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• Screening_for_human_epigenetic_variation_at_CpG_islands

  Many human characteristics, including susceptibility to disease, are determined genetically. An unexplored alternative to such genetic determination concerns epigenetic mechanisms such as DNA methylation. CpG islands (CGIs) are generally constitutively hypomethylated, however there are circumstances in which they become heavily methylated and, when coincident with a gene promoter, this invariably causes transcriptional silencing. CGI methylation occurs in normal tissues during processes such as X-inactivation, but abnormal patterns of methylation have also been implicated in disease. The vast majority of evidence relates to cancer, where silencing of multiple genes in this way appears to be a causal contributor to the cancer state. To address the role and extent of CGI methylation in ‘normal’ and diseased cells we applied MBD-affinity purification in conjunction with next generation sequencing in a panel of human brain autopsy samples. These samples represent a panel of individuals as well as specific brain regions and neurological pathologies.

  Study EGAS00001000074

• Vento_Placental_Cell_Atlas

  The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs).

  Study EGAS00001004187

• Cancer Single Cell Sequencing

  This study is to ascertain whether it is feasible to extract a single cell form a Cancer cell line, amplify it and sequence it.

  Study EGAS00001000003

• Resistance to selective FGFR2 inhibitors across FGFR2-driven malignancies

  18 patients were biopsied at resistance to an FGFR inhibitor with tumor WES and/or WTS performed to identify resistance mechanisms to selective FGFR2 inhibitors across FGFR2-driven malignancies.

  Dataset EGAD50000000439

• RIP-seq of SF3B4 binding RNA fragments

  There are 2 paired samples. The project aims to characterize SF3B4 binding RNA fragments within liver organoids to understand its role in splicing regulation

  Study EGAS50000001129

• Whole exome sequencing of 69 trios with bipolar disorder

  We performed whole exome sequencing to trios with bipolar disorder to elucidate genetic architecture of bipolar disorder including de novo mutations and transmitted variants.

  Study JGAS000273

• Searching for DNA methylation sites associated with panic disorder

  This study aimed to identify whole-genome DNA methylation profile of panic disoeder and to search DNA methylation sites associated with the disease

  Study JGAS000111

• A GWAS study with the AlpeDPD study cohort

  A genome-wide association study (GWAS) with patients treated with fluoropyrimidines was performed to identify genetic variants linked to the severe fluoropyrimidine-related toxicity.

  Study EGAS00001007855

• Congenital_Heart_Disease___Pilot

  This pilot study aims to generate pilot data to inform future study designs by resequencing the whole exomes of 10 unrelated individuals diagnosed with Congenital Heart Disease (CHD).

  Study EGAS00001000425

• Pediatric study using genome sequencing

  This study used whole genome sequencing to assess genome variants from DNA from pediatric individuals seen in genetics clinic who were thought to have genetic conditions.

  Study EGAS00001005553

• Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

  To identify predictive biomarkers of response and resistance to platinum agents in PDX models of triple-negative breast cancer

  Study EGAS00001006393

• Phenotypic characterisation of LRRN4CL over-expression

  This study aims to use RNAseq to identify differentially expressed transcripts in human melanoma cells that over-express the cell surface protein, LRRN4CL, relative to empty-vector control cells, to provide mechanistic insight into how LRRN4CL over-expression confers enhanced pulmonary metastatic colonisation abilities.

  Dataset EGAD00001006249

• RNA-Seq samples from the BELOB clinical trial study to find transcriptome associations with response to Bevacizumab and CCNU in glioblastoma patients

  RNA-Seq samples from the BELOB clinical trial study to find transcriptome associations with response to Bevacizumab and CCNU in glioblastoma patients

