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• single-cell RNA-seq Case-Control study of children progressing to Type1 diabetes

  Single-cell RNA sequencing was carried out on four selected PBMC samples of Finnish children at risk of developing Type 1 diabetes and their gender age and HLA matched control children using 10X genomic platform. All four Case children were positive for multiple islet specific autoantibodies and two of them also progressed to clinical disease during the follow up whereas the control children remain negative for all autoantibodies. Age at seroconversion for Case 2, 3, 5, and 9 children is 12, 18, 24, and 18 months, respectively. Age at sampling, in months, for the pairs was as follows (Case/Control): pair 2:24/24; pair 3: 12/18; pair 5: 12/12; pair 9:24/18.

  Study EGAS00001004070

• Immune heterogeneity in small cell lung cancer and vulnerability to immune checkpoint blockade

  Following the pivotal Phase III IMpower133 study, atezolizumab (anti–PD-L1), combined with carboplatin and etoposide (CE), was the first immune checkpoint inhibitor approved for first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) and is now a standard of care. A clearer understanding of therapeutically relevant SCLC subsets is needed to improve outcomes and to identify rational combination strategies. Transcriptomic analyses and nonnegative matrix factorization were conducted on 271 pre-treatment patient tumor samples from IMpower133 and four subsets with general concordance to previously reported SCLC subtypes were identified. Deeper investigation into the immune heterogeneity relevant to clinical outcomes uncover two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes that demonstrated hallmarks of immune cell infiltration. The balance of tumor-associated macrophage (TAM) to T-effector signals distinguished these inflamed subsets. Tumors with low TAM but high T-effector signals had a NE phenotype and demonstrated longer overall survival with PD-L1 blockade and CE versus CE alone than did tumors with high TAM and high T-effector signal, which had a non-NE phenotype. The delineation of SCLC immune heterogeneity offers a clinically relevant approach to discriminate SCLC patients likely to benefit most from immunotherapeutic approaches and highlights the complex mechanisms underlying response and resistance to immune checkpoint blockade. 

  Study EGAS50000000138

• Accurate detection of tumor-specific fusion genes reveals strongly immunogenic personal neo-antigens

  Fusion genes arising from cancer-associated somatic mutations are a potential rich source for highly immunogenic neo-antigens. However, their exploitation as targets for personalized cancer immunotherapy is currently limited by the lack of computational tools allowing transcriptome-wide identification of unique fusion genes in an accurate and sensitive manner. Here, we present EasyFuse, a computational pipeline, to detect individual and cancer-specific fusion genes in next-generation-sequencing transcriptome data obtained from human cancer samples. Using machine learning, EasyFuse predicts personal fusion genes with high precision and sensitivity and outperforms previously described approaches as qualified by an unprecedented ground-truth dataset of >1500 verification experiments in relevant patient samples. By testing immunogenicity with autologous blood lymphocytes from cancer patients we detected pre-established CD4+ and CD8+ T cell responses for 10 of 21 (48%), and for 1 of 30 (3%) of identified fusion genes, respectively. In conclusion, we demonstrate accurate detection of cancer-specific fusion genes. The high frequency of T cell responses detected in cancer patients support the relevance of private fusion genes as neo-antigens for personalized immunotherapies, especially for tumors with low point mutation burdens.

  Study EGAS00001004877

• Whole Genomes Define Concordance in Matched Primary, Xenograft, and Organoid Models of Pancreas Cancer

  Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any common solid epithelial tumour. Multiple failed clinical trials necessitate newer approaches to understand the molecular etiology of this disease. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) may serve as pre-clinical disease models; however, characterization remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of tumours and matched PDX and PDO from patients with PDAC. Our data show that PDX and PDO recapitulate PDAC tumourigenesis with respect to simple somatic mutations and copy number changes, and capture major structural variation events.

  Study EGAS00001002597

• Epigenome Wide DNA Methylation Study for Osteoporosis Risk

  Osteoporosis is characterized by low bone mineral density (BMD). The advancement of high-throughput technologies and integrative approaches provided an opportunity for deciphering the mechanisms underlying osteoporosis. In this study, we generated genomic (from whole blood DNA), transcriptomic and methylomic (from peripheral blood monocytes, PBMs), and serum metabolomic datasets from 143 premenopausal Caucasian females aged 25-40 years, including 74 with relatively high hip BMD (Z scores ≥ 0.8) and 69 with relatively low hip BMD (Z scores ≤ -0.8). The BMD Z score was defined as the number of standard deviations a subject's BMD differed from the mean BMD of their age-, gender-, and ethnicity-matched population. We identified differentially methylated CpG sites (DMCs) in peripheral blood monocytes (PBMs) at the whole methylome level between premenopausal women with high BMD and those with low BMD and deciphered how the DMCs influence the BMD variation through affecting the expression of the relevant genes. We also performed differential gene expression and metabolic analysis to assess their biological interaction and causal mechanisms. Our study provided novel insights into the pathogenesis of osteoporosis.

