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• Multi-modal spatial characterization of tumor-immune microenvironments in diffuse large B-cell lymphoma

  We have leveraged spatial transcriptomics together with proteomic and genomic analysis to investigate the spatial immunology and pathobiology of DLBCL. We define distinct cellular niches that differ in frequency across tumors, related to both Epstein-Barr virus (EBV) infection status and the anatomical site of the tumor, and show that residence within different cellular niches is associated with divergent functional states of T-cells and tumor B-cells due to different patterns of cell-cell communication. This provides a framework for understanding stereotyped patterns of spatial organization in DLBCL and immunological interactions associated with heterogeneity in immune cell infiltration and function across patients.

  Study EGAS50000001146

• Insertion Site Analysis of T cells in a CD19-CAR Study on the T-SCM effect in B-cell malignancies

  Integration site analysis (ISA) was performed using a previously described non-restrictive vector-genome Junction amplification method combined with high-throughput sequencing59. Briefly, amplified gDNA was fragmented by sonication to generate ~1000 bp fragments and ligated to a linker cassette (LC) with a known sequence. Two rounds of exponential PCRs (35 cycles each) were conducted using primers specific to the vector long terminal repeats (LTRs) and the LCs. A final PCR step introduced Illumina adapter sequences and a unique index for each sample, enabling multiplexing for next-generation sequencing on the Illumina NextSeq 2000. A set of 24 fusion PCR primers was designed to bind the vector LTR, and a set of 24 fusion PCR primers designed to bind the LC (all primers were purchased from Integrated DNA Technology). Fusion PCR products were purified, quantified, and pooled in an equimolar fashion. Prepared pooled libraries were quantified and loaded onto the Illumina NextSeq 2000. Sequencing reads were demultiplexed based on the sample-specific indices and analysis of sequencing reads including mapping and annotation to the human genome (hg18 version) was performed using the IS-Seq bioinformatic pipeline.

  Dataset EGAD00001015540

• Microbiome

  16S-sequencing: All stool samples were processed according to the standards of the Flemish Gut Flora Project (Falony et al., 2016). All samples were processed together and sequenced in as a single batch (dual index run DI23R22) which included positive controls (PC, identical stool sample), negative controls (PCR-mix) and ‘blanks’ or negative controls of the extraction (no sample). In addition, a Runella strain (RS) was included to check for potential cross-contamination, as this strain is not present in human samples. The V4 region of the 16S rRNA gene was amplified with the primer pair 515F and 806R (GTGYCAGCMGCCGCGGTAA and GGACTACNVGGGTWTCTAAT, resp.), modified to contain a barcode sequence between each primer and the Illumina adaptor sequences to produce dual- barcoded libraries (Tito et al., 2019). Sequencing was performed on the Illumina MiSeq. Sequences were processed using the LotuS (Hildebrand et al., 2014) and DADA2 pipeline (Callahan et al., 2016) using RDP 16 as the reference taxonomy.

  Dataset EGAD50000002027

• Emory University African American Vaginal, Oral, and Gut Microbiome in Pregnancy Cohort Study

  The Emory University African American Microbiome in Pregnancy Cohort Study prospectively enrolls African American women between 18-40 years of age without chronic medical conditions into a longitudinal follow-up study that involves completing microbiome sampling and data collection at two time points in pregnancy (8-14 weeks gestation and 24-30 weeks gestation). The study is investigating the role of the oral, vaginal, and gut microbiome on preterm birth and other pregnancy outcomes as well as biobehavioral factors that shape the microbiome among this socio-demographically diverse group of women. Microbiome sampling involves the oral, vaginal, and gut sites. Biobehavioral factors that are being explored for their association with microbiome composition at the three body sites include measures of sociodemographic status as well as diet and nutrition, infectious and stress exposures.

  Study phs001865

• Longitudinal Study of Vaginal Flora

  This prospective observational study aims to advance our knowledge of the natural history and abnormal alteration in vaginal microbial flora, and to identify risk factors that are associated with these changes. A total of 5500 healthy, non-pregnant women of reproductive age will be enrolled and followed up in Birmingham, Alabama, for one year (baseline visit plus once every three months afterwards, totaling 5 visits). Detailed information on sociodemographic status, medical history, hygiene practice, sexual behavior and psychosocial stress will be collected through in-person interviews. Routine gynecological and dental examinations will be carried out during the study visits. Samples of vaginal secretion and blood will be collected. Laboratory tests to quantify vaginal microbial flora and to identify infection of bacterial vaginosis as well as common sexually transmitted diseases will be conducted. Future submissions may contain metadata or molecular data from additional subjects.

  Study phs002367

• BLUEPRINT Hematopoietic Stem/Progenitor Cell Methylomes

  An optimized whole genome bisulfite sequencing protocol (µWGBS, Farlik et al. 2015 Cell Reports) was used to establish DNA methylation profiles of FACS-purified stem and progenitor cells types of the human blood lineage. Most cell types were sorted from the peripheral blood of three donors with eight pools of ten cells, two pools of 50 cells, and one pool of 1000 cells. HSCs and MPPs were also sorted from fetal liver (HSCs only), cord blood, and bone marrow. Single-cell methylomes using the scWGBS protocol (Farlik et al. 2015 Cell Reports) were established for six cell types (HSC, MPP, CMP, GMP, CLP, MLP0). Gene expression profiling using the Smart-seq2 protocol (Picelli et al. 2013 Nature Methods) was done for nine stem/progenitor cell types (HSC, MPP, CMP, GMP, CLP, MLP0, MLP1, MLP2, MLP3).

