidence for significant association in the linked families within an ~3 Mb region. We will genotype 768 SNPs spaced at ~4 kb to refine the candidate region and delineate specific candidate genes for further testing. We will screen the strongest associated candidate genes for additional variants and evaluate evidence for association in the entire ASD dataset (SA5). Develop and apply the Phenotypic Homogeneity Distinction (PHD) algorithm for identification of the phenotypic signature of linkage and/or association signals. The PHD algorithm identifies phenotypic covariates that discriminate a target sample subset (e.g. the positively linked families or families carrying the associated risk allele) from its complement. The resulting PHD discriminators will define a homogeneous subset from our newly-ascertained ASD dataset to use, as a confirmatory dataset and for localization within genes under study in our other aims. Test for gene-gene interactions. To fully explain the spectrum of autism risk, we will test for interactions between genetic variations associated with ASD (such as those in GABR subunit genes). We will build upon our experience using the MDR method and extend our analyses across biological pathways using the entire ASD data set.

Study phs000436

Inherited Genetic Variation and Predisposition to Testicular Germ Cell Tumor: UPenn Local TGCT Study

Testicular germ cell tumors (TGCT) are the most common cancer in men ages 20-40. The incidence of TGCT has more than doubled over the past forty years, without clear etiology. Both genetic effects and environmental exposures, specifically during the pre-natal period, are likely to play an important role in determining TGCT susceptibility. TGCT is known to develop from primordial germ cells (PGCs). We hypothesize that variation in genes that impact upon the differentiation and maturation of PGCs will be important determinants of TGCT susceptibility and based on this hypothesis have selected three important pathways for study, i) male germ cell development, ii) androgen and estrogen biosynthesis and metabolism, and iii) IGF signaling. The proteins involved in early male germ cell development, normally only expressed in PGCs, are markers of and are overexpressed in TGCT. Markers of increased exposure to estrogen (or relatively decreased exposure to androgen) in utero and exogenous estrogen exposures, such as endocrine disruptors, have been associated with TGCT case status in multiple studies. IGF signaling is necessary for testis differentiation and maturation in mice and interacts synergistically with the estrogen signaling pathway. Additionally, we are interested in examining genetic factors predisposing to TGCT in an unbiased fashion, and thus will conduct a Genome Wide Association Study. As well disease susceptiblity, genetics are likely to play a role in disease progression, disease outcomes and response to treatement. We will also assess association of inherited genetics with these outcomes. We will analyze the contribution of genetic variants in these pathways to TGCT risk using a population-based case-control study in the Philadelphia metropolitian area. Our goal is the collection of 550 TGCT cases and 1100 age, race and cell phone use matched controls without a history of TGCT, which will yield 500 and 1000 white cases and controls, respectively, available for final analyses. All cases will be enumerated through the New Jersey and Pennsylvania state cancer registries. We will use a two-tiered approach for case recruitment: hospital clinic-based followed by registry-based. Hospital based cases will be identified within the Univeristy of Pennsylvania Health System and the University of Pennsylvania Cancer Network. All cases identified through this mechanism will be recruited irregardless of diagnosis date. The remaining cases will be identified through the New Jersey and Pennsylvania cancer registries and contacted following their protocols. Controls will be identified through random digit dialing and address based sampling. Both cases and controls will complete a questionnaire addressing known, presumed, and hypothesized risk factors for TGCT and provide a biospecimen. Pathological slides will be reviewed to cases to confirm diagnostic sub-type of TGCT. Haplotypes and functional SNPs will be typed in the genes of interest, as well as throughout the genome. Analyses will be conducted for specific variants, common haplotypes, alone and in conjunction with each other and exposure data after appropriate adjustment for potential confounders. The findings from this study will greatly contribute to our understanding of determinants of TGCT susceptibility.

Study phs001307

Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE)

Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-releasing hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e. fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e. asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertains only to the 794 subjects from the CANDLE study for whom placental tissue transcriptomics was performed.

Study phs003619

Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)

Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-Releasing Hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e., fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e., asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertain only to the 408 subjects from the GAPPS study for whom placental tissue transcriptomics was performed.

Study phs003620

Best Endovascular vs. Best Surgical Therapy in Patients With Critical Limb Ischemia (BEST CLI-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. Objectives To compare the effectiveness of surgical treatment to the effectiveness of endovascular treatment in adults with chronic limb-threatening ischemia who are eligible for both treatment options. Background Peripheral artery disease (PAD) affects more than 200 million people worldwide. A portion of those individuals develop chronic limb-threatening ischemia (CLTI). CLTI is associated with severe health outcomes. CLTI is defined by ischemic foot pain at rest, ischemic ulcerations, or gangrene. Treatment for CLTI includes revascularization to improve limb perfusion and limit the risk of amputation. However, the choice of surgery or endovascular therapy for revascularization varies greatly. The extent to which this variability affects clinical outcomes in patients with CLTI is unknown. The BEST-CLI trial was initiated to determine whether endovascular revascularization was superior to surgical revascularization in patients with CLTI. Participants A total of 1434 participants with a single segment of great saphenous vein comprised cohort 1. Of these, 718 participants were randomly assigned to the surgical treatment group and 716 participants were randomly assigned to the endovascular therapy group. A total of 396 participants needing an alternative conduit comprised cohort 2. Of these, 197 participants were randomly assigned to the surgical treatment group and 199 participants were randomly assigned to the endovascular therapy group. Design BEST-CLI was an international, randomized, open-label trial. Participants were assigned to one of two cohorts based on the availability of a single segment of great saphenous vein. Participants in both cohorts were randomly assigned to either surgery or endovascular therapy. Follow-up was performed at 30 days after the procedure, 3 months, 6 months, and every 6 months thereafter up to 84 months after randomization. Telephone visits in lieu of clinic visits were planned at 30 months and every 12 months thereafter and at the end of the trial. Participants were followed for major adverse cardiovascular events (myocardial infarction, stroke, or death from any cause), quality of life, level of pain, and performance on the six-minute walk test. The primary outcome was a composite of major adverse limb events or death from any cause. A major adverse limb event was defined as above ankle amputation of the index limb or a major index-limb reintervention (new bypass, interposition graft revision, thrombectomy, or thrombolysis). Conclusions Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. Farber A, Menard MT, Conte MS, et al. Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia. N Engl J Med. 2022;387(25):2305-2316. PMID 36342173