  Study phs001960

• WES Breast Patient-derived Tumor Organoid

  This dataset includes 18 Whole Exome Sequencing (WES) samples from 5 subjects. WES is performed on a matched pair of case/control samples, e.g., tumor/control or organoid/control. For each patient, the same control sample is used for the analysis of tumor and organoid samples. The sample name structure identifies the type of sample: <subjectId>_[TON][12]_[Case|Ctrl]_EX2; where T, O, and N refer to Tumor tissue, Organoid, and control sample, respectively. The number 1 or 2 refers to the specific tissue, and Case and Ctrl indicate a tumor tissue (or organoid) and a control sample, respectively. For example, ICSBCS007_T1_Case_EX2 is the first tumor tissue of subject ICSBCS007; ICSBCS007_O1_Case_EX2 is the tumor organoid derived from that tumor sample, and ICSBCS007_N1_Ctrl_EX2 is the matching control sample. More information can be found in the sample information table.

  Dataset EGAD50000000961

• HIV-phyloTSI: Subtype-independent estimation of time since HIV-1 infection for cross-sectional measures of population incidence using deep sequence data

  Estimating the time since HIV infection (TSI) at population level is essential for tracking changes in the global HIV epidemic. Most methods for determining TSI give a binary classification of infections as recent or non-recent within a window of several months, and cannot assess the cumulative impact of an intervention. We developed a Random Forest Regression model, HIV-phyloTSI, which combines measures of within-host diversity and divergence to generate continuous TSI estimates directly from viral deep-sequencing data, with no need for additional variables. HIV-phyloTSI provides a continuous measure of TSI up to 9 years, with a mean absolute error of less than 12 months overall and less than 5 months for infections with a TSI of up to a year. It performs equally well for all major HIV subtypes based on data from African and European cohorts. We demonstrate how HIV-phyloTSI can be used for incidence estimates on a population level.

  Study EGAS50000000895

• NHLBI TOPMed: Study of African Americans, Asthma, Genes and Environment (SAGE)

  This is a parallel case-control pharmacogenetic study of bronchodilator drug response among African American children with and without asthma. Each participant had spirometry measured using the KoKo PFT System. Asthmatic participants were administered with 4 puffs of HFA Albuterol. Healthy participants were given a baseline spirometry test. The overall goal is to identify genetic factors which are predictive of drug response in children with asthma. The principal tools include a questionnaire and biological specimen collection. Participants were 8-21 years old at time of recruitment. Children with asthma have physician-diagnosed asthma, symptoms and medications.

  Study phs000921

• Development of Novel Synovial Sarcoma Organoids Models for Drug Discovery

  Although synovial sarcoma has been studied using established cell lines and mouse models, effective treatments remain limited. We treated five patients with synovial sarcoma between 2022 and 2023 and established organoid cultures from resected tumor specimens using a modified air-liquid interface method. After serial passaging, organoids were successfully xenografted into NOD-scid IL2Rgnull (NSG) mice in three cases. The established organoids retained SS18-SSX fusion transcripts and demonstrated histological and genetic similarities to the original tumors. These organoid models provide a reliable platform for studying synovial sarcoma biology and hold promise for the development of novel therapeutic strategies.

  Study JGAS000806

• Divergent WNT Signaling and Drug Sensitivity Profiles within Hepatoblastoma Tumors and Organoids

  Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic ‘fetal’ and WNT-high ‘embryonal’, displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes.

  Study EGAS50000000561

• Human CMV-specific CD8+ T cells

  In this study we established a comprehensive workflow to collect multi-omics single-cell data using a commercially available micro-well based platform. This included whole transcriptome, cell surface markers (targeted sequencing-based cell surface proteomics), T cell specificities, adaptive immune receptor repertoire (AIRR) profiles and sample multiplexing. With this technique we identified novel paired T cell receptor sequences for three prominent human CMV epitopes. In addition, we review the ability of dCODE dextramers to detect antigenspecific T cells at low frequencies by estimating sensitivities and specificities when used as reagents for single-cell multi-omics.

  Dataset EGAD50000000894

• ATAC-seq in hiPSC-derived neurons after BDNF and KCl stimulations

  Brain-Derived Neurotrophic Factor (BDNF) is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. Molecular mechanisms of BDNF promoting cellular survival and synaptic plasticity have been intensely studied, yet its role in genome regulation is obscure. Using human induced pluripotent stem cell (hiPSC)-derived neurons via lentiviral delivery of the neuronal transcription factor Ngn2, we performed a temporal profiling (1h, 6h and 10h) of chromatin accessibility upon BDNF treatment or depolarization (KCl) to identify BDNF-specific chromatin-to-gene expression programs.