  Study EGAS00001002070

• RNA-seq sequence data from DNMT3A microcephalic dwarfism patients.

  RNA-seq data generated from cells from control individuals and individuals with de novo DNMT3A variants causing microcephalic dwarfism.

  Dataset EGAD00001004471

• DNMT3A MOPD patient ChIP-seq data

  ChIP-seq data from controls and patients with de novo DNMT3A mutations resulting in microcephalic primordial dwarfism.

  Dataset EGAD00001004473

• Human Pilocytic Astrocytoma Single Cell RNA Sequencing

  Pilocytic astrocytoma (PA), the most common childhood brain tumor, is a low-grade glioma with a single driver BRAF rearrangement. Here, we perform scRNAseq in six PAs using methods that enabled detection of the rearrangement. When compared to higher-grade gliomas, a strikingly higher proportion of the PA cancer cells exhibit a differentiated, astrocyte-like phenotype. A smaller proportion of cells exhibit a progenitor-like phenotype with evidence of proliferation. These express a mitogen-activated protein kinase (MAPK) program that was absent from higher-grade gliomas. Immune cells, especially microglia, comprise 40% of all cells in the PAs and account for differences in bulk expression profiles between tumor locations and subtypes. These data indicate that MAPK signaling is restricted to relatively undifferentiated cancer cells in PA, with implications for investigational therapies directed at this pathway. Note that 931 out of 1234 samples in the Sequence Read Archive (SRA) passed QC and have transcript count data available from the Broad Institute Single Cell Portal. The transcript count data can be found at https://singlecell.broadinstitute.org/single_cell/study/SCP271/pilocytic-astrocytoma-single-cell-rna-seq#study-download

  Study phs001854

• KRT17High/CXCL8+ Tumor Cells Display Both Classical and Basal Features and Regulate Myeloid Infiltration in the Pancreatic Cancer Microenvironment

  Recent studies have uncovered the co-existence of basal and classical subtypes within pancreatic ductal adenocarcinoma (PDAC). We sought to characterize these intermediary cells using single-cell RNA sequencing of PDAC. We performed subtyping on 18 single-cell RNA sequencing human PDAC samples to identify multiple intermediary subtypes. We compared single-cell profiling of patient-matched blood and tumor samples to measure changes in the local and systemic immune microenvironments in CXCL8-high tumors vs. CXCL8-low tumors. Finally, we leveraged longitudinally patient-matched blood over the course of chemotherapy. In our studies we identified a cluster of KRT17high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines which in turn influence the myeloid compartment both locally and systemically. We utilized sequencing data from dbGaP study accession phs002070. In addition to that, we included sequencing from new specimens which are deposited to this submission, consisting of one additional tumor specimen and 5 PBMC samples, sequenced after chemotherapy (longitudinally matched to PBMC samples in phs002071.v1.p1). FASTQ files of these sequencing runs are available through this dbGaP submission.

  Study phs003436

• Programs, Origins, and Immunomodulatory Functions of Myeloid Cells in Gliomas

  Gliomas are challenging malignancies characterized by an immunosuppressive microenvironment filled with myeloid cells, whose roles in immune modulation are not fully understood. In this study, we utilized single-cell RNA sequencing (scRNA-seq) data from 85 primary human glioma tumors, related blood samples, and brain tumor organoid models. We found that nearly all glioma-associated myeloid cells express at least one of four distinct immunomodulatory activity programs. These programs include:1. Scavenger Immunosuppressive Program2. Complement Immunosuppressive Program3. Microglial Inflammatory Program4. Systemic Inflammatory ProgramAll four programs are found in both lower-grade and high-grade gliomas and are expressed across various myeloid cell types, whether derived from blood or resident origins. We validated the remarkable plasticity of myeloid cells by showing that the introduction of peripheral blood monocytes into glioma organoid models can induce the emergence of identities resembling microglia, macrophages, and dendritic cells, as well as all four immunomodulatory programs. Our study provides a valuable resource and a new framework for understanding the role of immunomodulatory myeloid cells in gliomas, laying the groundwork for developing effective immunotherapy strategies for glioma patients.

  Study phs003756

• High-coverage whole-genome sequencing reveals structural variations in triple-negative breast cancer

  Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors or human epidermal growth factor receptor 2 (HER2). Currently, apart from poly ADP-ribose polymerase (PARP) inhibitors, there are few effective therapeutic options for this cancer type. Here, we present a comprehensive characterization of genetic alterations in TNBC via high-coverage whole-genome sequencing along with transcriptomic and whole-exome sequencing. Silencing of BRCA1 gene impaired the homologous recombination (HR) pathway in a subset of TNBC, which exhibited similar phenotypes with tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were the early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2 or NOTCH3 and impacted tumor suppressor genes including RB1, PTEN and KMT2C. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblast cells, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC that had important clinical implications.

