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• A Natural History Study of CMT1B, CMT2A, CMT4A and CMT4C

  Charcot Marie Tooth disease (CMT) is an umbrella term that covers any inherited peripheral neuropathy. People with CMT have a problem with the nerves that go to the feet and hands that cause muscle and sensation loss, as well as difficulty with balance. There are at least forty genes that, when mutated, cause CMT. The purpose of this study is to look at the natural history of CMT to see how it changes over time. Particular emphasis will be put on studying people with CMT1B, CMT2A, CMT4A, and CMT4C, though all people with CMT are encouraged to participate. Participants are invited back on a yearly basis to determine how the changes are occurring. Objectives: Determine the natural history and genotype-phenotype correlations of disease-causing mutations in CMT1B, CMT2A, CMT4A and CMT4C as well as other forms of CMT Determine the capability of the newly developed CMTPeds score and the Minimal Dataset to measure impairment and perform longitudinal measurements in patients with multiple forms of CMT over a ten-year window This is a longitudinal study of individuals with CMT. Study participants will be invited to be re-evaluated every year. Evaluations will consist of neurological histories and examinations, selected nerve conduction studies (NCS) as well as completion of assorted clinical outcome measures including the CMTNS, Minimal Dataset, and Peds CMT Scale. Selected CMT patients and controls will also receive glabrous skin biopsies.

  Study phs001419

• Michigan Polybrominated Biphenyl (PBB) Exposure Registry

  Humans are exposed to chemicals such as brominated flame retardants (BFRs) at unprecedented levels, and a wide variety of health effects are attributed to such exposures. However, the biological mechanisms that link exposures to its consequences remain unknown. An industrial accident in the 1970's exposed over 4000 individuals in rural Michigan to polybrominated biphenyl (PBB), a BFR that was present in the food supply for years prior to detection and management. Health effects are still evident in these individuals and their children. Because this population has been assessed regularly since the exposure, it is an ideal group in which to examine the molecular mechanisms that contribute to susceptibility, vulnerability and health effects. The goal of this project is to identify the genetic variants that associate with the rate of PBB elimination over time and integrate genetic and epigenetic datasets and identify complex gene-environment relationships in PBB exposed individuals. We will leverage data generated as part of past and ongoing studies in the Michigan Polybrominated Biphenyl Registry. We anticipate that this study will provide insight into how genetic variants and the environment interact in relation to PBB exposure and its health effects. We also anticipate the results of this study will be informative for studies of BFRs and other endocrine disrupting compounds with similar chemical properties. Note that methylation array data is available from NCBI GEO under GSE116339: Exposure to Polybrominated Biphenyl (PBB) Associates with DNA Methylation Differences Across the Genome

  Study phs001862

• MP2PRT: Comprehensive Genomic Profiling to Identify Alterations Associated with Relapse for NCI Standard Risk (SR) B-Lineage ALL and NCI High Risk (HR) B-Lineage ALL with Favorable Genetic Features

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study, titled "Comprehensive Genomic Profiling to Identify Alterations Associated with Relapse for NCI Standard Risk (SR) B-Lineage ALL and NCI High Risk (HR) B-Lineage ALL with Favorable Genetic Features," is one of the selected studies under this program. For this study, genomic characterization (WGS 30X, WXS, Total RNAseq) was performed on NCI Standard Risk B-lineage ALL patients who relapse and subsets of NCI High Risk B-lineage ALL patients who relapse as well as two non-relapse control cases for each relapse case. It was hypothesized that the comprehensive characterization of these sample sets will allow the identification of somatic genetic features that will facilitate early intervention to improve cure rates for those enrolled on future trials. Data were generated and genetic subtype was integrated with clinical variables, including age, presenting white blood cell count, sex, race, and levels of minimal residual disease at the end of induction. Additional secondary alterations were identified and included if they occurred in more than 10 patients. The study has been completed and a manuscript has been prepared.

  Study phs002005

• Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR)

  The Pediatric Investigation for Genetic Factors Associated with Renal Progression (PediGFR) (RO1-DK082394) is an international collaborative study among three large prospective cohort studies of children with chronic kidney disease. The participating parent cohort studies are the Chronic Kidney Disease in Children (CKiD), the Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients (ESCAPE), and the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study. In these cohorts, pediatric subjects with CKD have been prospectively followed with standardized measurements for renal progression. The dbGaP data upload will utilize the structure of sub-studies to include the genotype and baseline phenotype for the three cohorts, as well as the RBC trait and anemia data for a sub-study under PI Susan Furth: Role of Genetic Variation in the Anemia of Chronic Kidney Disease (K24DK078737). In brief PediGFR is a prospective study of children with chronic kidney disease (CKD) to determine genetic factors associated with kidney function measured by the estimated glomerular filtration rate (eGFR) by Schwartz equation. The PediGFR_v2 Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000842 PediGFR_v2 Cohort. phs000843 4C phs000650 CKiD phs000844 ESCAPE

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• Rapid Whole Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units

  Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3,500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. As such, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant, identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree, and ruled out known candidate genes in one infants. Sequencing of parents or affected siblings expedited the identification of disease gene in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling. Reprinted from Saunders et. al, Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units. Sci. Transl. Med. 4, 154ra135 (2012; PMID: 23035047) with permission from AAAS.

  Study phs000564

• Rare Cancer Tumors Project

  A large proportion of common cancers affecting patients around the world have been selected for comprehensive cancer genome studies. Further efforts will be needed to tackle the remaining tumor types, including the rare forms of cancers. Although rare, these cancers tend to be more aggressive and fast growing with an early recurrence following initial chemotherapy and poor prognosis. Besides, patients diagnosed with rare cancers may have difficulty finding a physician knowledgeable in treating their type of cancer. While sample collection is a major challenge, the integrated genomic analyses would identify novel causative genes in these rare cancers, shed new light on the biology of the rare cancers, as well as guide novel targeted cancer therapies. Through efficient collaboration, the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine (BCM) has collected/is expected to collect 20 different types of rare cancers, 15-30 cases each. Whole-exome sequencing and high-resolution SNP array analysis were/will be performed for all cases and whole-genome sequencing was designed for a selected subset of the cases. The Rare Cancer Tumors Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in this sub-study, please click on the following sub-study below or in the "Sub-studies" section of this top-level study page phs000725 Rare Cancer Tumors Cohort. phs000754 Intracranial Germ Cell Tumors phs000861 Craniopharyngioma Tumors phs000859 Sezary Syndrome Genomic Analysis

  Study phs000725

• Spit for Science

  Spit for Science™ is a university-wide research opportunity with the scientific goal of understanding how genetic and environmental factors come together to influence substance use and emotional health across the college years and beyond. To address this goal, we have comprehensively and longitudinally studied eligible incoming freshmen (18 years or older) from a diverse urban university, assessing a wide range of risk and protective factors, including both biological susceptibility and environmental risk, and a variety of outcome measures, particularly alcohol use and other substances, and difficulties with emotional health. Our goal is to assess how risk and protective factors dynamically interact to contribute to behavior health outcomes over time and plan to use findings from the project to inform prevention and intervention efforts and aid in university policy and programming in ways that can support and promote student success. Methods: In the fall of their freshman year, first-time college students over the age of 18 are invited to complete an online survey containing broad questions about personality and behavior, as well as family, friends, and experiences growing up. Students can also provide a saliva sample and participate in the DNA component of the project (participation in the DNA component is not a requirement for participation in the survey). Each subsequent spring students are asked to complete a follow-up survey, enabling researchers to study patterns of substance use and emotional health across the college years.

  Study phs001754

• QUANTitative Chest Computed Tomography UnMasking Emphysema Progression in Alpha-1 Antitrypsin Deficiency

  AAT deficiency is a genetic disorder associated with emphysema. Spirometry, the lung function test that measures how well the lungs exhale air, is used to diagnose and track the progression of emphysema. Some studies have suggested that forced expiratory volume in 1 second (FEV1) measurements, a type of spirometry test, may lack accuracy in detecting disease progression in cases of severe AAT deficiency. Another method, high resolution chest CT scans, may be more accurate at measuring the progression of emphysema. The purpose of this study is to determine if high resolution CT scans are better at detecting the progression of emphysema than lung function tests. Results from this study may lead to the development of a more accurate way to assess lung tissue loss and may improve the understanding of lung destruction in AAT deficiency. This study will last 4 years and will enroll people with AAT deficiency who have nearly normal lung function test results. Study visits, each lasting about 4 hours, will occur at baseline and months 6, 12, 18, 24, and 36. At each visit, participants will undergo lung function tests, a CT scan, blood collection, and a physical exam. Female participants will have urine collected for a pregnancy test. All participants will also complete questionnaires to assess health status and lung function. Study researchers will call participants every 2 months to collect information on lung disease symptoms and medication changes.

  Study phs000698

• The Library of Integrated Network-Based Cellular Signatures (LINCS) - NeuroLINCS

  The NeuroLINCS Center is part of the NIH Common Fund's Library of Integrated Network-based Cellular Signatures (LINCS) program, which aims to characterize how a variety of human cells, tissues and the entire organism respond to perturbations by drugs and other molecular factors. As Part of the LINCS program, the NeuroLINCS study concentrates on human brain cells, which are far less understood than other cells in the body. Our initial focus is to produce diseased motor neurons from patients by utilizing high-quality induced pluripotent stem cell (iPSC) lines from Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) patients in addition to unaffected normal healthy controls. Using state-of-the-art OMICS methods (genomics, epigenomics, transcriptomics, and proteomics), we intend to create a wealth of cellular data that is patient-specific in the context of their baseline genetic perturbations and in the presence of other genetic and environmental perturbagens (e.g. endoplasmic reticulum stress). The primary data will be used to build cell signatures that convey the key features that distinguish the state of a cell and determine its behavior. Ultimately, the analysis of these datasets will lead to the identification of a network of unique signatures relevant to each of these motor neuron diseases. The datasets represented in this study are generated from assays interrogating RNA expression (RNA-seq), chromatin accessibility (ATAC-seq) and whole genome sequencing.

  Study phs001231

• Extent and Significance of Bacterial DNA Integrations in the Human Cancer Genome

  The integration of exogenous DNA into the human genome can cause somatic mutations associated with oncogenesis. For example, the insertion of HPV DNA into human chromosomes is the single most important event leading to tumorigenesis in cervical cancer. It is also now preventable with vaccines against HPV. In contrast to viral DNA integrations, the instances and repercussions of bacterial DNA integration into the somatic human genome are less clear. Yet bacterial DNA integrations (BDI) found to be associated with tumorigenesis could also be prevented using therapeutics like vaccines that limit exposure to the bacteria. Previous analysis of publicly available sequencing data from the Cancer Genome Atlas (TCGA) showed BDIs from Pseudomonas spp. rRNA into the 5'-UTR of four proto-oncogenes as well as in Ig (the immunoglobulin gene) of gastric cancer samples. The original samples from TCGA were not available to validate these findings. Therefore, a different cohort of gastric cancer patients was identified in order to establish the presence BDIs. Whole exome sequencing was completed on seven tumor samples and six adjacent gastric samples, as well as one intestinal metaplasia sample and one non-atrophic gastritis sample. Four of those samples were also investigated with transcriptomics and whole genome sequencing. Given that 15-20% of cancers worldwide are linked to infections, more work is needed to understand the role of infectious agents in oncogenesis and the mechanisms underlying that role.

  Study phs001936

• Reference Standards for Mosaic Variant Detection

  After conception, postzygotic mutations continuously occur throughout life in humans, causing somatic mosaicism in an individual. The variant type, time of origination, and locations of the mosaic mutations result in unique mosaic patterns in a combinatorial manner and further affect phenotypes, including various noncancerous diseases. Several efforts have, thus, been made to identify the mutational landscape and mechanisms underlying the mosaic mutations. From a technical aspect, the accurate detection of mutations is at the core of the mosaicism research, and the construction of a standard reference is a critical first step to serve as the basis for analytical validation and benchmarks for germline and somatic mutation detection. Furthermore, a reference standard for mosaic mutations is urgently needed to enable more advanced research.Herein, we generated robust, large-scale, and cell line mixture-based reference standards that contain abundant mosaic SNVs and INDELs along with wild-type sites and germ line variants. Moreover, the whole reference standard set mimics the cumulative aspect of mosaic variant acquisition in the early developmental stage through a progressive cell line mixing with confirmed genotypes. It can be used for optimizing the current use of mosaic variant detection strategies, as well as developing algorithms for future improvements.We previously generated an NCBI BioProject (PRJNA758606) to release much of these data. Only the data that are subject to authorized access constraints have been included in this submission to dbGaP. The two data sources are thus, complementary to each other.