  Dataset EGAD00001006329

• Genome-Wide Association Study of Patients with Coccidioidomycosis

  BackgroundValley Fever is typically an infection of the lungs caused by the fungi Coccidioides immitis and Coccidioides posadasii. The incidence of Coccidioidomycosis (CM), or infection with Coccidioides, has dramatically increased over the last 20 years. This is particularly true in the Southwest of the United States, where people often breathe fungal spores that arise from the soil. Reasons for increased infection rates are thought to include population growth and construction in these endemic regions, an increase in the number of people whose immune systems are compromised due to infection or treatment with drugs required for organ transplants, climate change, as well as improved testing practices and greater physician awareness. Mild CM most commonly presents itself with flu-like symptoms and rashes, which can last weeks to months. Individuals with compromised immune systems, specifically-- substantial suppression of the immune cells known as T cells, can develop severe pulmonary and disseminated disease. Infection that remains localized to the lungs is referred to as pulmonary disease, but when the infection spreads out of the lungs into other parts of the body it represents a more serious condition referred to as a disseminated disease, or disseminated CM. In nature, Coccidioides spp. exists as mold and lives in dust and soil. When the contaminated soil or dust is disturbed by human activity, animals, or weather, the Coccidiodies spores are released into the air. Airborne spores are taken up by breathing and settle in the lungs. Once in the moist and warm environment of the lung, spores transform into spherules, which divide and become filled with smaller spores, called endospores. When the spherules get large enough, they rupture and release these endospores, which can spread and disseminate to surrounding tissue. The cycle then repeats itself as these endospores develop into new spherules3. Different ethnic groups have been described to vary in their susceptibility to developing disseminated CM after initial infection with Coccidioides. For example, evidence suggests that African-American and Filipino patients suffer the disseminated disease at a greater rate than other ethnicities. The suggestion that race plays a role in the clinical expression of the disease is still a source of debate amongst the scientific community and any genetic mechanisms responsible for these differences have yet to be fully elucidated. If our genetic makeup influences our ability to limit the spread of infection, finding which DNA differences cause these variances could provide clues to how the body successfully fights infection, and provide opportunities to boost the body’s ability to do this. Further, if we are able to identify the specific genetic risk factors that correlate with the development of disseminated infection, physicians could perform genetic screenings to identify high-risk patients and provide them with preemptive antifungal therapy prior to developing disseminated disease.The genome, made up of DNA, contains all of the information needed for humans to develop and grow. Genome-wide association studies (GWAS) allow us to look for inherited differences that are more common between people who share a particular trait, for example, height or susceptibility to certain diseases, compared to those who do not share the trait. Although some traits and diseases are controlled by a single gene, the majority are influenced by contribution from several, or even many, different genes. To find evidence of genes that contribute to specific traits, GWAS typically compares genome information from large numbers of people who have a particular disease (referred to as “cases”) looking for DNA sequences that are common among these samples, and are different from DNA sequences seen in large numbers of people who lack the trait, but are as much like the cases as possible (referred to as “controls”). The DNA sequence data from each group, cases versus controls, are analyzed to see if there are specific genomic differences that tend to be associated with the disease. MethodsTwo separate GWAS approaches were taken to look for genetic differences that could be responsible for the observed differences between the different patient populations we are studying. The first method, known as genotyping, scans for differences at a set of positions across the genome, which includes both the genes that encode our proteins and the larger amount of DNA that does not. The second method, known as exome sequencing, allows us to compare the entire sequence of the portion of the genome that codes for proteins.  For this study, DNA from patients with either pulmonary or disseminated CM were genotyped and exome sequenced to look for DNA differences that are associated with one condition or the other. All patients were at least 18 years old, had no evidence of immunosuppression, and had proven or probable pulmonary coccidioidomycosis according to established diagnostic criteria. Of these patients, a subset demonstrated disseminated disease, i.e., they showed evidence of coccidioidal infection outside of the thorax by biopsy/aspiration, had radiographic imaging, and show positive coccidioidal serology. Our criteria for including patients with the pulmonary disease were that they must not require ongoing antifungal treatment or show evidence of active CM (in skin test positive patients), show no evidence of extrapulmonary dissemination, and have no evidence of ongoing pulmonary infection (pulmonary nodules are accepted) beyond six months from diagnosis.Patient DNA was purified from blood or from sputum samples by the labs of our collaborators, Drs. George Thompson (UC Davis School of Medicine) and John Galgiani (University of Arizona Health Sciences). Genome-wide association (GWAS) analysis was carried out to look for candidate loci associated with pulmonary versus disseminated disease, taking into account the population structure of the samples. Single nucleotide or insertion/deletion variants were identified from whole-exome sequences (WES) using the Picard/BWA/GATK pipeline. ResultsTable 1. Pulmonary versus Disseminated Cases of Coccidiomycosis for GWAS, Sorted by EthnicityEthnicityPulmonary CasesDisseminated CasesAsian85Black/African American1664Caucasian/White4015Filipino03Hispanic/Latino3414Indian21Mexican American1039Pacific Islander01Samoan03Vietnamese10Unknown16917More than one race02Total373134Table 1 shows the number of samples analyzed from patients with pulmonary versus disseminated disease, and patient ethnicity, where known. In all, we worked with 507 samples, including 134 samples from patients with disseminated disease and 373 samples from patients with pulmonary disease. Of these, 505 samples were genotyped using the Multi-Ethnic Global Array from Illumina Inc. In addition, we were able to generate whole-exome sequence from 498 patient samples. No significant associations were detected that differed between samples from patients with pulmonary versus disseminated disease; that is, no particular DNA sequences were found to be significantly enriched in patients with disseminated disease compared to patients with pulmonary disease. The ability to detect genetic association between specific sequences and genetically determined traits is influenced by several factors, including how many patient samples are available to compare, how many different genes contribute to the trait and how strong their contributions are. When the number of genes is small and the contribution of each gene is great, smaller numbers of patient samples are needed to detect an association. When more genes are involved, or the contribution from each gene is more modest, larger numbers of patient samples must be examined. While we were not able to detect any associated within this study, it does not mean that subsequent studies would not find this connection. Our study suggests significantly more samples should be analyzed in further studies.Whole-exome sequences were generated from 498 samples and were aligned to reference sequences to identify positions where the sequences differed from the reference. These data are being analyzed to determine if any variants are associated with pulmonary, versus disseminated, disease. 