Study phs003844

Data Access Committee of CiRA Foundation

The iPS Cell Stock Project promoted by the CiRA Foundation is intended to generate and distribute iPS cells for medical use so they can be effectively utilized for research and development of cell transplantation therapy and contribute to the advancement of regenerative medicine that may become a novel treatment for patients suffering from intractable diseases or trauma who are not expected to improve with conventional therapies. In order to achieve this objective, CiRA Foundation establish the DAC based on the basic policies and rules for handling analysis information including iPS cell stocks for the purpose of proper sharing of samples and analyzed data collected directly or indirectly from the donors of iPS cell stocks.

Dac EGAC50000000128

iNHL WXS Data Commitee

The iNHL WXS Data Commitee is responsible for managing access to datasets submitted to the European Genome-phenome Archive (EGA). Our committee ensures that access requests are evaluated in compliance with ethical guidelines, regulatory requirements, and the conditions specified by data submitters. Researchers requesting access to these datasets must provide a clear and valid scientific purpose, demonstrate affiliation with a recognized institution, and agree to the terms of use outlined in the Data Access Agreement. The iNHL WXS Data Commitee works to uphold data privacy and security while facilitating responsible data sharing to advance scientific discovery. For further information on our policies or the application process, please contact Hauke Busch (hauke.busch@uni-luebeck.de).

Dac EGAC50000000488

Data access policy

Investigators who download restricted data from this dataset should: - Not attempt to identify individual human research participants from whom the data were obtained. - Acknowledge in all oral or written presentations, disclosures, or publications the specific dataset(s) or applicable accession number(s) and the repositories through which the investigator accessed any data. Any user requesting access to this data must apply for authorization, which is granted by the Data Access Committee (DAC). The DAC will review and approve or disapprove all requests from the research community for data access. Decisions to grant access are made based on whether the request conforms to the specifications of the Research Ethics Committee approval and program specific requirements or procedures (if any).

Dac EGAC50000000504

Circulating Biomarker Laboratory within the Division of Cancer of Imperial College London

The purpose of the Circulating Biomarker Laboratory within the Division of Cancer of Imperial College London (ICL) is to assist ICL researchers working on solid tumours or/and haematological malignancies with a particular interest in the analysis of liquid biopsies. We are focusing on isolating and analysing single circulating tumour cells (CTCs) and cell-free circulating tumour DNA (ctDNA) from cancer patients' blood samples but also pure tumour poulations from heterogeneous Formalin-fixed paraffin-embedded (FFPE) tissue specimens with a view to monitoring tumour-related changes, such as mutations and copy number alterations at a single cell level.

Dac EGAC50000000768

Single Cell RNASeq for ARMS tumors

6 samples from 3 mice related to Alveolar Rhabdomysarcoma. In this study, we employ scRNA-seq to analyze ARMS tumors from a conditional mouse model of ARMS. The conditional knock-in mouse model of ARMS, in which the Pax3-Foxo1 allele is activated in the skeletal muscle cell lineage via Myf6Cre (Myf6CrePax3P3Fm/P3FmTrp53F2-10/F2-10; referred to hereafter as GEMM-ARMS) has been described previously23,24. These mice also carry Cre-activated reporters, eYFP to label Pax3::Foxo1-expressing cells and dsRED2 to labels Myh2-expressing cells. Some tumors are derived from GEMM-ARMS mice, and some are allografts of GEMM-ARMS tumors into immunodeficient mice

Dataset EGAD50000002241

Bleomycin Induced Pneumonitis WGS dataset

This is whole genome sequencing data from a cohort of 18 patients with germ cell tumours or Hodgkin Lymphoma, who developed clinically significant bleomycin-induced pneumonitis despite low clinical risk. DNA was extracted from whole blood, and 150-base paired-end reads were generated on an Illumina NovaSeq 6000 instrument to a minimum 30x depth. Sequence reads were aligned to the GRCh38 reference with BWA MEM, and germline variants were called following GATK best practice procedures. The dataset comprises per-sample read alignment files in BAM format, and a joint-called germline variant file in VCF format.

Dataset EGAD50000002221

Transcriptomic analysis of hiPSC-derived vascular cells from CADASIL and isogenic control patient lines

Bulk-RNA sequencing from hiPSC-derived cells (hiPSC; Endothelial Cells; Neural Crests Cells; Vascular Smooth Muscle Cells) from CADASIL patient lines (n=3) and respective isogenic-controls (n=3). CADASIL is a hereditary brain small vessel disease caused by pathogenic variants in the NOTCH3 gene, which lead to deposits of NOTCH3 protein in the walls of small arteries. This causes pathological vessel wall changes including degeneration of vascular smooth muscle cells. To investigate the impact of pathogenic NOTCH3 variants in hiPSC and differentiated cells we performed a bulk-RNA sequencing.

Dataset EGAD50000002181

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