  Study phs003399

• Center for Sub-Cellular Genomics

  A cell is a highly complex system with distributed molecular physiologies in structured sub-cellular compartments whose interplay with the nuclear genome determine the functional characteristics of the cell. A classic example of distributed genomic processes is found in neurons. Learning and memory require modulation of individual synapses through RNA localization, localized translation, and localized metabolites, such as those from dendritic mitochondria. Dendrites of neurons integrate distributed synaptic signals into both electrical and nuclear transcriptional response. Dysfunction of these distributed genomic functions in neurons can result in a broad spectrum of neuropsychiatric diseases such as bipolar and depressive disorders, autism, among others. The Center for Sub-Cellular Genomics' (CSG) mission is to develop new technologies to enable the dissection of complex genomic interactions within a single cell. New technologies include methods to target DNA and RNA sampling at sub-cellular resolution in live cells; high-throughput isolation and microfluidics chemistry for sub-cellular fractions; sub-cellular resolution mass-spectrometry; and computational tools for analysis of sub-cellular genomics data. The new technologies developed by CSG will enable the broader genomics community to associate sub-cellular processes to cell function and dysfunction. These technologies will be utilized in the center to generate a comprehensive atlas of genomic signatures of sub-cellular compartments in the mammalian neuron system. The technologies and neuron-focused data obtained here will be relevant to neurodegenerative and neuropsychiatric diseases including schizophrenia, depression, autism spectrum disorder, traumatic brain injury, and Alzheimer's.

  Study phs002120

• Molecular Characterization of Hemimegalencephaly

  Somatic mutations, in which a fraction of the cells in the body have a deleterious mutation, are well recognized in cancer but only recently appreciated in neurological disease. Given a somatic mutation in a population of progenitor cells, all daughter cells inherit the mutation and are able to express the resultant phenotype as a function of the differentiation program. We recently identified the first de novo somatic mutations in the developing brain in the condition hemimegalencephaly (HME), a catastrophic focal epilepsy condition associated with a malformation of cerebral cortical development (MCD). HME is one of the most severe MCD syndromes, characterized by massive hamartomatous overgrowth of either of the two cerebral hemispheres. Cerebral hemispherectomy is a frequent treatment for refractory epilepsy, allowing the sampling of diseased tissue. By comparing DNA from a diseased brain with DNA from blood/saliva, we identified de novo somatic mutations in PIK3CA, AKT3 or MTOR, part of the mTOR pathway. Mutations were present in 8-40% of sequenced alleles in various brain regions sampled during surgery and in some codons known to activate proteins.• Population informationPatient samples were collected from multiple centers. The population is Caucasian and Hispanic• Molecular technologies employedWhole-exome sequencing• Principal findings of the studyWe were the first to describe mTOR-related and non-mTOR mutations causing hemimegalencephaly, and we described two-hit mutational models to explain the genetic pathogenesis of hemimegalencephaly

  Study phs002156

• Esophageal Squamous Cell Carcinoma Precursor Study

  Esophageal cancer is the sixth most common cause of cancer death in the world. High-risk areas occur across central Asia and from eastern to southern Africa, and in these populations, nearly all of the cases are esophageal squamous cell carcinoma (ESCC). ESCC has a dismal prognosis, largely because symptoms usually appear late in the course of the disease, when the tumors are incurable. Early detection and treatment of curable precursor lesions and early invasive ESCC in asymptomatic high-risk adults offers the potential for long-term survival and reduced mortality from this disease. Previous studies have shown that routine cytology of non-endoscopically collected esophageal cell samples is not sensitive and specific enough to be clinically useful, so we are now looking for molecular markers of high-grade esophageal squamous dysplasia (HGD), the proven clinically important precursor lesion of ESCC, that can be used to increase the accuracy and utility of this initial screening exam. National Cancer Institute (NCI) and Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS) began collaborative studies of ESCC since the mid-1980s in China. The present proposal is designed to characterize the type and prevalence of DNA mutations in tissue samples of HGD and to establish biologic and questionnaire resources for further study. The proposed study has two components, a field study to obtain questionnaire data and biological samples, and a genomic analysis to perform sequencing of the biological samples and bioinformatics analysis of the sequencing. 

  Study phs002814

• UCSF Database for the Advancement of JMML - Integration of Metadata with Omic Data

  Juvenile myelomonocytic leukemia (JMML) is a rare and frequently fatal myeloproliferative/myelodysplastic disorder of early childhood with an estimated incidence of 1.2 cases per million. It is associated with a spectrum of diverse outcomes ranging from spontaneous resolution in rare patients to transformation to acute myeloid leukemia in others. The overwhelming majority of JMML patients (~95%) will harbor mutations in canonical Ras pathway genes, including NF1, NRAS, KRAS, PTPN11, and CBL. As Ras proteins are mutated in more than 30% of human cancers, the information gleaned from the study of JMML has provided insights into Ras signaling in cancer as well as a group of congenital diseases with tumor predispositions known as the “Rasopathies”. While oncogenic Ras is one of the most common mutations in human cancer, it remains one of the most vexing targets for efficacious therapy. To better understand this disease, a JMML tissue bank was established at UCSF that allows for consenting of subjects, biobanking of tissue and collection of follow up data from patients both locally and at other institutions. Through the collection and analysis of specimens, knowledge about the genetic, epigenetic, and biochemical basis of JMML has been gained. This integrated database will enable future JMML research, and importantly, additional Ras/MAPK pathway research by depositing linked, processed data to well annotated anonymized patients in an easily accessible online database

  Study phs002504

• Alpha1-Antitrypsin Deficiency Registry (AADR-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 characterize the clinical and laboratory course of patients with severe alpha 1-antitrypsin deficiency whether or not the patient is undergoing long-term augmentation therapy.Background: A hereditary disorder, patients with low serum levels of alpha-1-antitrypsin are at an increased risk for the early onset of emphysema. The only approved treatment for alpha-1-antitrypsin deficiency is augmentation therapy using a purified preparation of human alpha-1-antitryspin. Sample sizes for a randomized controlled clinical trial of augmentation therapy were determined to be infeasible; therefore, a multi-center registry was initiated in 1988 to explore the natural history of the disease and the relative efficacy of augmentation therapy in patients with a severe deficiency of alpha-1-antitrypsin.Participants: Eligible participants included individuals 18 years of age or greater for whom the Central Laboratory confirmed that the serum alpha 1-antitrypsin level is Conclusions: Participants receiving augmentation therapy had decreased mortality risk during follow-up. FEV1 decline among all participants did not differ by augmentation therapy; however, among participants with FEV1 35-49% predicted, FEV1 decline was significantly slower for participants on augmentation therapy than for those not receiving therapy. (Am J Respir Crit Care Med, 1998; 158:49-59)

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• Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis

  Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a ‘dysplasia with multiple joint dislocations’ however, the molecular aetiology of the disorder is currently unknown. In order to identify the genetic defects underlying PDD, we performed whole exome sequencing (WES) on 3 patients from 2 unrelated families, clinically diagnosed with PDD. WES resulted in the identification of bi-allelic variants in the established skeletal dysplasia genes, B3GAT3 (Family 1) and CANT1 (Family 2). Mutations in these genes have previously been reported to cause ‘multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects’ (B3GAT3) and Desbuquois dysplasia 1 (CANT1); disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3- and CANT1- related skeletal dysplasias to include PDD, and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.

  Study EGAS00001004145

• Characterization of HCV-specific CD4 T cells during DAA-Therapy

  Background: Chronic HCV-infection is characterized by a severe impairment of HCV-specific CD4 T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific CD4 T cells after viral elimination. Methods: HCV-specific CD4 T cell responses were longitudinally analyzed using MHC class II tetramer-technology, multicolor flow cytometry and RNA sequencing in a cohort of chronically HCV-infected patients undergoing therapy with direct-acting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed. Results: We observed that the frequency of HCV-specific CD4 T cells increased within two weeks after initiation of DAA therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. While cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific CD4 T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity. Conclusion: We identified a population of HCV-specific CD4 T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent re-infection and immunotherapeutic approaches for persistent viral infections.

  Study EGAS00001003950

• Cisplatin increases sensitivity to FGFR inhibition in patient-derived xenograft models of lung squamous cell carcinoma

  Lung squamous cell carcinoma (SqCC) is a molecularly complex and genomically unstable disease. No targeted therapy is currently approved for lung SqCC, although potential oncogenic drivers of SqCC have been identified, including amplification of the fibroblast growth factor receptor 1 (FGFR1). Reports from a recently completed clinical trial indicate low response rates in patients treated with FGFR tyrosine kinase inhibitors, suggesting inadequacy of FGFR1 amplification as a biomarker of response, or the need for combination treatment. We aimed to develop accurate models of lung SqCC and determine improved targeted therapies for these tumors. We show that detection of FGFR1 mRNA by RNA in situ hybridisation is a better predictor of response to FGFR inhibition than FGFR1 gene amplification using clinically relevant patient-derived xenograft (PDX) models of lung SqCC. FGFR1-overexpressing tumors were observed in all histological subtypes of non-small cell lung cancers (NSCLC) as assessed on a tissue microarray, indicating a broader range of tumors that may respond to FGFR inhibitors. In FGFR1-overexpressing PDX tumors, we observed increased differentiation and reduced proliferation following FGFR inhibition. Combination therapy with cisplatin was able to increase tumor cell death, and dramatically prolonged animal survival compared to single agent treatment. Our data suggest that FGFR tyrosine kinase inhibitors can benefit NSCLC patients with FGFR1-overexpressing tumors and provides a rationale for clinical trials combining cisplatin with FGFR inhibitors.

  Study EGAS00001002423

• Whole genome study of Hurthle cell thyroid carcinoma

  Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of disease and thus opportunities for more effective clinical management. Initially, two oncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing. Subsequently, 72 oncocytic thyroid carcinomas, one cell line and 5 Hürthle cell adenomas were examined by targeted sequencing for the presence of mutations in multiple endocrine neoplasia I (MEN1) gene. We report the identification of MEN1 loss-of-function mutations in approximately 7% of patients diagnosed with oncocytic thyroid carcinoma. Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these tumours. Menin, a ubiquitously expressed nuclear protein, is a well-characterized tumor suppressor whose loss is the cause of multiple endocrine neoplasia type 1 syndrome. Menin is involved in several major cellular pathways such as regulation of transcription, control of cell cycle, apoptosis and DNA damage repair pathways. Mutations of this gene in a subset of Hürthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis.

  Study EGAS00001000940

• Genome-wide study of the effect of blood collection tubes on the cell-free DNA methylome

  Background The methylation pattern of cfDNA, isolated from liquid biopsies, is gaining substantial interest for diagnosis and monitoring of diseases. We have evaluated the impact of type of blood collection tube and time delay between blood draw and plasma preparation on bisulfite-based cfDNA methylation profiling. Methods 15 tubes of blood were drawn from three healthy volunteer subjects (BD Vacutainer K2E EDTA spray tubes, Streck Cell-Free DNA BCT tubes, PAXgene Blood ccfDNA tubes, Roche Cell-Free DNA Collection tubes and Biomatrica LBgard blood tubes in triplicate). Samples were either immediately processed or stored at room temperature for 24 or 72 hours before plasma preparation. DNA fragment size was evaluated by capillary electrophoresis. Reduced representation bisulfite sequencing was performed on the cell-free DNA isolated from these plasma samples. We evaluated the impact of blood tube and time delay on several quality control metrics. Results All preservation tubes performed similar on the quality metrics that were evaluated. Furthermore, a considerable increase in cfDNA concentration and the fraction of it derived from NK cells was observed after a 72-hour time delay in EDTA tubes. Conclusion The methylation pattern of cfDNA is robust and reproducible in between the different preservation tubes. EDTA tubes processed as soon as possible, preferably within 24 hours, are the most cost effective. If immediate processing is not possible, preservation tubes are valid alternatives.