  Study JGAS000095

• Whole exome sequencing data for patients with Bosma arhinia microphthalmia syndrome (BAMS).

  The datasets includes 21 samples from 7 families with Bosma arhinia microphthalmia (BAMS). For details of the study please refer to the manuscript "De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development", Nature Genetics 2017. Each sample was exome sequenced and the family ID in sample description refers to the Individual ID in Supplementary figure 2 of the manuscript.

  Study EGAS00001002193

• sn-RNAseq profiling of the impact of a cytokine storm model in human cardiac organoids

  We developed conditions to model conditions of diastolic dysfunction caused by inflammatory factors in human cardiac organoids. Our organoid model is based on conditions promoting maturation (Mills et al., PNAS, 2017 and Voges et al., In Revision) and incorporating human pluripotent stem cell derived cardiomyocytes, epicardial cells, fibroblasts, endothelial cells and pericytes. Following 15 days of differentiation (Voges et al., Development, 2017) we formed human cardiac organoids incorporating both our multicellular differentiation (Mills et al., PNAS, 2017) and additional endothelial cells (Voges et al., In Revision). After another 12 days of maturation in 5 days maturation medium and 5 days weaning medium (Voges et al., In Revision) human cardiac organoids were either treated with weaning medium or “cardiac cytokine storm” comprised of 100 ng/ml IFNg, 10 ng/ml IL-1 β and 10 µg/ml poly(I:C). After 48 hours human cardiac organoids were harvested and snap frozen in -80C before nuclei isolation and single nuclei RNA sequencing.Pooled hCO (~40) were homogenized in 4 mL lysis buffer (300 mM sucrose, 10 mM Tris-HCl (pH = 8), 5 mM CaCl2, 5 mM magnesium acetate, 2 mM EDTA, 0.5 mM EGTA, 1 mM DTT)(all Sigma-Aldrich) with 30 strokes of a dounce tissue grinder (Wheaton). Large pieces of hCO were allowed to settle and homogenate was passed through pre-wetted 40 µm cell strainers (Becton Dickinson). Remaining hCO material in the douncer was resuspended in 4 mL and the douncing and filtering steps were repeated twice. All steps of the homogenization were performed on ice. The filtered homogenate was centrifuged at 1500 x g for 5 min at 4oC. Nuclei pellets were then re-suspended in PBS. A fraction of resuspended nuclei were then stained with hoechst nuclear stain (1:500 dilution) and counted on a haemocytometer under fluorescent microscope.The nuclei were then re-centrifuged (1500 x g for 5 min at 4°C) and resuspended at a density to load ~5,000 nuclei per sample. Cell were loaded into the Chromium Controller (10X Genomics) for gel bead emulsion (GEM) formation. Library preparation was conducted according to the manufacturer’s recommended protocol using the Chromium Next GEM Single Cell 3’ GEM, Library & Gel Bead Kit v3.1. Libraries were sequenced on the NextSeq 500/550 v2 (Illumina) with 150 bp reads.In the snRNA-seq we note the lower than expected percentage of non-myocytes and the loss of endothelial cells (Mills et al., PNAS, 2017 and Voges et al., In Revision), indicating the protocol requires further optimization for hCO samples.

  Study EGAS00001005174

• Cellular Diversity of the Developing Human Cerebral Cortex

  We sought to characterize cellular heterogeneity in the human cerebral cortex at a molecular level during cortical neurogenesis. We captured single cells and generated sequencing libraries using the C1TM Single-Cell Auto Prep System (Fluidigm), the SMARTer Ultra Low RNA Kit (Clontech), and the Nextera XT DNA Sample Preparation Kit (Illumina). We performed unbiased clustering of the single cells and further examined transcriptional variation among cell groups interpreted as radial glia. Within this population, the major sources of variation related to cell cycle progression and the stem cell niche from which radial glia were captured. We found that outer subventricular zone radial glia (oRG cells) preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR and related this transcriptional state to the position, morphology, and cell behaviors previously used to classify the cell type. Our results suggest that oRG cells maintain the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby contributing to the developmental and evolutionary expansion of the human neocortex. For study version 2, we have updated this data set to include additional primary cells that we infer to represent microglia, endothelial cells, and immature astrocytes, as well as additional cells from the developing neural retina, and from iPS-cell derived cerebral organoids. The genes distinguishing these cell populations may reveal biological processes supporting the diverse functions of these cell types as well as vulnerabilities of specific cell types in human genetic diseases and in viral infections. For study version 3, we have updated the data set to include additional primary cells, including those published in Nowakowski et al., 2017 (PMID:29217575). For study version 4, we have additionally performed parallel analyses of transcriptomes and physiological responses of 476 single cells isolated from developing human cortex. As a result, we were able to identify physiological response profiles of specific progenitor and neuronal cell types during human cortical development.For study version 5, we have additionally performed bulk RNA sequencing of organotypic primary cultures from the developing human cortex with or without exposure to SARS-CoV-2 to understand the infectability and transcriptomic effects of SARS-CoV-2 on the developing human cortex.For study version 6, we investigated the impact of LIFR signaling on neural proliferation and differentiation of human oRG cells. Specifically, we isolated oRG cells from the primary developing neocortex and cultured them for four weeks with and without LIF treatment. We then performed single-cell RNA sequencing using the Chromium Single Cell 3’ Reagent Kits (v3.1, Dual index) from 10x Genomics to understand the molecular and cellular changes of oRG differentiation upon LIF treatment.