  Dataset EGAD00001009100

• SNV and indel calls from 8921 individuals in the British Autozygosity Populations BioResource dataset

  This includes variant calls (single nucleotide variants and small insertions/deletions) from 8086 (mostly British Pakistani/British Bangladeshi) individuals from the following studies: 1. 5236 British Pakistani/British Bangladeshi adults from East London Genes and Health (ELGH) 2. 2624 British South Asian mothers from Born in Bradford (mostly Pakistani) (BiB) 3. 1061 British South Asian adults from Birmingham (mostly Pakistani) (Birm) All of the Birmingham and most of the Born in Bradford samples were previously sequenced as part of PMID: 26940866. In the sample list file, the columns of interest to most people will be: vcf.id - sample ID from the vcf cohort - which cohort they're in sex.assigned - sex inferred from coverage on the X and Y chromosomes. Individuals for whom this did not match their reported sex have been discarded total, chrX and chrY - coverage within bait regions across all chromosomes, chrX and chrY respectively Mapping was done with bwa-mem and variant calling was carried out with GATK HaplotypeCaller. We removed variant sites for which the following was true: SNPs: "QD &lt; 2.0 || FS &gt; 30 || MQ &lt; 40.0 || MQRankSum &lt; -12.5 || ReadPosRankSum &lt; -8.0" Indels: "QD &lt; 2.0 || FS &gt; 30 || ReadPosRankSum &lt; -20.0"

  Dataset EGAD00001005469

• ERG ALTERATIONS DEFINE A NOVEL SUBTYPE OF ACUTE LYMPHOBLASTIC LEUKEMIA

  Structural chromosomal alterations are a hallmark of acute lymphoblastic leukemia (ALL) yet many patients lack an identifiable abnormality on conventional cytogenetic analysis. Here, using integrated analysis of genome-wide DNA copy number and gene expression data of 1764 childhood and adult ALL cases, including whole-genome, exome and mRNA-sequencing of 72 cases, we report a novel subtype of B-progenitor ALL (B-ALL) representing 4-13% of B-ALL cases characterized by a distinct gene expression profile, and focal deletions of ERG (ETS related gene) in 56% of cases. These cases are characterized by expression of a ERG transcript that utilizes a novel exon in intron 6 of ERG spliced to the canonical reading frame of ERG exons 7-10, encoding a 27 kDa C-terminal ERG protein that retains the ETS and transactivating domains but lacks the N-terminal pointed and regulatory domains. This protein is a competitive inhibitor of wild-type ERG and is leukemogenic in vivo. ERG-altered ALL cases have a favourable outcome despite the presence of alterations associated with poor prognosis in non-ERG ALL, such as deletions of IKZF1. These findings identify a new subtype of leukemia characterized by a novel mechanism of ETS transcription factor dysregulation in cancer.

  Study EGAS00001000514

• ProstOmics: spatial and bulk multi-omics of prostate cancer

  In this ERC-funded ProstOmics project we have used spatial and bulk multi-omics on fresh frozen prostate cancer samples to investigate cancer biology and find for biomarkers to improve patient treatment. All tissue material were collected from prostate cancer patients undergoing radical prostatectomy who had not received any prior cancer-specific treatment.Of the 498 prostate tissue samples (114 patients) included in our project, 176 samples (N=37 patients) have been analyzed with bulk transcriptomics (RNA-seq). Some of these 176 samples were also analyzed with spatial transcriptomics (n=32, N=8, Visium 10x RNA-seq) and DNA methylomics (n=96, N=24, array). All datasets include metadata for histopathological evaluation. Patient metadata include information of age at surgery, time (months) until reported relapse, pre-surgery PSA and post-surgery T-stage.

  Study EGAS50000000413

• International consensus definition of DNA methylation subgroups in juvenile myelomonocytic leukemia

  Known clinical and genetic markers have limitations in predicting disease course and outcome in juvenile myelomonocytic leukemia (JMML). DNA methylation (DNAme) patterns in JMML have correlated with outcome across multiple studies, suggesting it as a biomarker to improve patient stratification. However, standardized approaches to classify JMML based on DNAme patterns are lacking. We therefore sought to define an international consensus for DNAme subgroups in JMML and develop classification methods for clinical implementation.