  Study phs002170

• Liquid biopsy to identify taxane resistance in castration-resistant prostate cancer patients

  Taxanes are life-prolonging treatments for patients with advanced prostate cancer. However, treatment resistance and lethal disease invariably develops. We here used liquid biopsies to identify and characterize resistance to cabazitaxel using a targeted sequencing panel (PCF-SELECT).

  Study EGAS50000001292

• Prediction of response to preoperative chemoradiotherapy in rectal cancer based on whole-exome sequencing and transcriptomic analysis

  Accumulating evidence suggests that radiotherapeutic success has an immune-associated component. We aimed to investigate the immunogenomic profiles associated with response to preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer.

  Study JGAS000158

• Multiomic cell-free DNA profiling to inform molecular classification and immunotherapy outcomes in endometrial cancer

  This study involved a cell-free DNA (cfDNA) framework integrating genomic, transcriptomic and epigenomic profiling to investigate patient response to immune checkpoint inhibitors in advanced endometrial cancer (EC) with mismatch repair deficiency (dMMR).

  Study EGAS50000001582

• High-powered complex trait association mapping through whole genome sequencing of a selected subpopulation of the INGI-Val Borbera genetic isolate

  The VBSEQ project aims to combine available extensive genetic and phenotypic data to the latest high-throughput genome sequencing technology and ad hoc statistical analysis to identify new rare genetic variants underlying complex traits. Up to 100 Val Borbera samples will be sequenced to a 6x depth.

  Dataset EGAD00001000730

• Angelman, Rett, Prader-Willi Syndromes Consortium (ARP) Angelman Syndrome Natural History Protocol

  This study is a longitudinal multidisciplinary investigation on the natural history, morbidity and mortality of Angelman Syndrome (AS). We will collect detailed longitudinal data on a cohort of AS individuals to gain a better understanding of the disease progression, and to follow the natural history of the clinical features of this cohort including assessment of quality of life and longevity. The participants to be recruited for the study will include 1) patients who have a documented molecular diagnosis of AS and 2) patients with a clear clinical diagnosis of Angelman Syndrome as determined by the Principal Investigator (PI) and the Co-investigators in this study but who do not have a known molecular defect. One of the goals of the natural history study will be to characterize the phenotypic differences between patients with Class I deletions and those with Class II deletions, particularly with respect to the issue of autism. A blood sample may be collected on the participants in order to create a DNA repository, and in some cases, to establish cell lines if further material is required for molecular studies. Alternatively, DNA may be obtained by buccal mucosa swabs/brushing. In those AS patients with known deletions involving the 15q11-q13 regions, a blood sample will be collected to perform comparative genome hybridization (CGH) microarray studies to characterize the extent of the deletion. No drugs or treatments will be administered through this protocol. In rare instances, a skin biopsy to establish a fibroblast cell line may be requested (using separate consent).