  Study phs000989

• The Role of CDX2 in Controlling ABCB1 Expression and Chemosensitivity in Human Colon Cancer

  This study reports the results of RNA sequencing (RNA-seq) experiments performed on two human colon cancer cell lines (HT-29, DLD-1) that were genetically engineered to achieve either the constitutive expression (in HT-29 cells) or the selective inactivation (in DLD-1 cells) of the transcription factor CDX2, a master regulator of embryonic gut development and a key regulator of multi-lineage differentiation in adult colon epithelial cells. Our previous studies had identified lack of CDX2 expression as a prognostic biomarker of poor prognosis and a predictive biomarker of benefit from adjuvant chemotherapy in Stage-II and Stage-III colon cancer patients (Dalerba et al., NEJM, 374:211-222, 2016; PMID: 26789870). The molecular basis of these associations, however, remained poorly understood. The present study was designed to identify which genes are under the transcriptional control of CDX2, in order to clarify their role in shaping colon cancer resistance to chemotherapy. Of the two lines included in this study, the first (HT-29) is CDX2-negative at baseline, and was infected with a lentivirus vector encoding for the cDNA of the human CDX2 gene under the control of a constitutive promoter (CMV). The second line (DLD-1) is CDX2-positive at baseline, and was infected with a series of lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the CDX2 gene. In both cases, infected cells were purified by fluorescence-activated cell sorting (FACS), based on the differential expression of a green fluorescent reporter (EGFP) that was also encoded by the lentivirus vectors, and transcribed in tandem with either the CDX2 cDNA (HT-29) or CRISPR/Cas9 gRNAs targeting CDX2 (DLD-1). The experiments were designed to include 3 experimental replicates per condition, and to compare the transcriptional profile of genetically engineered cells with that of autologous controls (i.e., HT-29 cells infected with an "empty" version of the same lentivirus vector used to over-express CDX2, DLD-1 cells engineered with a "non-targeting" CRISPR/Cas9 gRNA). In the specific case of DLD-1 cells engineered with CRIPSR-Cas9 constructs targeting CDX2, infected cells were sorted based on the differential expression of EGFP and then plated as single-cells, in order to sub-culture three isogenic clones, all of which were genetically sequenced to confirm bi-allelic knock-out of the CDX2 gene, and confirmed to lack CDX2 protein expression by Western blot. The results of our experiments demonstrate that, in human colon epithelial cells, CDX2 controls the expression of the ABCB1 efflux pump, by positively regulating the transcription of the corresponding gene.

  Study phs002903

• PFA ependymoma cancer study

  Sequencing data related the PFA ependymoma study (Michealraj et al., Cell 2020), a lethal glial malignancy of the hindbrain found in babies and toddlers.

  Study EGAS00001004312

• RNA-Seq data of de novo assembly individual EGYPT

  This is the blood RNA-Seq read data used for expression analysis such as haplotypic expression (mapped against GRCh38).

  Dataset EGAD00001006036

• Sequencing data for the manuscript "Multi-focal sampling of de novo metastatic prostate cancer reveals complex polyclonality and enables accurate clinical genotyping"

  This submission includes targeted and whole exome paired-end fastq files.

  Dataset EGAD00001009651

• Ewing's Sarcoma RNA-Seq

  28 Pretreated Ewing sarcoma tumor blood samples were collected from the Hospital for Sick Children (SickKids) and Mount Sinai Hospital in Toronto, Canada in accordance with each institution’s Research Ethical Board (REB) guidelines. Detailed clinical information (age at presentation, gender, tumor site, stage, etc.) were obtained from the corresponding institutional tumor banks. Transcriptome (RNA-Seq) sequencing was performed using established protocols on Illumina instruments.

  Dataset EGAD00001004188

• Assessment of de novo copy number variations in Italian patients with schizophrenia.

  We investigated de novo CNVs in the whole genomic DNA of schizophrenia patients and their parents and, specifically, in putative enhancer motifs.Study participants were part of a wider multicenter study, involving an Italian cohort of schizophrenia patients recruited by members of INRP - Italian Network for Research on Psychoses.Whole genomic DNA obtained from 46 family trios of schizophrenia probands was analyzed using the Enhancer Chip, a customized array CGH developed using the Agilent SurePrint G3 8X60K format, which is able to investigate the whole genome with a 300Kb resolution, specific disease loci at a tenfold higher resolution, and that was highly enriched in probes in more than 1.250 enhancer elements selected from the Vista Enhancer Browser (PLoS One. 2012;7(12):e52264).