  Study EGAS00001004682

• Single-cell RNA-seq of bronchoalveolar lavage (BAL) fluid in severe COVID-19 and SARS-CoV-2 stimulated classical blood monocytes

  We analyzed pulmonary monocyte and macrophage responses as well as and pulmonary pathology in two cohorts of patients with COVID-19 associated ARDS. Monocyte-derived macrophages accumulated in the lung during ARDS and acquired a profibrotic signature, characterized by high expression of known fibrogenic factors like TGFB1, SPP1 and LGMN. COVID-19 associated macrophages showed highly significant transcriptional similarity with profibrotic macrophage populations identified in idiopathic pulmonary fibrosis (IPF). Notably, overnight exposure to SARS-CoV-2, but not influenza A virus or viral RNA analogues, induced a similar phenotype in human monocytes from healthy volunteers in vitro. Patients with severe COVID-19 associated ARDS showed clear clinical, radiographic and histopathological features of scarring and fibrotic tissue remodeling. In conclusion, SARS-CoV-2 triggers profibrotic macrophage responses, fibroproliferative ARDS, and lung fibrosis

  Study EGAS00001004928

• Rare Disease Synthetic Dataset

  The purpose of this project is to provide public human datasets for the study of rare diseases. The use of public human genomic background combined with the in-silico insertion of real disease-causing variants enable to have a representative dataset for testing purposes without facing ethical and legal issues associated with the use of human sensitive data. This project aims to help development of technical implementations for rare disease data integration, analysis, discovery, and federated access.

  Dataset EGAD00001008392

• Strand-seq of hematopoietic stem and progenitor cells along human aging

  Somatic mosaicism (SM), referring to the presence of somatic mutations in sub-populations of cells within healthy individuals, is associated with an increased risk of a variety of diseases, including cancer. Blood is at particularly high risk of SM, given its rapid turnover and functionally- heterogeneous cell-type composition. While the roles of point mutations and large-scale rearrangements in blood SM have been scrutinised in recent years, the functional impact of mosaic structural variants (mSVs) remains poorly understood. Using haplotype-resolved single-cell multi-omics based on Strand-seq technology, we explored the mSV landscape of human hematopoietic stem and progenitor cells (HSPCs).

  Dataset EGAD00001009402

• A Single-Cell and Spatial Atlas of Early Human Olfactory Development

  The human nasal region is a complex structure derived from neural crest and placodal lineages, but its development remains poorly understood due to limited fetal tissue access and its intricate architecture. To address this, we created a single-nucleus and spatial transcriptomic atlas of the human fetal nasal region using tissue from 10 fetuses between 7 and 12 post-conceptional weeks. Single-nucleus RNA sequencing (snRNA-seq) revealed 34 distinct cell types, including epithelial, cartilaginous, immune, neuronal, glial, muscular, and vascular cells. By integrating snRNA-seq with multiplexed error-robust fluorescence in situ hybridization (MERFISH), we tracked dynamic changes in cell composition and gene expression over time in the olfactory epithelium (OE) and surrounding nasal regions. We identified novel markers of olfactory sensory neuron development and key pathways regulating epithelial patterning and OE morphogenesis. Notably, we observed early molecular signatures consistent with the "one neuron-one receptor" model, with spatially organized expression of 171 olfactory receptor genes. Together, this study presents the first integrated molecular and spatial framework of early human nasal development. It offers an unprecedented molecular blueprint of olfactory system formation and serves as a foundational resource for embryologists and developmental biologists studying sensory neurogenesis, epithelial patterning, and congenital disorders.

  Dataset EGAD50000001712

• Fetal origins of malignant germ cell tumours

  Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells (PGCs). They are uniquely able to generate embryonic and extraembryonic tissues, which in malignant GCTs carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we studied the phylogenetic and transcriptional diversity of 15 malignant gonadal GCTs and four normal testis biopsies by sequencing 131 whole genomes and 416 transcriptomes from 14 gonadal histologies, excised by laser capture microdissection. Our findings demonstrate that tumours were initiated by whole genome duplication likely in embryogenesis, within ~5-8 cell divisions post-PGC specification, followed by chromosome 12p gains associated with invasive disease. Of note, 12p imbalances were not only generated through GCT-typical isochromosomes, but also through non-isochromosomic configurations. Whilst tumours developed along homogenous phylogenetic pathways, they spawned manifold tissues independent of genetic subclonal diversification. A key feature of GCT tissues was the expression of fetal-specific genes. The transcriptional diversity notwithstanding, we found universal transcriptional elements correlated with hallmark 12p gains. Overall, our study reveals stereotyped phylogenies and transcriptomes underpinning the development of GCT that originate in fetal life and may lend themselves to therapeutic manipulation.

  Dataset EGAD00001007038

• Immunophenotype data for a subset of NSCLC cases in OAK

  The investigators would like to correlate NGS data from OAK to immunophenotype designation performed manually based on a panCK/CD8 immunohistochemistry stain for a subset of squamous cell carcinomas.

  Dataset EGAD50000001253

• ENGAGE - Amendment "500 genes exon sequencing"

  The ENGAGE project is a FP7 funded EU project aiming to combine genetic and phenotype information from European population based cohorts. In this sub-project we aim to do whole exome sequencing of individuals selected from Health 2000 and FINRISK cohorts. Individuals have been selected based on their metabolic trait phenotypes

  Dataset EGAD00001000403

• Chordoma_Targeted_Sequencing_Study

  This Study uses a focused bespoke bait pull down library method to target findings of Chordoma whole genome and whole exome sequencing studies in order to validate findings. This method will also be used on a larger set of tumour only samples in order to find precedence of these findings in a larger set of patient samples.