  Study EGAS00001004271

• Memory-like HCV-specific CD8+ T cells retain a chronic scar after cure of chronic HCV infection

  Chronic hepatitis C virus (HCV) infection is associated with CD8+ T-cell exhaustion characterized by limited effector functions and thus compromised anti-viral activity. Exhausted HCV-specific CD8+ T cells are comprised of memory-like and terminally exhausted CD8+ T-cell subsets. So far, little is not known about the molecular profile and fate of these cells after elimination of chronic antigen stimulation by direct acting antiviral therapy (DAA). Here, we report an antigen-driven molecular core signature underlying exhausted CD8+ T-cell subset heterogeneity in chronic viral infection with a progenitor/progeny relationship of memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate stage. Furthermore, transcriptional profiling reveals that the memory-like cells remain after DAA-mediated cure while terminally exhausted HCV-specific CD8+ T-cell subsets are lost. Thus, the memory polarization of the overall HCV-specific CD8+ T-cell response after cure does not result from re-differentiation of exhausted T cells. Consequently, antigen elimination has little impact on the exhausted core signature of memory-like CD8+ T cells that remains clearly different from bona fide T-cell memory. These results identify a molecular signature of T-cell exhaustion that is imprinted like a chronic scar in HCV-specific CD8+ T cells even after HCV cure, highlighting the requirement of re-programming to elicit full effector potential of exhausted T cells.

  Study EGAS00001004538

• Single_cell_characterization_of_T_cell_lymphoma_

  Lymphomas are types of blood cancer derived from lymphocytes, and can be classified into two main categories, Hodgkin's lymphomas (HL) and non-Hodgkin lymphomas (NHL). T-cell lymphoma is a type of NHL that develops from T lymphocytes and accounts for 10-15% of total NHL cases. As a rare disease, T-cell lymphoma is functionally, pathologically, and clinically complex and heterogeneous. The 2016 revision of the WHO classification has listed 29 subtypes of mature T/NK-cell neoplasms, among which over 25 are T lymphocyte in origin. These subtypes of T-cell lymphomas have different biological behaviours and clinical prognosis. Clinically, T-cell lymphoma ranges from indolent (slow-growing) to aggressive (fast-growing and spreading) disease. According to the guideline booklet provided by the Lymphoma Research Foundation (https://lymphoma.org/aboutlymphoma/nhl/), indolent T-cell lymphoma subtypes include adult T-cell leukaemia/lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), and mycosis fungoides (MF), while the aggressive subtypes include anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma (PTCL), and T lymphoblastic lymphoma (TLBL). PTCL and ALCL represent the most common subtypes of aggressive T-cell lymphoma whereas TLBL is a rare and aggressive subtype mostly diagnosed in children. In this study, we will use single cell RNA sequencing and single cell multiomic methods three aggressive T-cell lymphoma subtypes (ALCL, PTCL and TLBL) and try to gain a deeper insight into the genotypic and phenotypic features of these T-cell lymphomas.

  Study EGAS00001005750

• Genome-wide association study identifies common variants associated with breast cancer in South African Black women

  Genome-wide association studies (GWAS) have characterized the contribution of common variants to the development of breast cancer (BC) in populations of European descent, however no GWAS have been reported in resident African populations. This GWAS included 2,485 resident African BC cases and 1,101 population matched controls. Two risk loci were identified, one on chromosome 15, located between UNC13C and RAB27A (rs7181788, p = 1.01x10-08) and a second in an intron of USP22 on chromosome 17 (rs899342, p = 4.62x10-08). RAB27A is a member of the RAS oncogene family associated with invasive growth and metastasis, and UNC13C is involved in tumor progression. The rs899342 SNP is an eQTL for expression of USP22 in a wide range of tissues. Several genome-wide significant signals were detected in a hormone receptor subtype analysis. Comparison of a meta-analysis of other African ancestry BC GWAS datasets predominantly of West African ancestry with our South African data showed limited evidence of shared risk loci, suggesting potential heterogeneity in genetic risk factors for breast cancer in different African populations. A European ancestry derived polygenic risk model for BC was applied to our data, explaining only 0.79% of variance, with an area under the curve of 0.56. This study identified genetic risk factors for BC in a resident African population, but larger studies in this and other African populations are needed to further define the contribution of common variants to BC risk.

  Study EGAS00001008032

• How to encrypt files with EGACryptor

  File preparation Due to the processes used at the EGA for file archival the use of non-alphanumeric characters in a filename will cause issues in archival. By convention whitespaces in filenames are to be avoided and should be replaced with the underscore character (_). Before encrypting your files please make sure that any files that will be uploaded to EGA do not use special characters such as # ? ( ) [ ] / \ = + < > : ; " ' , * ^ | &  Crypt4gh EGACryptor Files encrypted with EGACryptor must be uploaded via FTP EGACryptor The EGACryptor v.2.0.0 is a JAVA-based application which enables submitters to produce EGA compliant encrypted files along with files for the encrypted and unencrypted md5sum for each file to be submitted. The application will generate an output folder that will by default mirror the directory structure containing the original files. This output folder can subsequently be uploaded to the EGA FTP staging area via an FTP or Aspera client. Download EgaCryptor Download EgaCryptor Using the EgaCryptor Using the EgaCryptor Encrypting single file Encrypting multiple files Encrypting all files in folder Points to note Troubleshooting Troubleshooting Download EGACryptor The required jar files can be obtained by downloading EgaCrytptor jar file After the file has been downloaded, extraction of the zipped archive is required. The EGACryptor has been built to work with Java Runtime Environments from version 6 and above and with the OpenJDK Environment. Please refer to the relevant resources for installation guidance. Installing the latest version of the OpenJDK will include the JCE files. If your installation of Java JRE is less than 1.8.0_151 will require the manual installation of the JCE Policy Files. You can verify the version of the Java SE Runtime Environment (JRE) installed by using the command: $ java -version If you need to install the JCE please follow the instructions below: Installing the JCE policy files (due to licensing terms and conditions the required policy files must be downloaded direct from the ORACLE website) : Download the unlimited strength JCE policy files (JRE 6 / JRE 7/ JRE 8) Uncompress and extract the downloaded file. This will create a subdirectory called JCE. This directory contains the following files: README.txt, COPYRIGHT.html, local_policy.jar and US_export_policy.jar Install the two policy JAR files by replacing the existing ones in your java home directory. Install the two policy JAR files by replacing the existing ones in your directory. The standard place for JCE jurisdiction policy JAR files is: /lib/security [Unix] or \lib\security [Win32] Notes: refers to the directory where the Java SE Runtime Environment (JRE) was installed. Additional performance enhancements that have been included in the EGACryptor V2.0.0: The ability to parallelise the processing of datasets through the use of the resources on a system. Multicore systems will allow the user to specify n-1 cores for an n-core system. The use of this feature on clusters may speed up the processing of datasets that have large file numbers but consult your local cluster guide to ensure that there are not monopolising resources that are needed by other system users. The default for this process remains single threaded. 3 levels of system usage can be specified. Full usage within the limits detailed above. A limited mode that will ensure that 50% of the system resources are available for other tasks. Maximum mode is limited to 75% of system resources, this allows encryption to be prioritised but allows for the system to be usable for light alternate tasks. Finally there is a throttling mode that allows you to specify the exact number of computational threads to be used. the EGACryptor is able to ingest a structured directory and will output a directory with the same structure containing the encrypted files along with the md5checksums for the plain and encrypted files. The entire output directory can then be uploaded to the EGA for archival. as with the input path, it is now possible to specify the output path. the options have been updated inline with the upgraded functionality. The tool can only be used via the command line. The EGACryptor is designed to perform a single task, encrypting your data, for upload of these files please refer to our uploading guide Using the EgaCryptor Below are the three ways on how the EGACryptor tool can be used: Encrypting a single file : java -jar ../EGA-Cryptor_2_0_0.jar -i example1.bam Encrypting multiple files : java -jar ../EGA-Cryptor_2_0_0.jar -i "example1.bam,example2.bam" Encrypting all the files within a folder java -jar ../EGA-Cryptor_2_0_0.jar -i path/to/target/directory By default the EGACryptor v2 will create a new output directory containing all encrypted files and the relevant checksums within the target directory. If a specific directory is desired this can be specified by using the -o flag. This can be achieved in a similar manner to the following example: java -jar ../EGA-Cryptor_2_0_0.jar -i /path/to/target/directory -o /path/to/output/directory The tool will output three files per input file: file.gpg ( encrypted file ) file.md5( file md5 sum value file ) file.gpg.md5 ( encrypted file md5 sum value file ) All output files must then be uploaded to your submission account using Aspera or FTP. Further documentation on how to upload files: FTP and Aspera. Points to note Remember to provide the path to EgaCryptor.jar and run the command from within the directory the file/s are located. ECryptor writes files to the source directory of your local file system, as a result you must have write-access permissions for the source directory. Troubleshooting If in doubt about the function of the EGACryptor it is recommended to first consult the built-in documentation. This can be accessessed by using the -h flag as stated in the following table. Built-in Commands Table: list of the command line options built into EGA-Cryptor v2.0.0. Command line Option Action --------------------- ----------- -f Set this option to allow application to create maximum threads to utilise full capacity of cores/processors available on machine -h Use this option to view the bult-in help menu * -i File(s) to encrypt. Provide file/folder path or comma separated file path if multiple files in double quotes -l Set this option to allow application to create maximum threads equals to 50% capacity of cores/processors available on machine -m Set this option to allow application to create maximum threads equals to 75% capacity of cores/processors available on machine -o Path of the output file. This is optional. If not provided then output files will be generated in the same path as that of source file (default: output- files) -t Set this option if user wants to control application to create maximum threads as specified. Application will calculate no. of cores/processors available on machine & will create threads accordingly Encryption Errors UnixFileSystem.createFileExclusively (Native Method) The error is thrown by UNIX ("UnixFileSystem.createFileExclusively(Native Method)"). It appears that the user does not have write-access to the file system where the file to be uploaded is located. EGACryptor always writes MD5 checksums into files before uploading them to the server, and these files are created in the same location where the uploaded file itself resides.Solution: address your directory permission issue and re-run the command. Install JCE Unlimited Strength Jurisdiction Policy files The JCE policy unlimited strength jurisdiction files should be installed according to your current java version If you are still facing difficulty with the EGACryptor v.2 after having consulted the documentation please contact the EGA Helpdesk.

  Documentation submission/data/file-preparation/egacryptor

• Kibbutzim Family study

  The Kibbutzim Family Study (KFS) aimed to investigate the environmental and genetic determinants of cardiometabolic traits (phenotype is LDL-C)

  Dataset EGAD00010001551

• Amplicon sequencing data from organoids of colorectal cancer patients.

  The dataset includes 13 bam files. Each bam file is a different colorectal cancer patient organoid.

  Dataset EGAD00001004313

• RBWES

  Retinoblastoma is a rare childhood cancer of the retina. We studied retinoblastoma by Whole-Exome-Sequencing.