  Study phs000576

• NHLBI GO-ESP: Family Studies (Familial Atrial Fibrillation)

  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. Large epidemiological studies have demonstrated a significant heritable component in atrial fibrillation (AF), especially the Lone forms, suggesting a monogenic syndrome. Although substantial genetic contribution has been made to the etiology of AF, the specific genes have not yet been identified. The familial form of this disease remains poorly characterized and largely undetermined. Here we seek to identify, characterize and determine the natural course of AF in our clinical practice. We identified four large multi-generation families (FAF 1-4). In FAF 1-2, most family members have symptomatic paroxysmal Atrial Fibrillation (AF) and were adequately treated with a combination of rate and rhythm therapies. By contrast, the AF substrate in FAF 3 and 4 was resistant to anti-arrhythmic drugs and ablation therapies.

  Study phs000362

• Cancer Moonshot Biobank

  The National Cancer Institute initiated the Cancer Moonshot Biobank to accelerate research through the collection and distribution of biospecimens for key research efforts. The Biobank will engage with over one thousand cancer patients, being treated with standard-of-care therapies, for longitudinal biospecimen and data collection. Cancer patients will be enrolled into the study from a diverse participant population engaged at medical institutions throughout the U.S. The biospecimens will be distributed to qualified scientists to accelerate research progress. The Biobank program, working closely with Leidos Biomedical, Inc. (LBR), will partner with community hospitals and other medical institutions, designated as Biospecimen Source Sites (BSS), to engage and consent eligible participants and collect biospecimens and associated clinical data; work with a central Biospecimen Core Resource (BCR) to support biospecimen collection, processing and storage activities and perform pathology quality control; work with LBR's Molecular Characterization (MoCha) lab to perform clinical tumor molecular characterization assays and return results to patients and their physicians; and make the biospecimens and associated data available to researchers to accelerate cancer research progress. Return of clinical results, a dedicated Patient and Provider Engagement (PPE) website, electronic informed consent, local participant engagement projects, and an embedded ethical, legal and social issues sub-study will together support patient and provider engagement in the program. Cancer Moonshot Biobank imaging data is being made available in The Cancer Imaging Archive (TCIA) on a release schedule that is coordinated with the program releases of data to dbGaP. The imaging data can be found at the following link: Cancer Moonshot Biobank Imaging

  Study phs002192

• A Single Complex Agpat2 Allele In A Patient With Partial Lipodystrophy

  Genetic lipodystrophies are a group of rare syndromes associated with major metabolic complications - including severe insulin resistance, type 2 diabetes mellitus, and hypertriglyceridemia - which are classified according to the distribution of adipose tissue. Lipodystrophies can be present at birth or develop during life and can range from local to partial and general. With at least 18 different genes implicated so far, definite diagnosis can be challenging due to clinical and genetic heterogeneity. In an adult female patient with clinical and metabolic features of partial lipodystrophy we identified via whole genome sequencing a single complex AGPAT2 allele [V67M;V167A], functionally equivalent to heterozygosity. AGPAT2 encodes for an acyltransferase implicated in the biosynthesis of triacylglycerol and glycerophospholipids. So far homozygous and compound heterozygous mutations in AGPAT2 have only been associated with generalized lipodystrophy. A SNP risk score analysis indicated that the index patient is not predisposed to lipodystrophy based on her genetic background. The partial phenotype in our patient is therefore more likely associated to the genetic variants in AGPAT2. To test whether the resulting double-mutant AGPAT2 protein is functional we analysed its in vitro enzymatic activity via mass spectrometry. The resulting AGPAT2 double mutant is enzymatically inactive. Our data support the view that the current classification of lipodystrophies as strictly local, partial or generalized may have to be re-evaluated and viewed more as a continuum, both in terms of clinical presentation and underlying genetic causes. Better molecular understanding of lipodystrophies may lead to new therapies to treat adipose tissue dysfunction in common and rare diseases.