  Study EGAS00001000280

• Osteosarcoma_Targeted_Sequencing_Study

  This Study uses a focused bespoke bait pull down library method to target findings of Osteosarcoma whole genome and whole exome sequencing studies in order to validate findings. This method will also be used on a larger set of tumour only samples in order to find precedence of these findings in a larger set of patient samples.

  Study EGAS00001000278

• Meningioma_Targeted_Sequencing_Study

  This Study uses a focused bespoke bait pull down library method to target findings of Meningioma whole genome and whole exome sequencing studies in order to validate findings. This method will also be used on a larger set of tumour only samples in order to find precedence of these findings in a larger set of patient samples.

  Study EGAS00001000282

• T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis

  Data Access Committee means the following members of the Institute of Experimental Immunology, UZH, and investigators of the publication, to which the Data Access refers and who are responsible for making the data access decisions for the genotype and gene expression generated by UZH or respectively the epigenetic data, which had been generated at Karolinska Institute. Christian Münz, PhD; Co-Director of Institute of Experimental Immunology, University of Zurich Roland Martin, MD; Affiliated Group Leader (to Institute Münz) of Institute of Experimental Immunology Institute of Experimental Immunology Ivan Jelcic, PhD, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland Maja Jagodic, PhD, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden

  Dac EGAC50000000464

• Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

  DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutational consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (&gt;250/Mb) – higher than all childhood and most cancers (&gt;7000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerases epsilon or delta. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germline bMMRD (p&lt;10e-13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase mutant cancers rapidly amass an excess of simultaneous mutations (~600 mutations/cell division), reaching but not exceeding ~20,000 exonic mutations in &lt;6 months. Thus implying a threshold compatible with cancer cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

  Study EGAS00001001112

• Genomic Predictors of Response to Immune Checkpoint Therapy

  Immune checkpoint therapies, including monoclonal antibodies to programmed cell death-1 (PD-1) and cytotoxic % lymphocyte associated protein-4 (CTLA-4), yield durable clinical responses across many tumor types, including metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, predictors of response to these therapies in RCC are still unknown. Genomic characterization of large clinical cohorts of patients treated with anti-CTLA-4 and anti-PD-1 agents in melanoma and NSCLC have suggested that high mutational burden, high neoantigen burden, and high expression of certain genes in pre-treatment tumors may be associated with patient response to these therapies. In this study, we sought to investigate genomic predictors of response to anti-PD1 therapy in metastatic RCC in two independent clinical cohorts using whole exome and whole transcriptome sequencing.

  Study phs001493

• Harnessing_transposons_for_drug_resistance_gene_discovery_in_cancer

  This study involves a forward genetic screen to identify common insertion sites in drug resistant clones. We will be utilising piggybac transposon systems in order to generate multiple drug resistant clones in a range of human cancer cell lines.

  Study EGAS00001000468

• Direct Comparative Analysis of 10X Genomics Chromium and Smart-seq2

  Single cell RNA sequencing (scRNA-seq) is widely used for profiling transcriptomes of individual cells. The droplet-based 10X Genomics Chromium (10X) approach and the plate-based Smart-seq2 full-length method are two frequently-used scRNA-seq platforms, yet there are only a few thorough and systematic comparisons of their advantages and limitations. Here, by directly comparing the scRNA-seq data by the two platforms from the same samples of CD45- cells, we systematically evaluated their features using a wide spectrum of analysis. Smart-seq2 detected more genes in a cell, especially low abundance transcripts as well as alternatively spliced transcripts, but captured higher proportion of mitochondrial genes. The composite of Smart-seq2 data also resembled bulk RNA-seq data better. For 10X-based data, we observed higher noise for mRNA in the low expression level. Despite the poly(A) enrichment, approximately 10-30% of all detected transcripts by both platforms were from non-coding genes, with lncRNA accounting for a higher proportion in 10X. 10X-based data displayed more severe dropout problem, especially for genes with lower expression levels. However, 10X-data can better detect rare cell types given its ability to cover a large number of cells. In addition, each platform detected different sets of differentially expressed genes between cell clusters, indicating the complementary nature of these technologies. Our comprehensive benchmark analysis offers the basis for selecting the optimal scRNA-seq strategy based on the objectives of each study.

  Study EGAS00001003973

• Genetic factors underlying premature coronary heart disease in patients with normal coronary arteries

  The study will analyse by exome sequencing 42 Greek patients with premature MI and no vessel disease to identify genetic factors underlying this condition.

  Dataset EGAD00001000402

• RAD21-ChIP-Seq of cohesin-mutated and wildtpye adult AMLs

  ChIP-Seq targeting the major cohesin core subunit RAD21 to represent cohesin occupancy and binding sites in cohesin-mutated (STA2 or RAD21 mutations) and wildtpye adult AMLs.