  Dataset EGAD00001007591

• Development and Use of Network Infrastructure for High-Throughput GWA Studies

  The "Development and Use of Network Infrastructure for High-Throughput GWA Studies" project is collaboration between Group Health Cooperative (GH), the University of Washington (UW), and the Fred Hutchinson Cancer Research Center (FHCRC). It is one of 5 sites participating in The Electronic Medical Records and Genomics (eMERGE) Network funded by the National Human Genome Research Institute (NHGRI) with additional funding from the National Institute of General Medical Sciences (NIGMS). The overall eMERGE project is designed to assess whether linking biorepositories of patients in healthcare delivery systems with electronic medical records (EMRs) is an efficient strategy for high-throughput genome wide association (GWA) studies and whether information can be pooled across sites. The primary phenotype in the Group Health/UW Aging and Dementia eMERGE study project is dementia. Phenotyped participants originated from four population-based sources. Seattle-area members of GH (a large integrated health care system in Washington State) consented and enrolled in 1) the University of Washington Alzheimer&#39;s Disease Patient Registry (ADPR) and 2) the Adult Changes in Thought (ACT) study, 3) Marshfield Clinic Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults, 4) Vanderbilt&#39;s BioVU, a de-identified DNA biobank. The ADPR (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is a population-based registry of incident dementia cases designed to identify all new dementia cases within GH from 1987 to 1996. Potential dementia cases were identified through referrals from primary care physicians, mental health services, and neurologists, as well as review of CT scans, neurology, emergency room, geriatrician, and mental health clinic logs, and hospital discharge diagnoses. Medical history, physical, laboratory testing, and neuropsychological testing were performed on all consenting potential cases. These data were reviewed by a consensus conference including a neuropsychologist, study physicians, and an epidemiologist. After discussion of the case, dementia status is assigned using DSM-III-R criteria. Alzheimer&#39;s disease status was assigned using the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer&#39;s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The study base of the ADPR population was stable with an attrition rate of less than 1%/year. The ACT study (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is an ongoing community-based cohort study designed to determine the incidence of Alzheimer&#39;s Disease (AD), other types of dementia, and cognitive impairment and to determine risk factors for these conditions. The original cohort of 2,581 was enrolled in 1994-1996. An expansion cohort of 811 was enrolled in 2000-2002. Continuous enrollment to keep 2,000 persons enrolled and at-risk for dementia outcomes was begun in 2005. To date the study has accrued more than 4,000 participants. Dementia-free participants are enrolled in this cohort and evaluated every two years by study personnel with many evaluations including an assessment of cognitive functioning using the Cognitive Abilities Screening Instrument (CASI), which is an extended version of the Mini-Mental State Examination that has been widely used in epidemiological studies of the elderly. Persons with CASI scores lower than 86 or in whom interviewers suspect unusual cognitive decline are followed up with dementia diagnostic evaluations which include physical and neurological examinations and neuropsychological tests. Medical records are reviewed, and laboratory tests and neuroimaging are obtained if not available. The dementia diagnoses and dementia subtypes are determined during a consensus conference attended by the examining clinicians and other study physicians, a neuropsychologist, and research nurse. After discussion of the case, dementia status is assigned using DSM-IV criteria. Alzheimer&#39;s disease status was assigned using NINCDS-ADRDA criteria. Individuals diagnosed with dementia are seen again one year following diagnosis using the same procedures. Individuals not diagnosed with dementia are returned to the pool of at-risk individuals and are seen at their next routinely scheduled biennial visit. The ACT sub-sample is stable; for the original cohort, median enrollment in GH was 19 years prior to joining the ACT study, and 85% of the cohort has &#8805; 10 years of GH enrollment. DNA for the ADPR participants were obtained through a companion study, Genetic Differences in Cases and Controls (PI: Walter Kukull; NIH/NIA R01 AG007584). DNA obtained through both studies were extracted from blood using Gentra Systems Puregene methods. DNA concentration is determined by UV optical density. All samples are checked for quality by OD 260/280 ratio. For long-term storage, samples are aliquoted and stored at -70&#176;C. The Marshfield study, Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults. PMRP was started in 2002 as a 3 Phase project. Completed in April 2004, the objectives of Phase I were to build and develop a large population-based biobank with DNA, plasma and serum samples to facilitate genomics research. Phase 1 was also to educate, inform and consult with the Marshfield Epidemiologic Study Area population and communities concerning potential studies, create the DNA foundation of the personalized medicine database and build the bioinformatics tools to store securely and analyze genotypic and phenotypic data. Phase I tasks included operation of the ethics and security advisory board, scientific advisory board and community advisory group. More than 18,000 residents aged 18 and above from 19 different zip codes surrounding Marshfield, WI were invited to participate in Phase I. After providing written informed consent, participants completed brief questionnaires that included questions about demographics, some environmental exposures, family history of disease, and adverse drug reactions, as well as family members living in the area. Participants provided 50ml of blood from which DNA was extracted and plasma and serum samples were stored. The informed consent process allowed access to electronic medical records and included language about non-disclosure of personal research results. A tick-off box was included so that participants could either allow or decline subsequent recontact for future research studied. The objectives of Phase II are to create the phenotypic database, establish the scientific and administrative infrastructure to support genetic mapping of the DNA and the initial discovery projects and genotype a sufficient portion of the genetic material to support these discovery projects. The objectives of Phase III are to expand the discovery projects, complete the genotyping of the genetic database and expand physician/health care provider education and community consultation. The Vanderbilt BioVU model uses discarded blood leftover from clinical care and de-identified clinical information, both of which are tracked with a Research Unique Identifier that is permanently disconnected from the medical record number used to generate it. The Vanderbilt IRB determined that the project does not qualify as "human subject" research under &#167;46.102(f)(1)(2). The program has been reviewed by OHRP twice (the latest immediately prior to launch), and the determination of the Vanderbilt IRB that the project is consistent with the 8/10/2004 guidance has been validated. The model includes a simple opt out mechanism developed for patients who do not wish to have their samples included. Planning (including community involvement, ethics and IRB discussions, focus groups, development of operating procedures and pilot studies to assess them) began in May 2004, and the resource commenced sample collection in February 2007 and as of May 2009 contains approximately 56,000 samples. The current resource will be available to all Vanderbilt investigators who sign a Data Use Agreement. The resource represents Vanderbilt&#39;s broad patient population and thus provides a potential resource for research in a range of common and rare diseases as well as drug response or medication safety. BioVU patient protection model: There has been extensive involvement by the ethics community and the IRB to put in place procedures to provide privacy protection. The overall protection plan is multifaceted and includes a combination of technology and policy: (1) creation of the SD described above; (2) return of only the specific clinical data items requested by investigators (rather than the complete de-identified chart); (3) submission of any specific proposed project to the IRB and to a separate protocol review committee, both of which must approve; (4) implementing a Data Use Agreement that permits only approved queries and data analyses, specifically prohibits attempts at re-identification (at the risk of institutional sanctions), and mandates redeposit of all genetic information generated in a research study back into a genomic database; and (5) tracking and auditing all use.

  Study phs000234

• Center for Craniofacial and Dental Genetics: Study of Dental Caries and Cleft Lip/Palate in Guatemala

  This study provides an opportunity to investigate the genetics of both dental caries and orofacial clefts (OFCs) in one set of families ascertained in Guatemala. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). Furthermore this study brings together multiple research priorities of the University of Pittsburgh Center for Craniofacial and Dental Genetics (www.ccdg.pitt.edu). A genome-wide panel of 610,000 SNPs was genotyped at the Broad Institute to be comparable to our other pertinent GENEVA studies that are also part of dbGaP (dbGaP accession number phs000095, "Dental Caries: Whole Genome Association and Gene x Environment Studies" and dbGaP accession number phs000094, "International Consortium to Identify Genes and Interactions Controlling Oral Clefts"). The goal of this study is to investigate genetic determinants to dental caries and to OFCs in a novel study population. To date, most genetic studies of dental caries have been conducted in Caucasians, and of OFCs in Caucasians and Asians. The Guatemalan population under study is rural and ethnically mixed with a high proportion of Native-South-Americans. Thirty-six Guatemalans from this dataset were also part of the recent GWAS studies of cleft lip and cleft palate (Beaty et al., 2010 and 2011, dbGaP Study Accession: phs000094, "International Consortium to Identify Genes and Interactions Controlling Oral Clefts"). In addition to the families ascertained in Guatemala, some subjects were genotyped with this cohort to augment the data in the parent GENEVA study (Dental Caries: Whole Genome Association and Gene x Environment Studies, dbGaP accession number phs000095), in particular individuals from the IOWA and PITT GENEVA study sites. Their data are available with the parent study. Dental caries (also known as tooth decay) remains the most common chronic disease of childhood, five times more common than asthma and seven times more common than environmental allergies, with more than 40% of children exhibiting caries when they enter kindergarten. In 2005, it was estimated that dental health care costs were approximately $84 billion, of which 60% or about $50 billion were related to treatment of dental caries. The etiology of dental caries has been studied for many years. Multiple factors contribute to a person&#39;s risk for caries, including: 1) environmental factors such as diet, oral hygiene, fluoride exposure and the level of colonization of cariogenic bacteria and 2) host factors such as salivary flow, salivary buffering capacity, position of teeth relative to each other, surface characteristics of tooth enamel and depth of occlusal fissures on posterior teeth. In spite of all that is known about this disease, there are still individuals who appear to be more susceptible to caries and those who are extremely resistant, regardless of the environmental risk factors to which they are exposed, implying that genetic factors also play an important role in caries etiology. This conclusion is supported by studies in both humans and animals, with the most compelling evidence coming from studies of twins reared apart in which investigators found significant resemblance within monozygotic (MZ) but not dizygotic (DZ) twin pairs for percentage of teeth and surfaces restored or carious and estimated the genetic contribution to caries as 40%. Other recent studies of twins reared together estimated the heritability for caries, adjusted for age and gender, as ranging from 45-64%. In our study populations of families, we also estimated caries heritability as approximately 54%-70% of variation in primary dentition caries scores and 35%-55% in the permanent dentition (Wang et al., 2010). Orofacial clefts (OFCs), particularly cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CP) are a major public health problem, affecting one in every 500-1000 births worldwide thus representing the most common facial birth defect and one of the most common of all congenital anomalies. CL/P is a major structural birth defect that is notable for significant lifelong morbidity and complex etiology. The extensive psychological, surgical, speech and dental involvement emphasize the importance of understanding the underlying causes of CL/P. Therefore, many research groups have attempted to elucidate the etiology of CL/P, with some recent success by our research group and others (see Beaty et al., 2010, 2011; Dixon et al., 2011). It is clear that CL/P can occur as part of Mendelian syndromes, that certain chromosomal abnormalities include CL/P in the phenotype, and that certain teratogens can increase the risk of having an offspring with CL/P. However, phenotypes of known etiology comprise only a small portion of all individuals with a CL/P or CP, and the major focus of research into OFCs is to develop an understanding of the etiology of nonsyndromic (NS) forms of clefting. A major focus of the University of Pittsburgh CCDG has been to study additional phenotypes within nonsyndromic OFC families in order to identify sub-clinical expressions of OFC risk genes or risk variants, e.g. SNPs (see Weinberg et al., 2006). A detailed oral exam is conducted as part of these extended phenotypic studies, including a dental caries exam. Note that although there are some reports in the literature of higher caries experience in individuals with clefts, the most recent meta-analysis of those literature reports concluded that individuals born with these defects do not have a higher frequency of caries (Hassl&#246;f and Twetman, 2007). Notably, we investigated the association of CL/P and caries in three of our study populations (including part of the Guatemalan population in this GWAS study) and also found no increase in caries rates of CL/P cases versus controls (Jindal et al., 2011). This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to dental caries and oral clefts through large-scale genome-wide association studies of well-characterized Guatemalan families and individuals. Genotyping was performed at the Broad Institute of MIT and Harvard. The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR, U01-DE018903). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000440

• Paired-end Whole Exome-seq analysis of GBM, additional patient.

  Dataset contains one paired-end Whole Exome sequencing sample. One normal blood sample is also included.

  Dataset EGAD00001011989

• PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development

  The coding variant (p.Arg192His) in the transcription factor PAX4 is associated with an altered risk for type 2 diabetes (T2D) in East Asian populations. In mice, Pax4 is essential for beta cell formation but its role on human beta cell development and/or function is unknown. Participants carrying the PAX4 p.His192 allele exhibited decreased pancreatic beta cell function compared to homozygotes for the p.192Arg allele in a cross-sectional study in which we carried out an intravenous glucose tolerance test and an oral glucose tolerance test. In a pedigree of a patient with young onset diabetes, several members carry a newly identified p.Tyr186X allele. In the human beta cell model, EndoC-βH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content, and altered hormone gene expression. Deletion of PAX4 in human induced pluripotent stem cell (hiPSC)-derived islet-like cells resulted in derepression of alpha cell gene expression. In vitro differentiation of hiPSCs carrying PAX4 p.His192 and p.X186 risk alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content that can be reversed with gene correction. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function, and its contribution to T2D-risk.