  Study EGAS00001003177

• Colorectal cancer organoids expressing BRAF (fusion) genes

  Fusion genes may be oncogenic drivers and potential targets for personalized therapies in a variety of cancer types. The BRAF gene is frequently involved in oncogenic fusions, with fusion frequencies of 0.2-3% throughout different cancers. BRAF can be fused to a wide variety of genes, however, BRAF fusions rarely occur in the exact same gene configuration, making assessment of the fusion relevance and decision for drug treatment challenging. Here, we devised a colorectal cancer organoid-based platform to functionally characterize diverse BRAF fusions, containing various partner genes (AGAP3, DLG1 and TRIM24). We compared these BRAF fusions with respect to cellular behaviour, downstream signaling activation and response to targeted therapies. We found that 5’ partner choice of BRAF affects cellular localization and intracellular signaling capacities of the fusion genes. The DLG1-BRAF fusion gene showed distinct localization to the plasma membrane and exhibited increased levels of MAPK pathway activation under unperturbed conditions. Furthermore, the different BRAF fusions showed varying sensitivities to the targeted inhibition of ERK and BRAF, with the DLG1-BRAF fusion being the most sensitive. Additionally, RNA-sequencing identified distinct subsets of genes affected by the DLG1-BRAF fusion gene. Importantly, all fusion genes conveyed resistance to the clinically relevant EGFR/HER2/HER4-inhibitor afatinib, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify mCRC patients amenable to cetuximab treatment. In summary, we developed a platform to efficiently assess molecular and cellular effects of fusion genes, and revealed that differential drug responses and distinct gene expression profiles can be induced by different BRAF fusions .

  Study EGAS00001003558

• Longitudinal study of whole blood gene expression in Kenyan children exposed to malaria

  We have collected RNA samples from whole blood of Kenyan children exposed to malaria in the Kilifi region of Kenya. Collections were performed each year from 2015 until 2018. This is a follow-up study to that described in Bediako et al. (in preparation). The SIMS consortium is seeking to identifying the underlying reasons why some children are more susceptible to malaria than others. In this study we hope to track changes in children’s immune systems over time which relate to the number of malaria episodes they experience. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001015405

• Prematurity and Respiratory Outcome Program: Clinical Research Center Study of Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies

  Approximately 550,000 babies born prematurely each year in the United States suffer from birth at a time in development when the respiratory tract and immune system would normally be protected and maintained in a naïve state. This project is a component of the NIH Prematurity and Respiratory Outcomes Program (PROP) whose goals are the identification of disease mechanisms and biomarkers to stratify premature infants, at the time of discharge, for their risk of subsequent pulmonary morbidity. This Clinical Research Center (CRC) project will investigate prematurity-dependent alterations in cellular innate and adaptive immune systems resulting in increased susceptibility to respiratory infections and environmental irritants, and leading to respiratory morbidity in the first year of life. Prior studies have established developmental (maturity) and disease-related changes in circulating and pulmonary lymphocyte populations, but a comprehensive assessment of their relationship to disease risk/outcome has not been undertaken. We hypothesize that cellular and molecular immuno-maturity is altered due to intrinsic and extrinsic factors presented by premature birth in such a way as to reduce resistance to viral infections and to promote cytotoxic damage to the lung. We will evaluate immunologic maturity by comprehensively phenotyping lymphocyte populations in peripheral blood sampled at premature delivery, at the time of discharge from the hospital and at twelve months corrected age. The lymphocytic phenotype will be analyzed particularly in the context of gestational age and maternal-fetal stressors capable of modulating oxidative stress (oxygen exposure, infection and environmental tobacco smoke exposure). Additionally, we will assess changes in the molecular phenotype of isolated CD8 lymphocytes, a cell type preferentially recruited to the lungs of premature infants and capable of contributing to disease pathogenesis, by genome-wide expression profiling, in order to uncover novel disease pathways and define a gene expression signature associated with disease risk. We propose to build a statistical model, using cellular and molecular phenotypes and additional clinical variables, for stratifying risk of lung morbidity within the first year of life. Finally, we will assess the development of the gut microbiome in the preterm subjects to correlate with the observation of development of the adaptive immune system.

  Study phs001297