  Dataset EGAD00001011199

• Center for Craniofacial and Dental Genetics (CCDG): Genetics of Orofacial Clefts, Sub-types, and Subclinical Phenotypes - CIDR

  The purpose of this project is to identify the genetic factors contributing to nonsyndromic orofacial clefts (OFCs), common subtypes, and related subclinical phenotypes. The most common subtypes of OFCs are cleft lip alone (CL), cleft lip with cleft palate (CLP), and cleft palate alone (CP). CL and CLP can be unilateral (left or right) or bilateral. Related subclinical phenotypes include occult lip muscle defects, characteristics of craniofacial morphology, and subtle speech abnormalities, which are distributed within families of affected individuals, and may reflect the underlying genetic susceptibility revealing clues about OFC etiology. The multi-ethnic dataset comprises participants recruited from Pennsylvania, Puerto Rico, Colombia, Philippines, Nigeria, and Ghana, and includes individuals with OFCs (cases), their unaffected relatives, and unrelated healthy controls. The specific aims of this project are to perform genome-wide association (GWAS) scans of (1) OFCs, (2) cleft subtypes (CL, CLP, CP, and laterality subtypes), and (3) cleft-associated subclinical phenotypes to identify variants associated with manifestations across the cleft-risk spectrum. Phenotyping for participants involved characterization of the overt clefts in cases, including affected structures (lip, alveolus, hard and soft palates), visible microforms, completeness, and laterality. Individuals with syndromic forms of OFCs were excluded from participation. Subclinical features were collected for all participants, including unaffected relatives and controls. Orbicularis oris (upper lip muscle) defects were assessed by high-resolution ultrasonography and scored by three independent raters. Lip print patterns were assessed by digital photography and scored for paramedical whorls by three independent raters. Velopharyngeal insufficiency was assessed with perceptual screening by a speech-language pathology expert. This dataset has potential to improve knowledge of the genetic contributors to OFCs, subtypes, and associated subclinical phenotypes by facilitating genetic association discovery, meta-analysis, and replication efforts. Findings may ultimately be useful for predicting OFC risk and recurrence, and may enhance our understanding of OFC biology.

  Study phs002815

• RNA-seq of Glioblastoma stem cells

  Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumors, such as Glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention. We show, using single-cell chromatin accessibility, that primary GBMs harbor a heterogeneous self-renewing population whose diversity is captured in patient-derived glioblastoma stem cells (GSCs). In depth characterization of chromatin accessibility in GSCs identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely essential transcription factors and present within GBMs in varying proportions. Orthotopic xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature predictive of low patient survival. Our chromatin-driven characterization of GSC states improves prognostic precision and identifies dependencies to guide combination therapies.

  Study EGAS00001003070

• H014: HES5 mediates NOTCH signaling by interaction with AKT to drive liver carcinogenesis

  Notch signaling plays a pivotal role in liver development and aberrant Notch signaling may lead to hepatocellular (HCC) or cholangiocellular carcinoma (CCA) development. Using whole exome sequencing of 54 human HCC samples, we discovered 19 somatic missense mutations in 15 different Notch pathway genes affecting 24.6% (14 of 57) of patients. Prediction of functional impact of these Notch pathway mutations revealed HES5-R31G to have high relevance. We found HES5 to be strongly activated by Notch signaling. In vitro, HES5 reduced cell migration and clonogenicity and in vivo, HES5 inhibited MYC-dependent liver tumor formation. But together with AKT, HES5 increased liver tumor formation in a mouse model. HES5 directly binds to AKT and AKT expression leads to increase HES5 protein levels. Furthermore, HES5 exhibits a negative feed-back loop by inhibiting NOTCH1 and HES1 gene expression. In contrast, HES5-R31G appears to be non-functional possibly by loss of nuclear translocation

  Study EGAS00001003329

• Serum proteomics of aortic diseases

  Aortic diseases are a rare but potentially life-threatening condition. We present a serum proteomic study for a spectrum of aortic diseases including thoracic aortic aneurysms (n = 11), chronic dissections (n = 9), acute aortic dissections (n = 11), and surgically treated dissections (n = 19) as well as healthy controls (n = 10) and patients of coronary heart disease (n = 10) to represent non-aortic cardiovascular disease. In total, we identified and quantified 425 proteins across all 70 samples. The different aortic diseases represented distinguishable proteome profiles. We identified protein clusters that positively or negatively correlate with disease severity, including increase of cytosolic tissue leakage proteins and decrease of components of the coagulation and complement system. Further, we identified a serum proteome fingerprint of acute aortic dissections, consisting, among others, of enriched inflammatory markers such as C-reactive protein and members of the S100 protein family. The study underlines the applicability of serum proteomics for the investigation of aortic diseases and highlights the possibility to establish disease-specific prognostic markers.