  Dataset EGAD50000000516

• How are we funded?

  How are we funded? The EGA is provided infrastructure, administrative support, advisory input, and other relevant and necessary aspects by: CRG The EGA at the CRG is funded and supported by “La Caixa Foundation”, The Generalitat de Catalunya (Catalan Government), the Spanish Ministerio de Asuntos Económicos y Transformación Digital (Spanish Government) and the Instituto de Salud Carlos III. The Generalitat de Catalunya contributes with funding to the CRG and to the Barcelona Supercomputing Centre (BSC). The Barcelona Supercomputing Center is decisively contributing to EGA by providing the required compute, storage and networking resources, as well as key personnel for shared operations of EGA infrastructure. EMBL-EBI As part of the European Molecular Biology Laboratory (EMBL), the EGA at EMBL’s European Bioinformatics Institute receives funding from the governments of EMBL’s member states. The UK government, via UK Research and Innovation, also continues to support EMBL-EBI technical infrastructure, with EMBL supporting operational costs. A major source of funding for the EGA both at CRG and EMBL-EBI are competitive projects.The EGA resource continues to be funded through strategic engagement in collaborative partnerships and projects. Please see our projects page for more information. Other funders include the European Commission, the US National Institutes of Health, the Wellcome Trust, UK Research Councils, and our Industry Programme partners. Last updated on October, 2024.

  Documentation about/projects-and-funders/funders

• GCAT | Genomes for life

  The GCAT project is a prospective cohort study that was designed to recruit the general population of Catalonia, the north-east region of Spain. This study is a long-term genomic, environmental and lifestyle cohort project that aims to evaluate and track multiple pathologies as well as biologically related traits. By the end of 2017, the GCAT Study had recruited a total of 20 000 participants aged 40–65 years. Participants who agreed to take part in the study completed a self-administered computer-driven questionnaire, and underwent blood pressure, cardiac frequency and anthropometry measurements. For each participant, blood plasma, blood serum and white blood cells are collected at baseline. The GCAT Study has access to the electronic health records of the Catalan Public Healthcare System. Participants are followed biannually for/during, at least, 20 years after recruitment. Therefore, the GCAT Study offers a unique opportunity to integrate diverse data to allow the identification of novel relations among different biomarkers and conditions. Results may lead to the development of new genetic, genomic, epigenomic and proteomic diagnoses and screening tests, as well as new public health recommendations. The only currently available population-based prospective cohort study in Spain to the date, including more than 4899 genotyped participants and 800 whole genome sequences is now stored in the EGA archive under accession id EGAS00001003018.

  Blog gcat-genomes-for-life

• SS18-SSX-mediated hijacking of BAF complexes drives synovial sarcoma

  Synovial sarcoma (SS) is defined by a recurrent t(x;18) chromosomal translocation, which produces the hallmark SS18-SSX oncogenic fusion. Incorporation of SS18-SSX into BAF complexes renders BAF complexes aberrant in two distinct manners: the addition of 78aa of SSX onto SS18, and concomitant loss of BAF47 assembly. However, the importance and functional contributions of each of these perturbations on BAF complex targeting and gene expression regulation remain unclear. Here we use an integrative set of genomic approaches in human cancer cell lines and primary tumor samples to define the mechanistic consequences of the SS18-SSX fusion oncoprotein. We find that SS18-SSX hijacks BAF complexes to broad polycomb domains to activate bivalent genes, driving a unique gene expression program distinct from other loss-of-function BAF complex malignancies. Importantly, restoration of BAF47 rescues enhancer activation but is dispensable for proliferative arrest in cell lines. These results demonstrate that gain-of-function SS18-SSX-mediated BAF complex targeting and gene activation is the driving event in SS, and present a mechanism by which distinct functions of BAF complexes can be co-opted to drive oncogenesis.

  Dataset EGAD00001004135

• CyTOF of 27 DLBCLs

  Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell-of-origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B-cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naïve patients. We found that malignant B-cells from each patient occupied unique regions in 37-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case we were able to demonstrate direct correspondence between protein-level phenotypic subsets and DNA mutation-defined subclones. In summary, CyTOF analysis can resolve both inter- and intra-tumoral heterogeneity among primary samples, and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones.

  Dataset EGAD00001005419

• eMERGE: Northwestern (NUgene) WGS

  The NUgene Project is a biorepository with longitudinal medical information from participating patients at Northwestern Medicine affiliated hospitals and outpatient clinics. Participants&#39; DNA samples are coupled with data from a self-reported questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 3 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated enterprise data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. The electronic MedicalRecords and Genomics (eMERGE) Network is a consortium of 9 clinical sites with EMR linked DNA biobanks, including Northwestern University and its NUgene biobank, funded by the NHGRI (National Human Genome Research Institute) to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 100,000 individuals using EMR-derived phenotypes and DNA from linked biorepositories. Using electronic phenotyping methods, the consortium has been and is using DNA samples from all participating sites to explore the genetic determinants of approximately 80 phenotypes, including both diseases and traits, for which the electronic phenotyping algorithms have or are being published on PheKB.org. Thus, for the eMERGE network, ~900 NUgene subjects were selected, as described in the study inclusion/exclusion criteria section below, to be genotyped using whole genome sequencing (WGS), for use in the eMERGE network as eMERGE subjects. The criteria used below were selected so that these subjects will likely meet the criteria to be cases and/or controls, of diverse races and/or ethnicities, for at least 1 of the ~80 phenotypes being studied within eMERGE, and could be recontacted for future research if needed.

  Study phs001191

• Effect of Breast Feeding on Immunologic Priming in Young Infants

  The mechanisms generating immunoglobulin heavy chain (IgH) biodiversity result in over potentially unique immunoglobulin sequences within an individual. However, over the course of B cell development, B cell receptor (BCR) selection constrains the repertoire significantly. In newborn infants compared to adults, developmental regulation of terminal deoxynucleotidyl transferase (TdT) activity in the bone marrow, selective use of V, D and J gene segments in the IgH locus during fetal life, and immaturity of somatic hypermutation (SHM) and class switch recombination (CSR) mechanisms are likely to contribute to a less diverse IgH repertoire, although the extent of repertoire biodiversity in newborns has not been extensively examined. Furthermore, the fetal IgH repertoire is tightly controlled and for the most part independent of environmental antigenic influences. As a result, the neonatal repertoire, in contrast to older children and adults, is less impacted by the selective pressures of the microbiome, pathogen exposure, and environmental antigens. Evidence for developmental differences in TdT activity is seen in shorter CDR3 lengths and decreased junctional diversity in BCR in both term and preterm newborns. Next Generation Sequencing (NGS) is a sensitive approach to evaluate the neonatal IgH repertoire and assess the relative contribution of each aspect of IgH rearrangement and affinity maturation to overall IgH biodiversity prior to and following isotype class switch. NGS and bioinformatics accurately assess biodiversity by determining the number of unique sequences within the IgH repertoire. Combined with novel analytic tools, NGS provides an approach to compare the extent of somatic hypermutation (SHM), N insertions, V/D/J gene segment usage, and CDR3 length between newborns and adults. Taken together, these measures can be used to assess the earliest events in B cell development using the newborn Ig transcriptome to evaluate the IgM, IgG, and IgA IgH repertoires. The goal of this study was to define the extent of IgH biodiversity in newborns and examine the factors that contribute to the generation of biodiversity during early life. Establishment of the bioinformatics pipeline can be applied to examine the immune deficiency, response to vaccine and infection at molecular population level.

  Study phs002073

• LCCC1122: Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212

  In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a &#34;window of opportunity&#34; trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

  Study phs001405

• Exceptional Responders Initiative

  The Exceptional Responders Initiative is a pilot study to investigate the underlying molecular factors driving exceptional treatment responses of cancer patients to drug therapies. Study researchers will examine molecular profiles of tumors from patients either enrolled in a clinical trial for an investigational drug(s) and who achieved an exceptional response relative to other trial participants, or who achieved an exceptional response to a non-investigational chemotherapy. An exceptional response is defined as achievement of either a complete response or a partial response for at least 6 months duration in a trial or treatment where the overall response rate is &#60; 10%. The hope is to discover underlying molecular features that can be further investigated and may eventually predict benefit from a given drug or class of drugs for a particular patient. This pilot project will successfully characterize approximately 100 cases of tumor tissue and, when available, case-matched germline DNA. All samples will undergo whole exome sequencing, and cases with sufficient nucleic acids will undergo additional analyses (e.g. whole genome sequencing, mRNA-sequencing, mi RNA sequencing, promoter methylation analysis, SNP etc). Each case will be annotated with demographic and clinical information, along with follow-up information minimally sufficient to correlate molecular profiles with response. Both retrospective and prospective collections will be considered. The project will also accept sequencing data and clinical data from patients who have had sequencing performed outside of this project. All data will be de-identified and placed in a controlled access database so other investigators may use them for additional insights. Clinically annotated tissue specimens meeting the criteria will be provided by groups participating in the Exceptional Cases Initiative to a Biospecimen Core Resource (BCR), which will perform quality control on the tissues, and will use a standard operating procedure to isolate nucleic acids. The nucleic acids will be shipped to a sequencing center to perform whole exome sequencing and analysis. These findings will be made available to the broader cancer research community in a controlled access database.

  Study phs001145

• NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Pulmonary Arterial Hypertension)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The syndrome of pulmonary hypertension (PH) is a pulmonary disease that carries very high morbidity and mortality. Pulmonary arterial hypertension (PAH) is a category of PH (WHO Group 1) that includes several entities (idiopathic or heritable PAH, and PAH associated with other diseases such as connective tissue diseases including scleroderma-associated PAH) and carries a dismal prognosis, in particular when it relates to scleroderma-associated PAH (median survival of about 4 years). It is believed that the severity of structural changes involving the pulmonary vasculature and right ventricular failure are genetically determined. The &#39;Genomics and Genetics of Pulmonary Arterial Hypertension&#39; study at Johns Hopkins University aims to identify genetic determinants associated with risk of PAH in a cohort of European American and African American participants with and without PAH. The study also focuses on patients with scleroderma, who are further stratified according to those who have or do not have PAH. The broad goals of the Lung GO/ESP-GO falls into two general categories: (i) discovery of all variants (i.e., common and rare) in all protein-coding regions of the human genome (i.e., the exome) conferring risk to complex pulmonary diseases including PAH. The Johns Hopkins University PAH cohort offers a unique opportunity to elucidate genetic variants that cause PAH.

  Study phs000290

• Identification of Modifiers of 22q11.2 Deletion Syndrome in Whole Genome Sequence - CIDR

  This project aims to identify genetic modifiers of congenital heart disease (CHD), which occurs among 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge syndrome/velo-cardio-facial syndrome) patients. In contrast to the prevalence of ~0.8% in the general population, about 60%-70% of 22q11.2DS patients have CHD, of which most are conotruncal heart defects, making 22q11.2DS a very ideal model to study the genetic underpins of CHD. The chromosome 22q11.2 region is susceptible to meiotic chromosome rearrangements leading to hemizygous deletions, because there are large blocks of low copy repeats, termed LCR22s, that are dispersed in the region. Non-allelic homologous recombination during meiosis can lead to specific-sized deletions. Approximately 90% have a typical hemizygous 3 million base pair (Mb) deletion between LCR22-A and -D, while some have nested deletions between LCR22-A and B or LCR22-A and C. Our goal is to perform a case-control association study, in which cases have CHD, while controls have normal heart structures, all with 22q11.2DS. All individuals are unrelated and have been collected from collaborators in the US, Canada and Europe. All subjects received a clinical diagnosis of 22q11.2DS and signed informed consent to allow a blood sample to be collected for research. The DNA samples were de-identified in 2 steps to protect their privacy. We then determined deletion type using multiplex ligation-dependent probe amplification (MLPA). This information is provided for the great majority of subjects. We also obtained cardiac phenotype information from echocardiogram reports as well as reported race and ethnicity (Hispanic vs. non-Hispanic information), which is required for the analysis. We will obtain 30X whole-genome sequence data from NIH CIDR. We will first annotate the sequence variants identified to uncover rare ( For genotype data, we will provide the raw fastq data from whole-genome sequencing as well as the called variants file in a VCF file. For phenotype data, we will provide the sample relationship files (ped files), CHD affection status, deletion type, and race.