  Study EGAS00001002159

• GWAS membranous nephropathy Stanescu et al., 2011 UK cohort, chr2 region of interest, imputed

  334 biopsy-confirmed membranous nephropathy (MN) cases and 349 ethnically matched healthy controls: the British cohort of the Stanescu et al., 2011 GWAS. Genotyped and imputed region of interest on chromosome 2 (hg19 chr2:160500000-161500000), as used to determine Neanderthal introgression near the PLA2R1 MN risk locus (lead SNP: rs4664308).

  Study EGAS00001007700

• Single Chromatin Fiber Profiling in the Human Brain

  We developed a human postmortem brain-applicable ‘Fiber-seq' protocol for genome-scale, PCR-free single molecule sequencing of on average 8-10kb long chromatin fibers, to map nucleosome positioning and nucleosome-depleted regions which include, for example, active promoters and enhancers. We generated two Fiber-seq reference sets, one from sorted non-neuronal NeuN- prefrontal cortex (PFC) nuclei from a 32 year old female donor, with total of 11,143,795 reads/fibers, and median of 30-fold genomic coverage. The other reference set was generated on sorted prefrontal NeuN+ neurons, from two 24 year old brain donors (1 female/1 male), with a combined total read/fiber count of 4,749,556 and median of 20-fold genomic coverage. Each of the peaks in the Fiber-seq libraries seq signal correlated with the ATAC peak levels in the neuronal and non-neuronal ATAC-seq libraries, respectively (promoters, clusters 1, 3; NeuN+, r = 0.574; NeuN-, r=0.683, PHowever, Fiber-seq detected 19,978 highly significant peaks which, while showing some non-significant/near-background ATAC-Seq alignments, lacked a corresponding site-specific enrichment in conventional short-read ATAC- and ChIP-seq datasets. However, 60% of these peaks were in repetitive DNA elements. Therefore, long read single chromatin fiber sequencing, which exceed the base pair length of conventional short-read libraries by two orders of magnitude, could capture many actively regulated repeat elements at the site of specific gene loci, that otherwise would remain unmappable by conventional ATAC-, and histone- ChiP-seq.

  Study phs003771

• Sequencing data for oesophageal and related samples - Rogerson et al (RNA)

  Data supporting: "Repurposing of KLF5 activates a cell cycle signature during the progression from Barrett’s Oesophagus to Oesophageal Adenocarcinoma." Rogerson et al. RNA-seq data 2 samples

  Dataset EGAD00001005915

• Sequencing data for oesophageal samples - Killcoyne, Gregson et al (sWGS)

  Data supporting: "Genomic copy number predicts esophageal cancer years before transformation." Killcoyne, Gregson et al. sWGS data 1000 samples BAM files

  Dataset EGAD00001006033

• Sequencing data for oesophageal and related samples - Ococks, Frankell, Masque Soler et al (ctDNA)

  Data supporting: “Longitudinal tracking of 97 esophageal adenocarcinomas (EAC) using liquid biopsy sampling.” Ococks, Frankell, Masque Soler et al. ctDNA (BAM files) 333 samples

  Dataset EGAD00001006373

• Bulk transcriptomics of Human High-Grade-B-Cell-Lymphomas differentiated according to IGH status

  GCB DLBCL MB2 DE and HGBCL-DH-BCL2(-BCL6) cases classified according to IGH status in IGH+ or IGH-undetectable

  Dataset EGAD50000001524

• Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants

  We have sequenced four samples to identify variants in KMT2A gene. Three samples were sequenced with WGS, one was sequenced by WES (Patient2).

  Dataset EGAD00001004838

• ALPI deficiency and inflammatory bowel disease

  Inflammatory bowel diseases (IBDs) are complex and severe disorders ascribed to alterations in the dialogue between the microbiota and the host immune system (Bouma & Strober, 2003; Maloy & Powrie, 2011). By using whole‐exome sequencing (WES), we report the identification of compound heterozygous ALPI mutations in two unrelated patients displaying severe intestinal inflammation and autoimmunity. ALPI encodes the Intestinal alkaline phosphatase, a brush border metalloenzyme that catalyses phosphate hydrolysis of the lipid moiety of LPS and thereby drastically reduces LPS pro‐inflammatory activity (Schromm et al, 1998; Goldberg et al, 2008).

  Study EGAS00001002847

• Mutations in GNAI2 Cause Developmental and Immune Dysregulation

  To define a genetic syndrome of dysmorphism, brain malformations, skeletal defects, endocrine and immune dysfunction, 11 patients from 11 unrelated families who had similar features were studied. Whole exome sequencing was performed to identify disease-causing mutations. A disease segregated with de-novo or autosomal dominant mutations in a single gene, GNAI2, encoding the Gαi2 protein. We define a new Congenital Disorder associated with Gαi2 mutations and downstream functional effects.

  Study phs002817

• Exome_sequencing_in_patients_with_cardiac_arrhythmias

  The institut du thorax in Nantes (FR), the Academic Medical Center in Amsterdam (NL) and the University Hospital of Muenster (DE) have recruited 20 large families comprising at least 3 patients with cardiac arrhythmias and showing history of sudden cardiac death. For each family, the exome of one affected individual has been sequenced at the Wellcome Trust Sanger Institute (UK), in order to identify new genes associated with high risk of sudden cardiac death.