  Study EGAS00001006201

• Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer

  The evolution of cancers from low grade to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between cell intrinsic genetics and transcriptional alterations and the extrinsic microenvironment. To define the key mechanisms underpinning metastatic development, we focused on the most lethal form of prostate cancer, metastatic castration-resistant prostate cancer, and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions from 9 patients obtained from rapid autopsy. We found that intra-tumour heterogeneity is an indicator of key evolutionary processes, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. Unexpectedly, microenvironments across metastatic sites played a limited role while clonal evolution primarily promoted transcriptional noise. Intra-patient functional convergence of tumour ecosystems was observed across metastatic sites, pointing towards system-level selection pressures that drive the heterogeneity landscape of mCRPC. Our findings reveal functional evolutionary convergence of metastatic disease into units of intra-tumour heterogeneity identifying critical determinants of metastatic progression for therapeutic targeting. Note: matched WGS for some tumour single-cell experiments, as well as germline WGS for patients CA0027, CA0034, CA0035, CA0043, and CA0076, can be found in EGAS00001006598.

  Study EGAS50000001312

• Transcriptomes of human CD4+ T lymphocytes - Metabolic project

  Human CD4+ T cells are essential mediators of immune responses. By altering the mitochondrial and metabolic states, we defined metabolic requirements of human CD4+ T cells for in vitro activation, expansion, and effector function. T cell activation and proliferation were reduced by inhibiting oxidative phosphorylation, while early cytokine production was maintained by either OXPHOS or glycolytic activity. Glucose deprivation in the presence of mild mitochondrial stress markedly reduced all three T cell functions, contrasting the exposure to resveratrol, an antioxidant and sirtuin-1 activator, which specifically inhibited cytokine production and T cell proliferation, but not T cell activation. Conditions that inhibited T cell activation were associated with the downregulation of 2′,5′-oligoadenylate synthetase genes via interferon response pathways. Our findings indicate that T cell function is grossly impaired by stressors combined with nutrient deprivation, suggesting that correcting nutrient availability, metabolic stress and/or the function of T cells in these conditions will improve the efficacy of T cell-based therapies.

  Study EGAS00001005565

• PASCAL-MID Targeted amplicon sequencing of CD34+ HSPCs (CGD)

  High-throughput amplicon sequencing were performed on CD34+ hematopoietic stem and progenitor cells (HSPCs) derived from 4 healthy donors and one unaffected heterozygous carrier of a CYBB c.252G>A variant causing X-linked granulomatous disease. Targeted genome editing were performed in the HSPCs of CYBA and CYBB genes using CRISPR-Cas9 and recombinant AAV6. To assess gene editing outcomes in CD34+ HSPCs, the targeted loci were amplified from genomic DNA and sequenced on an Illumina iSeq100.

  Dataset EGAD50000001651

• WES analysis of DMD-ASD, DMD-ID and DMD-Control individuals for de novo and rare risk variants analysis

  This project generated a whole-exome sequencing (WES) dataset of 83 boys with a pathogenic variant in the DMD gene, along with WES data from the parents of 38 of them, totaling 159 samples. In addition to DMD, 12 boys also had ID (12 DMD-ID samples), 36 boys had ASD (DMD-ASD samples) and 35 did not present ID or ASD diagnosis (DMD-Control samples).

  Dataset EGAD50000001113

• Mitochondrial DNA (mtDNA) sequences from subjects with intellectual disability (ID) and austism spectrum disorder (ASD)

  Sequences from 95 subjects presenting intellectual disability (ID) and 98 subjects presenting intellectual disability and a diagnosis of autism spectrum disorder (ASD). The mtDNA was amplified by long-range PCR with 3 pairs of primers producing overlapping fragments. The three fragments were mixed in equimolar ratios and each sample was sequenced in an Ion Torrent Personal Machine according to manufacturer's user guide (reference genome: NC_012920.1 (rCRS)).

  Dataset EGAD00001004213

• mRNA-seq of in vitro differentiation from induced pluripotent stem cells to hepatocyte-like cells

  Fastq files of mRNA-seq data of induced pluripotent stem cells (iPSC), definitive endoderm (DE) and hepatocyte-like cells (HLC). The dataset comprises data from the in vitro differentiation protocol Cellartis (Takara Bio, "CEL", n = 4) and several interventions (11x3 replicates).