  Study phs002514

• Security Overview

  Security Overview The European Genome-phenome Archive (EGA) houses consented human data under controlled access. Access decisions are handled by the relevant Data Access Committee (DAC), which autonomously manages requests through the DAC Portal. This document provides an overview of EGA’s practices in ensuring the security of data stored at EGA. As security is a prime concern of the EGA, the EGA is a member of the Global Alliance for Genomics and Health (GA4GH) Data Security work stream. The EGA contributes and helps develop the recommendations outlined the GA4GH Security Technology Infrastructure document, which defines guidelines, best practices, and standards for building and operating an infrastructure that promotes responsible data sharing in accordance with the GA4GH Privacy and Security Policy. Explore the EGA dataflow to gain deeper insights! Accessing data in the EGA involves several steps. First, users need to create an EGA account. Once logged in, they can request access to data controlled by a DAC through the EGA website (see documentation). The DAC oversees these requests through the DAC Portal, and if approved, grants the necessary permissions to the user's EGA account, allowing them to access and download all relevant data and metadata for the requested dataset(s). The key points of EGA security strategy are: 1 Regular Risk Assessment The EGA regularly identifies and assesses risk related to the following: Breach of confidentiality,Breach of privacy or autonomy,Malicious or accidental corruption or destruction of data archived at EGA,Disruption of services provided by the EGA. 2 Risk mitigation The EGA implements and maintains safeguards to minimise the risks identified above in accordance with the 6 control objectives listed in Appendix 1 and outlined in the GA4GH Security and Infrastructure document.If a breach is discovered, the EGA applies a defined protocol to minimise damage. 3 Identity and authorisation management The EGA authenticates the identity of individuals or software accessing controlled access data held at the EGA.The EGA ensures an appropriate level of assurance (LoA) is applied to the identity consistent with the risk associated with that individual, such as multi-factor authentication for DACs.The EGA provides the minimum access rights and privileges consistent with the user’s identity, allowing access consistent with the GA4GH Privacy and Security Policy, as determined by the appropriate DAC. 4 Audit Logs The EGA maintains a set of logs recording: Changes to user access rights,Data access requests,Resource usage. 5 Cryptography, communication security, and data integrity The EGA ensures data transmission integrity using a hash function.All data transmitted to or from the EGA is end-to-end encrypted.All data at EGA is stored using strong encryption.Encryption keys are not stored in the same system as the encrypted data.All data archived at EGA must be accompanied by a signed submission statement ensuring appropriate consent or ethical approval has been obtained, and is in accordance with all applicable laws and regulations. The EGA has a defined protocol defining the response in the event of a security breach, and is continuing to work with the GA4GH Data Security Work Stream to help define best practice and associated standards for breach responses. Appendix 1 GA4GH Control Objectives Control Objective 1: Implement technology safeguards to minimise the risk of unauthorised access, use, or disclosure of confidential and private data.Control Objective 2: Implement technology safeguards to minimise the risk of discovery, access, and use of individuals’ clinical and genomic data, and individual identities, other than as authorised by applicable jurisdictional law, institutional policy, and individual consents.Control Objective 3: Implement technology safeguards to minimise the risk of accidental or malicious corruption or destruction of data.Control Objective 4: Implement technology safeguards to minimise the risk of disruption, degradation, and interruption of services enabling access to data.Control Objective 5: Implement technology safeguards to minimise the risk of potential security attacks and misuse of authorised accesses and privileges.Control Objective 6: Implement technology safeguards to promptly detect the failure to attain the above control objectives and to respond with proper countermeasures.Appendix 2Refer to the document below to learn more about EGA long-term data preservation policy and procedures at EMBL-EBI.Long-term data preservation

  Documentation about/security

• HCA_Thymus_Disease_DiGeorge_Transplant_RNA

  Single cell transcriptomics study of thymic transplant biopsies Allogeneic thymus transplantation is the only curative therapy for complete DiGeorge Syndrome (cDGS), a rare severe primary immunodeficiency characterised by athymia. GOSH is one of only two centres worldwide to offer this treatment. Despite a lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus becomes repopulated by recipient bone marrow derived precursor cells and supports development of functional T-cells. The mechanisms underlying thymopoiesis in this context are poorly understood, but over time we observe reconstitution of T-cell immunity, with the ability to produce host naïve T-cells showing a broad T-cell receptor (TCR) repertoire and to generate MHC-restricted T-cell proliferative responses. Although lifesaving, the achieved immunological reconstitution is typically not complete with circulating T-cell numbers usually remaining below the age related normal ranges. Additionally, we observe persistence of donor-derived T-cells of unknown clinical significance. To gain more insight into the mechanisms by which MHC-mismatched transplanted thymus supports T-cell development with self-tolerance, as well as into the basis of suboptimal T-cell immunity, we now aim to investigate immune reconstitution after thymus transplantation in further detail by using single-cell transcriptomics, applied to thymic transplant biopsies and peripheral blood samples collected during standard post-transplant patient care. By identifying which lineages of host- derived cells repopulate the thymic tissue after transplantation, we will be able to address the role of MHC in positive and negative T-cell selection during T-cell differentiation. We will also be able to clarify the exact ontogeny of the persistent donor T-cells, as well as their possible role. Understanding the mechanisms of action of HLA-mismatched transplanted thymus will contribute to treatment optimisation. Additionally, our research provides a unique opportunity to further investigate key immunological concepts, such as tolerance and autoimmunity, challenging existing paradigms in thymus immunology. 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/

  Study EGAS00001004025

• Upcycling and merging data to challenge the dogma and identify new therapeutic targets for Glioblastoma

  Glioblastoma is the most common brain tumour. Characterised by a poor prognosis and its recurrence after multimodal treatments, the search for preventable risk factors has been mainly inconclusive up to date. Recently, the data merge from datasetsdeposited at the EGA allowed Aaron Diaz’s team to discover that the glioblastoma cells shift toward a mesenchymal phenotype when the tumour is recurring. Challenges in glioblastoma research As for virtually all cancer types, many efforts have been made to unveil the molecular features responsible of the disease, and several cellular pathways have indeed been identified as being frequently mutated in glioblastoma. Nonetheless, targeted therapies based on identified genes have so far failed to improve outcome, thus survival mostly relies on a standard treatment unchanged since 2005. This is a frustrating situation for both the scientific and medical communities, and above all for the patients, still facing a dreadful path. Some researchers hypothesised that this may be due to the inability to efficiently target cancer stem cells, the originators of the other cell types, thus inducing cancer relapse. In 2019 Charles P. Couturier and colleagues sequenced RNA from single cells of freshly excised glioblastomas of 16 patients, and demonstrated that glioblastoma cells replicate normal brain cell development with a conserved neural cancer cell hierarchy centered around glial progenitor-like cells. In this way, they helped identify the possible target cells to improve efficacy and durability of treatment. Data upcycling at the EGA: the glioblastoma case study Single cell RNA sequencing is generated with a laborious and expensive protocol. The quality of the starting material is crucial (cells sample freshly extracted from the patients) and often several attempts are needed before producing reliable quality sequencing results. Collecting big numbers of patients is also challenging. The sequencing data produced by Kevin Petrecca’s group in Montreal, Canada and deposited at the EGA (EGAS00001004422) was recently upcycled by Lin Wang in San Francisco, California and pooled with their freshly produced ones, and then deposited at the EGA as Dataset EGAS00001004909 The data merge allowed Aaron Diaz’s team to discover that the glioblastoma cells shift toward a mesenchymal phenotype when the tumour is recurring. They profiled 86 primary-recurrent patient-matched paired glioblastoma samples with single-nucleus RNA, among other techniques. These very comprehensive results lead the team to challenge the findings from several other cancer fields where chemotherapy standard chemo-radiation therapy selection pressure at the level of genomic alterations; this is indeed not the case for glioblastoma, where the pressure results in phenotypic transition between cellular states. Several technical controls were made to ensure that the merge of the data was not introducing a bias in the results, and an Inter-table analysis demonstrated nearly equal contribution to overall variance from each of the studies included, indicating that the findings were not due to inter-laboratory technical effect. A novel principal-component analysis showed that the largest contribution to variation in primary glioblastoma neoplastic cells was an axis between MES (mesenchymal) and proneural expression programs. In summary, treating glioblastoma often makes a MES, as commented by Lucy Stead about this remarkable work. Check Aaron Diaz’s team Nature Cancer paper, with strong technical tools, state of the art analysis and data from different sources converging to the same outcomes that made possible a significant step toward a better handling of a frightful cancer. References Couturier, C.P., Ayyadhury, S., Le, P.U. et al. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nat Commun 11, 3406 (2020). Stead, L.F. Treating glioblastoma often makes a MES. Nat Cancer 3, 1446–1448 (2022). Wang, L., Jung, J., Babikir, H. et al. A single-cell atlas of glioblastoma evolution under therapy reveals cell-intrinsic and cell-extrinsic therapeutic targets. Nat Cancer 3, 1534–1552 (2022). Related links: Kevin Petrecca’s group dataset deposited at the EGA: EGAS00001004422 Lin Wang dataset deposited at the EGA: EGAS00001004909

  Blog upcycling-and-merging-data-to-challenge-glioblastoma

• Effects of 2DG, Galactose, or Oligomycin on the epigenome remodeling induce by T cells activation.

  T cell activation is known to require a metabolic shift towards glycolysis, triggered by TCR-engagement . To substantiate the role of glycolysis in transcriptional reprogramming during antigen-driven T cell activation, we utilized a well-established ex-vivo model to recapitulate the process of antigen stimulation without the requirement for additional antigen-presenting cells . We initially explored and validated the conditions for both metabolic and epigenetic reprogramming. Antigen-mediated CD4+ T cells activation initiates context-specific gene-expression programs that drive effector functions and cell fates through changes in the epigenetic landscape . To evaluate global changes in histone modifications, we isolated CD4+ T cells from peripheral blood (PB) of healthy control (HC) human donors and either maintained them in resting conditions or stimulated with anti-CD3/CD28 for 24h. Rapid changes in the CD4+ epigenome and transcriptome were observed within 24h as measured by RNA-sequencing (RNA-seq) and H3K27ac chromatin immunoprecipitation followed by DNA-sequencing (ChIP-seq).To explore the requirement for metabolic reprogramming in regulating transcriptional responses after initial TCR engagement, CD4+ T cells from PB of healthy donors were isolated and activated in either the presence or absence of oligomycin (inhibitor of ATP synthase blocking the production of ATP by OXPHOS), 2-deoxyglucose (2DG; competitively inhibiting production of glucose-6-phosphate from glucose), or replacement of glucose with galactose. Galactose is metabolized through glycolysis, utilizing the Leloir pathway which is energy neutral, forcing cells to use all the pyruvate production to sustain the TCA cycle for OXPHOS and ATP synthesis at the expense of lactate production. Employing ChIP-seq and RNA-seq, inhibition of OXPHOS-mediated ATP production by oligomycin had only a limited effect on H3K27-acetylation or activation-induced transcription during the first 24h of activation. In contrast, inhibition of glycolysis by 2DG treatment compromised both H3K27-acetylation and transcriptional changes. However, under conditions of galactose-metabolism where lactate production is abrogated, activated CD4+ T cells were still able to globally remodel H3K27 acetylation and reprogram the transcriptome.