  Study EGAS00001000063

• Novel de novo pathogenic variant in the GNAI1 as a cause of severe disorders of intellectual development with autistic features

  Our probands A and B are boys-monozygotic twins with the clinical diagnosis of severe intellectual impairment, developmental stagnation, and dysphasia. They were diagnosed at the Department of Medical Genetics and Genomics (University Hospital Brno). Parents provided written informed consent, which was approved by the Research Ethics Committee of Masaryk University and Ethics Committee of University Hospital Brno. Peripheral blood samples were collected in sterile heparinized tubes for cytogenetic analysis. Genomic DNA samples were obtained from 1 ml peripheral blood in EDTA, according to the standard DNA isolation process using the MagNaPure system (Roche Diagnostics, Basel, Switzerland). Quality and quantity were checked using a DeNovix DS-11 Spectrophotometer (DeNovix Inc., Wilmington, DE, USA) and Qubit® 2.0 (Thermo Fisher Scientific, Inc., Waltham, MA, USA).

  Dataset EGAD00001007736

• Exome trios in patients with gastroschisis (2019-04-08)

  Gastroschisis (MIM 230750) is a herniation of the intestines through a defect of the abdominal wall lateral to the umbilicus (usually on the right side), and it is not covered by a membrane [Ledbetter, 2012]. Gastroschisis is a congenital anomaly with increasing incidence, easy prenatal diagnosis and extremely variable postnatal outcomes. On the basis of clinical manifestations, epidemiologic charateristics, and the presence and type of additional malformations, gastroschisis could be considered a heterogeneous condition with no gene/s discovered yet. This congenital anomaly affects approximately 1-3 infancts per 10,000 live births [Calzolari et al.1995;Parker et al.,2010] Current knowledge about causative mutations/variants. To date, no single gene has been linked to gastroschisis. Some publications have tried to link this malformation to variants in genes (such as AEBP1 (adipocyte enhancer binding protein) gene [Feldkamp et al,. 2012] or the VEGF-NOS3 pathway [Lammer et al., 2008]. Previously, a Scribble mutant mouse model (circletail) was reported to exhibit gastroschisis, however recent studies demonstrated that the Scribble knockout fetus exhibits exomphalos phenotype of gastroschisis [Carnagham et al., 2013]. 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/ . This dataset contains all the data available for this study on 2019-04-08.

  Dataset EGAD00001004942

• Defective mitophagy and enhanced oxidative stress dictate regulatory T cell impairment in autoimmunity

  Regulatory T cell (Treg) impairment is a common denominator of autoimmune pathologies. Despite the extensive characterization of Treg cell phenotype in autoimmunity, the molecular mechanisms underlying their deterioration remain ill defined. To investigate Treg dysfunction during autoimmunity we performed transcriptomic analysis of CD4+CD25highCD127- Treg cells from peripheral blood of patients with autoimmunity.

  Study EGAS00001004470

• Human Skin Cancer Atlas, Medical University of Vienna Data Access Policy

  Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. Here, we elucidate the yet unresolved intra-tumoral CAF variety in three skin cancer types at molecular and spatial single-cell resolution in a large cohort. We show that two out of three CAF subtypes contribute to tumor immune surveillance with distinct mechanisms. Matrix CAFs (mCAFs) ensheath tumor nests and synthesize extracellular-matrix to prevent T cell invasion. Immunomodulatory CAFs (iCAFs), which express proinflammatory and immunomodulatory factors, are only detected in high abundance in aggressive tumors. Strikingly, iCAFs but not tumor cells are (apart from immune cells) the exclusive cell type producing chemokines and, thus, play a key role in immune cell recruitment and activation. Mechanistically, we show that cancer cells transform adjacent healthy fibroblasts into cytokine-expressing iCAFs, which subsequently recruit immune cells and modulate the immune response. In conclusion, targeting CAF variants holds promise for improved efficacy of immunotherapy.

  Dac EGAC50000000154

• Quantitative analysis of a novel DNA hypermethylation panel using bronchial specimen for lung cancer diagnosis

  The dataset includes IDAT raw files for 10 samples and the analyzed DMP file which describes the differential methylation positions based on Illumina Infinium MethylationEPIC BeadChip. All samples (5 lung cancer cases vs. 5 benign lung disease controls) were obtained from bronchial washings at the site of the lesion under bronchoscopy manipulation. The histological type of the five lung cancer cases is adenocarcinoma and squamous cell carcinoma.

  Dataset EGAD00010002465

• RNAseq of 76 samples from Uveal Melanoma tumors

  Hotspot mutations in the spliceosome gene SF3B1 are reported in 20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1 R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss.