  Dataset EGAD00001005935

• Alzheimer's Disease Genetics Consortium (ADGC) Genome Wide Association Study -NIA Alzheimer's Disease Centers Cohort

  The National Institute on Aging (NIA) Alzheimer&#39;s Disease Centers (ADCs) cohort includes subjects ascertained and evaluated by the clinical and neuropathology cores of the 29 NIA-funded ADCs. Data collection is coordinated by the National Alzheimer&#39;s Coordinating Center (NACC). NACC coordinates collection of phenotype data from the 29 ADCs, cleans all data, coordinates implementation of definitions of AD cases and controls, and coordinates collection of samples. The ADC cohort consists of autopsy-confirmed and clinically-confirmed AD cases, and cognitively normal elders (CNEs) with complete neuropathology data who were older than 60 years at age of death, and living CNEs evaluated using the Uniform dataset (UDS) protocol who were documented to not have mild cognitive impairment (MCI) and were between 60 and 100 years of age at assessment. ADCs sent frozen tissue from autopsied subjects and DNA samples from some autopsied subjects and from living subjects to the National Cell Repository for Alzheimer&#39;s Disease (NCRAD). DNA was prepared by NCRAD for genotyping and sent to the genotyping site at Children&#39;s Hospital of Philadelphia. ADC samples were genotyped and analyzed in separate batches. [Reprinted from AC Naj et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer&#39;s disease. Nature Genetics 43, 436-441 (2011). doi:10.1038/ng.801. PMID: 21460841.]

  Study phs000372

• Whole Genome Sequencing in the Inner City Asthma Consortium (ICAC) Cohorts

  We performed whole-genome sequencing on individuals from the Asthma Phenotypes in the Inner City (APIC) and Urban Environment and Childhood Asthma (URECA) study cohorts, which consist of children with asthma who live in low-income neighborhoods across 10 U.S. cities. APIC was a one-year, prospective, observational study of children ages 6-17 with asthma. URECA was a prospective, observational study featuring a birth cohort of children with a high risk of developing asthma based on family history. We performed whole-genome sequencing on 1,035 individuals (ages 5-17 yrs; 67% Black, 25% Hispanic; 66% with MD-diagnosed asthma; APIC=508, URECA=527). Sequence read processing, quality control, and variant calling were performed using the Genome Analysis Toolkit suite (GATK v4). Variant call sites were annotated according to the filters applied in our common variant (minor allele frequency &#8805; 1%) association studies, based on predicted false positive rates, genotype quality and depth, and population-adjusted Hardy-Weinberg equilibrium. Principal components of ancestry were calculated using high quality, linkage-disequilibrium-pruned single-nucleotide variants, accounting for subject relatedness, using PC-Air and PC-Relate.

  Study phs002921

• Colorectal adenomas, NKI-AvL TGO series Stool-Proteomics

  Colorectal cancer (CRC) develops from normal epithelium, through a benign precursor lesion called adenoma, by accumulation of genetic alterations affecting oncogenes and tumour suppressor genes. About 5% of colorectal adenomas are estimated to progress to CRC. However, it is important to identify which adenomas actually are at high-risk of progression, because these should serve as intermediate endpoints for e.g. CRC screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high-risk, although this classification lacks solid evidence. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression.For this tissue dataset, we applied low-pass whole genome sequencing to 98 non-advanced and advanced adenomas. These adenomas were classified as lesions with low-risk or high-risk of progression, according to the presence of specific DNA copy number changes (Carvalho et al, CancerPrevRes, 2018).

  Study EGAS00001002953

• ART-NKI II HNSCC RNA-Seq

  RNA-Seq data of 25 HNSCC specimens from patients treated at The Netherlands Cancer Institute, Amsterdam and enrolled in the ARTFORCE trial. HNSCC biopsy samples obtained prior to treatment (chemo-radiotherapy) were used for polyA mRNA sequencing.

  Dataset EGAD00001005721

• Inherited CD28 deficiency in otherwise healthy patients with disseminated warts and giant horns

  this dataset corresponds to 3 patient of HPV-driven warts single cell RNA data generated through the 10X genomics platform and aligned on GRCh38 reference using the cell ranger tools.

  Dataset EGAD00001006644

• Fetal Chorioamniotic Membranes Show Molecular Changes in Placenta Previa and Placenta Accreta Spectrum

  Placenta previa and the placenta accreta spectrum (PAS) are understudied pregnancy disorders with serious consequences for both mother and infant. To better understand the molecular and cellular etiologies of these diseases, we performed 3SEQ of formalin-fixed paraffin-embedded (FFPE) fetal chorioamniotic membrane samples from PAS, previa, and gestationally age-matched spontaneous pre-term birth samples to identify molecule signatures of these diseases. These samples were subsequently validated using a second validation cohort of previa, PAS, and control patients. FFPE archival samples provide opportunities for retrospective molecular investigation of many diseases.

  Study phs002075

• Finding structural variation and functional consequences from the primary leukemia cells (AML) at the single-cell level

  In this study, we aimed to identify somatic structural variation of acute myeloid leukemia (AML) at the single-cell level and investigate its direct consequence on the nucleosome occupancy using scNOVA approach. For this purpose, we performed strand-specific single-cell sequencing of primary leukemia samples from 32-year-old male donor.

  Dataset EGAD00001006782