  Study EGAS00001007115

• Genome-wide differential DNA methylation signatures in pediatric acute lymphoblastic leukemia

  The aim of our study is to provide a comprehensive analysis of DNA methylation in a large collection of primary pediatric acute lymphoblastic leukemia (ALL) samples taken at diagnosis and relapse of the disease as well as non-leukemic control blood cells from healthy individuals. Complementary gene expression data available at the Gene Expression Omnibus under series GSE26878.

  Study EGAS00000000135

• INTEGRATIVE MOLECULAR ANALYSIS OF SKIN TUMORS FROM CYLD CUTANEOUS SYNDROME PATIENTS

  CYLD cutaneous syndrome (CCS) is a rare autosomal dominant disorder characterized by germline CYLD mutations and by multiple benign skin tumors dependent on NF-kB pathway. We assembled a large cohort of CCS rare skin tumors that was profiled with whole exome or genome sequencing, RNA sequencing and methylation arrays to better understand genetic mechanisms of CCS tumorogenesis.

  Study EGAS50000000247

• Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile

  The Multiple Myeloma Research Foundation (MMRF) CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile) trial (NCT01454297) is a longitudinal observation study of 1000 newly diagnosed myeloma patients receiving various standard approved treatments that aim at collecting tissue samples, genetic information, Quality of Life (QoL) and various disease and clinical outcomes over 10 years.

  Study phs000748

• Childhood Cancer Data Initiative (CCDI): Clonal Evolution During Metastatic Spread in High-Risk Neuroblastoma

  The goal of this study is to deliver a detailed characterization of the patterns of disease dissemination at diagnosis, during progression and in response to therapy in high-risk neuroblastoma. Longitudinal and spatially distinct tumors were collected from patients. Clinical data includes diagnosis and treatment information. Biospecimen data includes whole genome sequencing (WGS) and whole transcriptome sequencing (WTS).

  Study phs003111

• Whole-Genome Sequencing (WGS) of a Malignant Granular Cell Tumor (GCT) with Metabolic Response to Pazopanib

  We report one case study of a malignant granular cell tumor patient with metabolic response to pazopanib. In this study, we used whole-genome sequencing of the tumor with the matched blood to characterize the somatic mutation profile in this tumor. This is the first reported whole-genome sequencing study of the rare malignant granular cell tumor.

  Study phs000978

• National Cancer Institute (NCI) Waldenstrom Macroglobulinemia Genome-wide Association Study

  A discovery GWAS is performed, consisting of genotyping 221 Waldenstrom macroglobulinemia (WM) cases on the Illumina Omni Express 12v1.1 platform and analyzing the genotypes together with those of 3798 previously genotyped controls in a model taking into account gender, age, and principal components of ancestry (i.e., significant eigenvectors). Directly genotyped data are supplemented by imputation using the Haplotype Reference Consortium.

  Study phs001284

• NCI's Datasets for General Research Use

  This collection contains all of NCIs authorized individual-level genomic datasets currently in dbGaP that are approved for General Research Use (GRU) and have no further limitations beyond those outlined in the model Data Use Certification Agreement. Access to this study will include any additional authorized individual-level GRU datasets that become available. Renewal of this study is required annually.

  Study phs003014

• Myocardial Infarction Genetics Exome Sequencing Consortium: Ottawa Heart Study

  The Ottawa Heart Study is a cross-sectional case-control study designed to identify genes that predispose to angiographically defined coronary artery disease. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000806

• Genetic Determinants of Susceptibility to Severe COVID-19 Infection

  The goal of the project is to identify genetic susceptibility variants associated with acute COVID-19 infection susceptibility and severity using whole genome sequencing. The target of the project will include WGS data from whole blood samples of up to approximately 2000 COVID-19 patients (including critical/severe patient subgroup, asymptomatic/mild subgroup) from domestic and international medical institutions.

  Study phs002245

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS)

  Cohort Description The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) is a multi-center, observational, longitudinal case-control study designed to guide future development of therapies for COPD. SPIROMICS has recruited 2,983 COPD cases and controls, 40-80 years old with 20+ pack-years of smoking at 12 US sites in 2010&#8211;2015.

  Study phs002909

• Molecular Analysis of Alliance A031201 Study

  This is the first study examining the relationship between clonal hematopoiesis and clinical outcomes in prostate cancer patients. We used a targeted gene sequencing panel to identify patients in the A031201 clinical trial with and without clonal hematopoiesis. We found that clonal hematopoiesis did not affect overall or progression free survival in A031201 but was associated more adverse cardiac events.

  Study phs003717

• ICARUS-BREAST01-RNAseq

  Efficacy, safety and biomarker analysis of ICARUS-BREAST01: a phase 2 Study of Patritumab Deruxtecan in patients with HR+/HER2- advanced breast cancer. RNA-squencing is available for 44 samples comprising 22 samples collected at entry into the trial and 22 samples collected during treatment (cycle 1 day 3, cycle 1 day 19, or cycle 2 day 3) from 22 patients.

  Study EGAS50000000543

• Longread sequencing of selected 12q-amplified osteosarcomas

  Longread sequencing of selected 12q-amplified osteosarcomas for verification of SV data. This was carried out in order to verify findings from mate-pair sequencing regarding the structure of the chromosome 12q-amplicons and whether material from other chromosomes is also intertwined and amplified in a bid to further characterise these tumours beyond CDK4 and MDM2 amplification.

  Study EGAS50000000495

• Exome Sequencing in an Ancestrally Diverse Autism Cohort

  Autism spectrum disorder (ASD) is a collection of neurodevelopmental disorders manifested by impaired social communication, repetitive behaviors, and restricted interests. We performed whole exome sequencing (WES) on a total of 754 individuals from 195 families, including 222 probands with ASD, from diverse ancestral backgrounds. We identified potentially pathogenic variants in known and novel ASD or neurodevelopmental disease genes.

  Study phs003603

• Whole-exome sequencing data of ovarian clear cell carcinoma in East Asia

  This is a genomic study to uncover the molecular landscape of ovarian clear cell carcinoma (OCCC) in East Asia. This dataset contains normal-tumor paired samples of 104 patients with OCCC diagnosed in two branches of Chang Gung Memorial Hospital, Taiwan. These are paired-end, whole-exome sequencing data, sequenced by Illumina NovaSeq with target depth of 150X.

  Study EGAS50000000031

• DAC-2023-07-05-Ritz (DAC-007) - Diagnosis of tuberculosis infection in children with a novel skin test and the traditional tuberculin skin test: an observational study

  Diagnosis of tuberculosis infection in children with a novel skin test and the traditional tuberculin skin test: an observational study This is only the location for the raw data and any check if the dataset may be relevant please refer to the MF-DAC Zenodo community (https://zenodo.org/records/11237107).

  Study EGAS50000000780

• Mutational Profile in Newly Diagnosed Diffuse Large B-Cell Lymphoma: GAINED Study

  The GAINED study (NCT01659099) is a randomized phase 3 trial comparing obinutuzumab (G) to rituximab (R) in combination with ACVBP or CHOP14 induction, followed by PET-guided consolidation. This post-hoc analysis focuses on primary mediastinal B-cell lymphoma (PMBL) patients, confirmed through expert pathological review and characterized using gene-expression profiling (GEP) and Next-Generation Sequencing (NGS)

  Study EGAS50000000929

• The Genomic Map of Poland in Open Access

  The main goal is to prepare and share WGS/WES of Polish population In this project NGS (next generation sequencing) was performed using Illumina NOVASEQ 6000 and Illumina DRAGEN aligner was used. Shared BAM and BAM.BAI files Library Construction Protocol: Illumina DNA PCR-Free Prep, Tagmentation. Reference Genome: GRCh37.

  Study EGAS50000000091

• SECRETO Oral metagenome study

  The main goal of the project is to study the associations between the oral metagenome and young-onset cryptogenic ischemic stroke (CIS). The dataset includes information for n=329 participants who underwent saliva sampling. Participants for the SECRETO Oral study were enrolled between December 2013 and November 2019. Shotgun metagenomic sequencing was performed using the Illumina NovaSeq 6000 platform.

  Study EGAS00001007505

• Biomarkers for Noise-Induced Sleep Disruption

  This project aims to investigate gene expression biomarkers for noise-induced sleep disruption and cognitive changes. The project is a sub-study, part of the larger ASCENT COE project 86 designed to test the ability of broadband pink noise to serve as a countermeasure for sleep loss from simulated aircraft noise. Gene expression research was sponsored by the Federal Aviation Administration.

  Study phs003932

• Targeted pancancer RNA-Seq

  This dataset contains targeted RNA-Seq generated with the Illumina RNA Pan-Cancer panel. It comprises 2200 cancers from children and adults. The cancers represent a wide range of CNS, solid and haematopoeitic tumours. Samples are from pathology specimens including FFPE, fresh frozen, bone marrow aspirate and peripheral blood.The data is used for tumour driver identification. SNVs, indels and fusion detection.

  Study EGAS50000000700

• MorphoITH: A Framework for Deconvolving Intra-Tumor Heterogeneity Using Tissue Morphology

  The ccRCC-ITH study WES dataset is derived from a morphology guided multi-regional sequencing dataset used to study the relationship between morphology and genetic evolution. It contains whole exome sequencing data of 18 tumor and 2 adjacent normal samples from 2 UTSW patients, who have consented to depositing their genomic data to public repository. Tumor samples come from different tumor sites, including primary tumor, thrombus and metastases. WES was performed using 75bp paired-end fragments at an average read depth > 50x on a NovaSeq 6000 platform (Illumina, San Diego, CA, USA). The raw data is in fastq format.

  Dataset EGAD50000001550

• Elucidating the development of cervical cancer and identifying therapeutic targets based on cancer genome analysis.

  The objective of this project is to analyze genomic aberrations and gene expression changes, such as mutations, deletions, and amplifications, in human cervical cancer cells at the somatic cell level, and to contrast these with clinicopathological information to elucidate the molecular mechanisms and characteristics of lcervical cancer development and progression at the genetic level.

  Study JGAS000803

• Reference Panel for Imputation Analysis Based on Whole Genome Sequencing Data of 3,256 Japanese Individuals(BioBank Japan genotype data)

  This reference panel was constructed using whole genome sequencing data from 3,256 Japanese individuals and the 1000 Genomes Project. It provides high accuracy and utility in analyzing genetic polymorphisms, while also reflecting the genetic diversity specific to the Japanese population. This dataset is expected to contribute to the advancement of genetic research and personalized medicine.

  Study JGAS000746

• Evidence for Enhancer Activity in Intron 1 of TNFRSF1A Using CRISPR/Cas9 in Human Induced Pluripotent Stem Cell-derived Macrophages

  Use of CRISPR/Cas9 technology to study the TNFRSF1A gene, which plays a key role in autoimmune diseases such as ankylosing spondylitis, multiple sclerosis, and inflammatory bowel disease. By editing a specific regulatory element within the TNFRSF1A locus, we have identified the role of an enhancer element that is not well understood.

  Study EGAS50000000703

• BAP1 study

  Background: Mutations in BAP1 have been identified in many aggressive cancers. Current therapeutic strategies for BAP1-deficient tumors are not effective. Goal: Discover novel strategies for BAP1-deficient tumors. Details: In our study, we identified a potential therapeutic strategy for BAP1-deficient cancers. We used multi-omics approaches to understand the underlying mechanisms behind why the discovered potential therapeutic strategy is effective.

  Study EGAS50000000235

• PARADIGM: Combined ctDNA and serum PSA for dynamic monitoring of metastatic prostate cancer starting first-line treatment

  The prognosis of newly-diagnosed metastatic prostate cancer is highly variable. The PARADIGM prospective cohort study evaluated predictors of survival in blood collected at the start of each of the first six treatment cycles from 114 high-volume metastatic patients starting androgen deprivation therapy combined with docetaxel or an androgen receptor pathway inhibitor.

  Study EGAS50000001357

• CLUSTER Consortium RNAseq PBMC Dataset of pre-methotrexate UK JIA patients cohort

  This is the RNAseq PBMC dataset (paired FASTQ files, n = 82 paired files) generated from pre-methotrexate treatment JIA patients cohort samples. Total PBMC were isolated from pre-treated blood of JIA patients and clinical metadata is also included in this dataset. Samples were sequenced on the NovaSeq6000 instrument (Illumina, San Diego, US) at 300pM, using a 100bp paired read run with corresponding 8bp dual sample index and 5bp or 8bp unique molecular index reads. Run data were demultiplexed and converted to FASTQ files using Illumina’s BCL Convert Software v3.75.