  Dataset EGAD00001004398

• Characterizing Individual Cells Obtained from Bone Marrow Biopsies of MPN Patients

  We profiled the transcriptomes of individual cells obtained from bone marrow aspirates of 7 treatment-naïve newly diagnosed JAK2-mutant myeloproliferative neoplasm (MPN) patients (3 polycythemia vera and 4 essential thrombocythemia patients), and 2 healthy controls. The submitted data corresponds to sequencing reads mapped to the human reference genome GhRC38 build using CellRanger for a total of 9 samples (one per patient). In addition, to reconstruct the lineage histories of single cells in MPN patients, we performed whole-genome sequencing of single-cell-derived colonies of hematopoietic stem and progenitor cells from 2 essential thrombocythemia (ET) patients: 22 JAK2-mutant colonies and 20 WT colonies for patient ET 1; and 13 JAK2-mutant colonies and 21 WT colonies for patient ET 2. The submitted data consists of sequencing reads aligned to the human reference genome GhRC38 build using bwa-mem. Each file corresponds to the whole-genome sequencing data for one colony.

  Study phs002308

• ETMR_Meth

  77 ETMR samples were profiled using methylation array. DNA from frozen tissue and formalin-fixed, paraffin-embedded (FFPE) materials were analyzed with the Illumina Infinium HumanMethylation450 (450k) and MethylationEPIC (EPIC) array according to manufacturer’s instructions and with a modified method that was previously described (Torchia et al. Cancer Cell. 2016; Triche et al. Nucleic Acids Res. 2013).

  Dataset EGAD00010001669

• Sequencing data for oesophageal and related samples - Ganguli et al (sWGS)

  Data supporting: "TBC" Ganguli et al (sWGS for 75 samples)

  Dataset EGAD00001011189

• Sequencing data for oesophageal and related samples - Abbas et al (RNA)

  Data supporting: "Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma" Abbas et al (RNA for 197 samples)

  Dataset EGAD00001011269

• Center for Common Disease Genomics [CCDG] - Cardiovascular: The Bangladesh Risk of Acute Vascular Events (BRAVE) Study

  The Bangladesh Risk of Acute Vascular Events (BRAVE) study is a hospital-based case-control study in Bangladesh which was established by the Cardiovascular Epidemiology Unit of Cambridge University in the UK in partnership with the key local cardiology and research centres to examine environmental, genetic, lifestyle and biochemical determinants of myocardial infarction (MI) among this South Asian population. By the end of 2016, this study has recruited ~8000 clinically confirmed first-ever MI cases (with a significant proportion being early-onset MI), and ~8000 healthy controls frequency-matched by age and sex. This site hosts data from ~500 whole genomes and ~1500 whole exomes (50% cases and 50% controls)

  Study phs001398

• Single Cell Analysis of Psoriasis Resolution following IL-23 Blockade

  Full-thickness skin biopsies were obtained from five individuals with severe psoriasis who were receiving risankizumab treatment. Skin biopsies were taken from lesional and non-lesional sites at baseline, and from lesional sites at day 3 and day 14 of therapy. All biopsies were taken from site-matched areas on the lower back/buttocks. Single-cell RNA sequencing was performed using a 10x Genomics platform. Myeloid and fibroblast populations showed the strongest change in gene expression after 3 days. An inflammatory, transient WNT5A+/IL24+ fibroblast state was identified, which was elevated in abundance in lesional skin versus non lesional skin, and decreased after 14 days of treatment. R1 and R2 FASTQs files are available.

  Study phs003351

• NHLBI TOPMed: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE)

  ECLIPSE was a longitudinal observational study of 2164 COPD subjects and a smaller number of smoking controls (337) and nonsmoking controls (245) followed regularly for three years, with three chest CT scans (at baseline, one year, and three years) (Vestbo et al., 2008, PMID: 18216052). Subjects were enrolled at clinical centers in the US, Canada, Europe, and New Zealand. Inclusion criteria included subjects ages 40-75, at least 10 pack-years of smoking, and spirometry in GOLD grades 2-4 (COPD cases) or normal spirometry with post-bronchodilator FEV1 >85% (predicted) and FEV1/FVC>0.7 (controls). Study visits were performed at enrollment, three months, and every six months thereafter with spirometry, questionnaires, and other clinical evaluations. The ECLIPSE CT scans have been analyzed with the VIDA software for emphysema and airway phenotypes. ECLIPSE has provided key insights into the clinical epidemiology of COPD, including COPD exacerbations (Hurst, et. al., 2010, PMID: 20843247) and lung function decline in COPD (Vestbo, et. al., 2011, PMID: 21991892). ECLIPSE has been used in a number of genetic studies of COPD susceptibility and protein biomarkers (Faner, et. al., 2014, PMID: 24310110). Genome-wide gene expression microarray data are available in 147 induced sputum samples from COPD subjects and 248 peripheral blood samples from COPD and control subjects. Phenotype data for ECLIPSE subjects is available through dbGaP phs001252.