  Dataset EGAD50000001457

• CLUSTER Consortium RNAseq CD8 Dataset of pre-methotrexate UK JIA patients cohort

  This is the RNAseq CD8 dataset (paired FASTQ files, n = 85 paired files) generated from pre-methotrexate treatment JIA patients cohort samples. CD8 cells were sorted from isolated total PBMC by cell sorter (BD FACSAriaTM III, BD Biosciences). Clinical metadata is also included in this dataset. Samples were sequenced on the NovaSeq6000 instrument (Illumina, San Diego, US) at 300pM, using a 100bp paired read run with corresponding 8bp dual sample index and 5bp or 8bp unique molecular index reads. Run data were demultiplexed and converted to FASTQ files using Illumina’s BCL Convert Software v3.75.

  Dataset EGAD50000001456

• CLUSTER Consortium RNAseq CD4 Dataset of pre-methotrexate UK JIA patients cohort

  This is the RNAseq CD4 dataset (paired FASTQ files, n = 86 paired files) generated from pre-methotrexate treatment JIA patients cohort samples. CD4 cells were sorted from isolated total PBMC by cell sorter (BD FACSAriaTM III, BD Biosciences). Clinical metadata is also included in this dataset. Samples were sequenced on the NovaSeq6000 instrument (Illumina, San Diego, US) at 300pM, using a 100bp paired read run with corresponding 8bp dual sample index and 5bp or 8bp unique molecular index reads. Run data were demultiplexed and converted to FASTQ files using Illumina’s BCL Convert Software v3.75.

  Dataset EGAD50000001455

• CLUSTER Consortium RNAseq CD14 Dataset of pre-methotrexate UK JIA patients cohort

  This is the RNAseq CD14 dataset (paired FASTQ files, n = 80 paired files) generated from pre-methotrexate treatment JIA patients cohort samples. CD14 cells were sorted from isolated total PBMC by cell sorter (BD FACSAriaTM III, BD Biosciences). Clinical metadata is also included in this dataset. Samples were sequenced on the NovaSeq6000 instrument (Illumina, San Diego, US) at 300pM, using a 100bp paired read run with corresponding 8bp dual sample index and 5bp or 8bp unique molecular index reads. Run data were demultiplexed and converted to FASTQ files using Illumina’s BCL Convert Software v3.75.

  Dataset EGAD50000001458

• CLUSTER Consortium RNAseq CD19 Dataset of pre-methotrexate UK JIA patients cohort

  This is the RNAseq CD19 dataset (paired FASTQ files, n = 83 paired files) generated from pre-methotrexate treatment JIA patients cohort samples. CD19 cells were sorted from isolated total PBMC by cell sorter (BD FACSAriaTM III, BD Biosciences). Clinical metadata is also included in this dataset. Samples were sequenced on the NovaSeq6000 instrument (Illumina, San Diego, US) at 300pM, using a 100bp paired read run with corresponding 8bp dual sample index and 5bp or 8bp unique molecular index reads. Run data were demultiplexed and converted to FASTQ files using Illumina’s BCL Convert Software v3.75.

  Dataset EGAD50000001459

• Systematic identification of long non-coding RNAs potentially involved in gastrointestinal carncer

  Recent work has suggested various important functions and molecular mechanisms for long non-coding RNAs (lncRNAs) and they are also thought to play critical roles in cancer. However the importance of lncRNAs in cancer biology is still unclear. In this study, we aim to comprehensively identify novel lncRNAs that are critically involved in tumorigenesis and progression in gastrointestinal cancer.

  Study JGAS000011

• Mechanisms on relapse after allogeneic hematopoietic cell transplantation in CMML

  Disease relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT), and mechanisms on relapse still remain to be elucidated. We experienced a patient with chronic myelomonocytic leukemia (CMML) who underwent haploidentical HCT from his daughter and developed relapse. To understand the mechanisms on relapse after HCT, we analyze blood samples at HCT and at relapse.

  Study JGAS000317

• Cancer genomics for elucidation of molecular mechanisms of carcinogenecis and progression in lung cancer

  The objective of this project is to analyze genomic aberrations and gene expression changes such as mutations, deletions, amplifications, and hypermethylation in human lung cancer cells at the somatic cell level, and to contrast these with clinicopathological information to elucidate the molecular mechanisms and characteristics of lung cancer development and progression at the genetic level.

  Study JGAS000756

• Reproducible gut microbial signatures in bipolar and schizophrenia spectrum disorders: A metagenome-wide study

  This is a case-control study in which differences in the gut microbiome of patients with bipolar disorder and schizophrenia spectrum disorders were assessed. The study contains the samples in this dataset, except for G002, G025, G041, G093, G106, G107, G120 and G123. These samples were not yet available at the time the study was performed.

  Study EGAS50000000969

• RNA-seq data of proliferative vitreoretinal diseases and healthy human retinal pigment epithelium

  This Data Access Committee (DAC) evaluates access requests for RNA-seq data generated from: - Membranes from proliferative vitreoretinal diseases, including proliferative vitreoretinopathy and epiretinal membranes. - Retinal pigment epithelial cells isolated from healthy ocular globes obtained from deceased donors. Collection and analysis of these residual human materials were conducted with the approval of the ULB-Erasme Ethical Committee (P2019/066 A2022/136) and of the Eye Bank (CHU Liège), with no need for informed consent in compliance with Belgian law. All data are pseudonymised, and access is restricted to qualified researchers whose proposed use of the data is consistent with the applicable ethical approval and legal requirements, including the General Data Protection Regulation (GDPR).

  Dac EGAC50000000721

• Whole genome sequencing data of paediatric ETV6::RUNX1 acute lymphoblastic leukemia

  ETV6::RUNX1 (E::R) subgroup is the second most frequent form of B cell acute lymphoblastic leukemia (B-ALL) in childhood. This subgroup of ALL generally presents with low-risk features and responds well to chemotherapy with ensuing favorable prognosis. Some patients, however, have a slow response to induction treatment and carry increased risk for relapse.

  Study EGAS50000001599

• Bulk-mRNA sequencing comparing hiPSC derived vascular cells from CADASIL patient lines

  CADASIL is a hereditary brain small vessel disease caused by pathogenic variants in the NOTCH3 gene and causes degenration of Vascular Smooth Muscle cells in the brain. We performed bulk-mRNA sequencing and transcriptomic analysis from hiPSC derived vascular cells (hiPSC;Endothelial Cells; Neural Crest Cells; Vascular Smooth Muscle Cells) comparing CADASIL patient lines and respective isogenic-controls.

  Study EGAS50000001507

• Sputum fungal microbiota in an overall healthy population in Guangdong province, China

  This repository contains raw sequencing data for sputum fungal microbiota in an overall healthy population in Guangdong province, China. The aim of the study is to provide a comprehensive insight on the multi-kingdom airway microbiome, how it may underlie the interplay between exposure and healthy outcomes, and whether it can be employed to inform airway health and diseases.

  Study EGAS00001006720

• Sputum bacterial microbiota in an overall healthy population in Guangdong province, China

  This repository contains raw sequencing data for sputum fungal microbiota in an overall healthy population in Guangdong province, China. The aim of the study is to provide a comprehensive insight on the multi-kingdom airway microbiome, how it may underlie the interplay between exposure and healthy outcomes, and whether it can be employed to inform airway health and diseases.

  Study EGAS00001006721

• Whole-genome and transcriptome sequencing of primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

  Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lymphoma with an aggressive clinical course and a very poor prognosis. We subjected tumor biopsies from patients with pcAECyTCL to whole-genome sequencing and RNA-sequencing to investigate genomic alterations and deregulated gene expression in the disease.

  Study EGAS00001004332

• Grey_Platelet_Syndrome__GPS_

  As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such pedigree, Grey Platelet Syndrome (GPS) is a rare congenital bleeding disorder caused by a reduction or absence of alpha granules in platelets. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.

  Study EGAS00001000091

• Population_sequencing_phasing

  Whole-genome sequencing of human individuals from Polynesian and Native American populations, as well as 10x Genomics Chromium data from Polynesian, Native American and Aboriginal Australian populations, allowing for experimental phasing of haplotypes. 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 please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001852

• ICGC_Benchmarking_Exercise

  The main objective of this benchmark is the comparison of the full sequencing pipeline of different ICGC partners, including procedures, methods and performance of library preparation and whole-genome deep-sequencing. A secondary objective will be a follow-up comparison of data analysis pipelines for identification of germline and somatic variants subsequent to the results of the ICGC Somatic Variant Calling Pipeline Benchmark.

  Study EGAS00001000433

• The_International_1q_type_2_diabetes_consortium

  The aim of this project is to identify rare variants in the 1q region associated with type 2 diabetes. To this end 651 case samples and 651 control samples from six populations have been pooled (pool sizes range from 27-33 individuals), and are being sequenced. The hybridization solution being used captures the exons and UTRs of genes in the 1q region.

  Study EGAS00001000062

• Investigating_the_impact_of_MBD4_on_the_mutability_of_the_germline

  We will be testing the hypothesis that MBD4 PTV germline carriers also show an increased number of C toT germline mutations in their offspring. 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/

  Study EGAS00001002861

• Exome_sequencing_of_Congenital_Heart_Disease_families_Toronto

  Atrio-ventricular septal defects (AVSD) are a specific form of congenital heart structural defect that result from abnormal or inadequate fusion of endocardial cushions during cardiac development. This project is focused on identifying rare coding variation that substantially increases risk of AVSD, by exome sequencing of AVSD patients and some of their family members, and comparing to control datasets from other sources.

  Study EGAS00001000317

• Age-related remodeling of apparently normal esophageal epithelia by common cancer drivers

  Driver mutated clones multi-focally emerged from early adulthood and over years, increase their number and size, ultimately remodeling the entire esophageal epithelia in extreme elderly. Our results suggest that clonal expansion in esophageal epithelia is an inevitable consequence of normal aging, differentially impacting the development of cancer depending on mutation type and exposure to drinking and smoking.

  Study EGAS00001003008

• Multiple Sclerosis ImmunoChip data

  The purpose of this study is to leverage the custom content of the ImmunoChip consortium; incorporating candidate loci from 12 autoimmune diseases, to both fine-map previously identified multiple sclerosis loci and identify new multiple sclerosis candidates. As a fine-mapping array, both common and rare variation are included within a subset of ~180 candidate loci across the genome.

  Study EGAS00001003219

• Chromatin 3D interactions mediate genetic effects on gene expression

  Studying the genetic basis of gene expression and chromatin organization is key to characterize the effect of genetic variability on the function and structure of the human genome. Here, we unravel how genetic variation perturbs gene regulation using a dataset combining activity of regulatory elements, gene expression and genetic variants across 317 individuals and two cell types.

  Study EGAS00001003485

• Genetic landscape of pediatric Adrenocortical Tumor

  Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in paediatric ACT and outline a hypothetical model of paediatric adrenocortical tumorigenesis.

  Study EGAS00001000257

• Whole Exome Sequencing of High grade T1 non-muscle invasive bladder cancer

  High-grade T1 (HGT1) bladder cancer (BC) is the highest risk subtype of non-muscle-invasive BC with unpredictable outcome and poorly understood risk factors. Here we performed whole exome sequencing across 61 HGT1 samples to identify genomic predictors of good outcome, recurrence or progression. This study includes somatic mutation calls and clinical data for 61 HGT1 tumors.

  Study EGAS00001004603

• Gene_Characterization_in_Carbohydrate_metabolic_alterations__neonatel_diabetes___congenital_hyperinsulinemic__in_early_childhood

  Whole Exome Sequencing of trios (proband + parents) or probands only with Neonatal Diabetes Mellitus (NDM) or Congenital Hyperinsulinism of Infancy (CHI) of unknown genetic origin. 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/

  Study EGAS00001002074