  Study phs001472

• The Cardiogenics study

  Cardiogenics is an European collaborative project, it started in January 2007 and was funded by the European Commission through its Sixth Framework Program (reference LSHM -CT-2006-037593) until 2011. It involved several laboratories from France (INSERM UMRS937), Germany (Lübeck University; Regensburg University), United Kingdom (the Welcome Trust Sanger Institute; University of Leicester) and Sweden (Uppsala University Hospital) and was coordinated by a management group composed of scientists from these different institutions. Under the coordination of the management group the laboratories are still developing projects using Cardiogenics data sets. As part of the Cardiogenics project, RNA from monocytes and macrophages of 363 patients with coronary artery disease and 395 healthy individuals was prepared and genome-wide expression was assessed in both cell types using the Illumina HumanRef 8 v3 Beadchip . The DNA of all these individuals was genotyped using the Human 610 Quad custom arrays. Both data sets were used to conduct eQTL analyses. A subsample of subjects included in an allelic-imbalance substudy were also genotyped using the Illumina Human Custom 1.2M array. Detailed description of these datasets can be found in Shah S et al. Circ Cardiovs Genet 2011; Rotival M et al. Plos Genet 2011, Almlöf et al. Plos One 2012 and Garnier S et al. Plos Genet 2013

  Study EGAS00001000411

• NIH RECOVER: A Multi-Site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults

  The NIH Researching COVID to Enhance Recovery (RECOVER) initiative comprises a set of three combined retrospective and prospective, longitudinal, observational meta-cohort studies with nested case-control studies designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection (PASC or Post-COVID syndrome) in a diverse study population representative of the general COVID-19 population in the US. Enrolled patients with and without known SARS-CoV-2 infection will be observed for clinical signs and symptoms of PASC and will be assessed for risk and resiliency factors and potential mediating factors associated with the severity and progression of PASC. The objective of the RECOVER initiative is to enhance knowledge of recovery from SARS-CoV-2 infections in order to support development of novel diagnostic and therapeutic interventions. Overarching scientific objectives are as follows: Characterize the incidence and prevalence of sequelae of SARS-CoV-2 infection. Characterize the spectrum of clinical symptoms, subclinical organ dysfunction, natural history, and distinct phenotypes identified as sequelae of SARS-CoV-2 infection.Define the biological mechanisms underlying pathogenesis of the sequelae of SARS-CoV-2 infection. The RECOVER observational studies comprise three cohorts across the lifespan (adult, pediatric, and tissue pathology (autopsy)). The data collection and data analysis plans for each cohort have been harmonized to use common data elements where feasible. Brief descriptions of each cohort are provided in the following paragraphs:1) NIH RECOVER: A Multi-site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults (this study)The RECOVER adult cohort study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals who will enter the cohort with and without SARS-CoV-2 infection and at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study will be conducted in the United States and subjects will be recruited through inpatient, outpatient, and community-based settings. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptom screen will be reported by subjects or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical examinations and radiologic examinations will be performed at local study sites with cross-site standardization. A summary of information available by request in the RECOVER Adult Cohort (this study) can be reviewed via the "Adult Cohort Dataset Release Notes" and the "REDCap Codebook for the Adult Cohort" documents.2) The RECOVER Post Acute Sequelae of SARS-CoV-2 (PASC) Pediatric Cohort Study: A Multi-Center Observational Study (data not yet released)The RECOVER pediatric study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals ages newborn-25 years who will enter the cohort with and without SARS-CoV-2 infection at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study recruit participants inpatient, outpatient, and community-based settings in the United States. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptoms will be reported by participants or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical and radiologic examinations will be performed at local study sites with cross-site standardization.3) NIH RECOVER: A Multi-site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection (data not yet released)The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in (i) non-hospitalized patients who die 30 days or later from symptom onset of COVID-19, and (ii) hospitalized patients who die 30 days or later after discharge from a hospitalization for COVID-19. The study will include decedents who had previously fully recovered from SARS-CoV-2 infection (i.e., >30 days from onset in non-hospitalized, or >30 days from discharge in hospitalized patients), and decedents who meet clinical criteria of PASC as defined by the recent World Health Organization publication (see Section 5.4 below). The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of patients who died 15-30 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003463

• Growth Hormone (GH) -secreting Pituitary Adenoma

  Data from 12 fresh-frozen somatotropinomas and their corresponding blood samples. Details are given in Valimaki et al. Whole-genome sequencing of Growth Hormone (GH) -secreting Pituitary Adenoma. Provisionally accepted, 2015.

  Study EGAS00001001293

• Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation

  Whole-genome sequencing (WGS) and RNA-seq data from patient-derived xenografts (PDXs) obtained from CLL and RT primary samples as described in Playa-Albinyana et al.

  Study EGAS00001006965

• Dataset-linking-WGS-via-README-for-EGAS00001004884

  This dataset contains 139 Tumor and Control WGS files for samples for Gerhauser et al.,Cancer Cell, 2018, 34:996-1011. WGS and sequencing protocol was earlier described in Weischenfeldt et al, Cancer Cell, 2013.

  Dataset EGAD00001007669

• Sequencing data for oesophageal and related samples - Katz-Summercorn, Jammula et al (RNA)

  Data supporting: “Multi-omic cross-sectional cohort study of pre-malignant Barrett’s esophagus reveals structural variation and retrotransposon activity occur early in cancer evolution.” Katz-Summercorn, Jammula et al. RNAseq (BAM files)

  Dataset EGAD00001006353