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• InterPregGen-GWAS-KAZ-2

  Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls. This dataset includes OmniExpress genotyping of maternal and fetal PE cases and controls from Kazakhstan. This study is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator).

  Dataset EGAD00010001947

• InterPregGen-GWAS-KAZ-3

  Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls. This dataset includes Infinium GSA genotyping of maternal, paternal and fetal PE cases and controls from Kazakhstan. This study is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator).

  Dataset EGAD00010001949

• Spatially resolved antigen receptor and gene expression data from breast cancer patients

  The dataset includes spatially-resolved and single-cell antigen receptor, as well as gene expression, data from two different HER2+ breast cancer patients. The tumor piece obtained during surgery from each patient was divided into several regions and tissue sections were used for spatial transcriptomics (Visium, 10x genomics). As indicated, some tissue sections were analyzed by a new method (Spatial VDJ) to spatially resolve antigen receptor sequences (target capture), which was developed in our publication. In parallel, tissue pieces from the same tumor were dissociated for single-cell gene expression analysis (10x genomics GEX, VDJ, and feature barcoding/Hash Tag Oligonucleotide). The deposited data is in the form of fastq files. All processed data, metadata, micrographs of the tissue sections (of those used for spatial transcriptomics), and scripts used for the analysis are publicly available at Zenodo (DOI: 10.5281/zenodo.7961605). Final libraries were sequenced on NextSeq2000 (Illumina) or NovaSeq6000 (Illumina) and analyzed with Cell Ranger, Seurat, Space Ranger, and STutility pipelines.

  Dataset EGAD00001011061

• Spatially resolved antigen receptor and gene expression data from human tonsil tissue

  The dataset includes spatially-resolved gene expression and antigen receptor data from two Tonsil samples (1 and 2). Tissue sections from the tonsil samples were used for spatial transcriptomics (Visium, 10x genomics). Tonsil 2 tissue sections were analyzed by a new method (Spatial VDJ) to spatially resolve antigen receptor sequences (target capture), which was developed in our publication. Nearby or adjacent tissue sections (from Tonsil2) were also analyzed by a bulk antigen receptor sequencing approach (amplicon sequencing), by a method also newly developed by us in the same publication (Bulk SS3 VDJ). For Visium, the data were anonymized (all SNPs removed) using Bamboozle (Ziegenhain and Sandberg, Nature Communications 2021). The deposited data is in the form of fastq files. All remaining data, metadata, micrographs of the tissue sections (of those used for spatial transcriptomics), and scripts used for the analysis are available at Zenodo (DOI: 10.5281/zenodo.7961605). Final libraries were sequenced on NextSeq2000 (Illumina) or NovaSeq6000 (Illumina) and analyzed with Seurat, Space Ranger, and STutility pipelines.

  Dataset EGAD00001011062

• Genome-Wide Association Study of Preterm Birth

  Preterm birth (PTB, born before 37 weeks of gestation) is a leading cause of neonatal mortality and post-natal morbidity. PTB affects one in nine all live births in the U.S. Notably, the highest rate of PTB occurs among African Americans (one in six). PTB is a complex trait, likely determined by multiple environmental and genetic factors and their interactions. We demonstrated strong familial aggregation of preterm and low birthweight in the US Blacks and Whites (Wang et al, NEJM, 1995) and conducted the largest candidate gene study of preterm birth at that time (Hao et al, HMG, 2004). We showed that a subset of mothers with certain metabolic gene variants are particularly vulnerable to the adverse effects of cigarette smoking on low birthweight and preterm births (Wang et al, JAMA, 2002). We also published a number of papers that examined the effect of maternal pre-pregnancy BMI, micronutrient status, stress and environmental toxins on the risk of preterm birth and related conditions. This project, supported by a grant from the NICHD (2R01HD41702, PI, Xiaobin Wang), aimed to conduct a genome-wide association study (GWAS) and apply advanced statistical methods to identify susceptibility loci of PTB in a predominantly urban low-income African American sample, a subset of the Boston Birth Cohort. PUBLIC HEALTH REVELANCE: We anticipate that this study will lead to the identification of novel genetic loci of PTB and gene-environment interactions. Such findings not only will provide important insights into mechanisms leading to PTB, but also may help identify women at high-risk of PTB, which in turn, may lead to the development of early and targeted interventions that can prevent PTB or mitigate the severity and consequences of PTB.

  Study phs000332

• Targeted sequencing data of regulatory regions in 200 Spanish ASD trios

  This study consists of genomic sequencing data obtained through targeted sequencing of regulatory regions (85,394 human cCREs from ENCODE v2, version 2, https://screenv2.wenglab.org/) in 200 ASD (Autism Spectrum Disorder) trios (father and mother unaffected and proband affected). The aim of the project is to detect genomic variants (rare and inherited variants) in regulatory regions that contribute to autism.

  Dataset EGAD50000002029

• Single-cell colony targeted DNAseq

  Targeted DNA sequencing was applied to colonies grown from single-cells of patient A.6. The protocol followed is described in https://doi.org/10.1038/s41467-021-21650-1 and the methods of the manuscript

  Dataset EGAD00001010193

• Poikiloderma syndrome RNAseq

  We will sequence the RNA of lymphoblast samples, transformed with EBV, which have poikiloderma syndrome with mutations in c16orf57. The aim of the experiment is to characterise RNA structural effects in this disease.

  Dataset EGAD00001000324

• Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes

  Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis.

  Dataset EGAD50000000567

• Detection of Genes Predisposing to Hematologic Malignancies

  We have been conducting genetic studies on families at high risk of different hematologic malignancies, in order to define the related tumors in the families, define precursor and other related conditions, and map and identify susceptibility genes. We have focused mainly on four types of lymphoid malignancies: chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and Waldenström macroglobulinemia (WM). A few families with a rare lymphoma subtype, hairy cell leukemia (HCL) are included. In addition, single large pedigrees with acute myeloid leukemia (AML), and juvenile myelomocytic leukemia (JMML) are included. Families are ascertained for having at least two patients with the same hematologic malignancy and are classified by the type of malignancy that predominates in the family. Multiple types of lymphoid malignancies are often found in the same family. Other data has shown that these conditions aggregate together in families. Verification of cancer diagnoses is obtained through medical records, pathology reports, and flow cytometry. Family members with precursor traits are also included, monoclonal B-cell lymphocytosis (MBL) in CLL families and IgM monoclonal gammopathy of undetermined significance (MGUS) in WM families.

  Study phs001219

• Gut microbiome modulates response to anti PD1 immunotherapy in metastatic melanoma patients

  There is a growing appreciation of the role of the microbiome in cancer, and evidence in pre-clinical models that the gut microbiome may modulate responses to immune checkpoint blockade though this has not been well-characterized in patients. We analyzed the oral (n=86)and gut (n=43) 16S microbiome in melanoma patients on PD-1 blockade. Significant differences were noted in the diversity and composition of the gut microbiome between responders and non-responders in patients with a fecal microbiome sample, with significantly higher alpha diversity and relative abundance of Ruminococcaceae bacteria) in R. Metagenomic studies (n=25) revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling demonstrated enhanced systemic and anti-tumor immunity in patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplant from responding patients. Together, these data have important implications for treatment with immune checkpoint blockade in cancer. The fastq files associated with this dataset are stored at ENA under the following accession numbers: PRJEB22894 (Fecal 16S), PRJEB22874 (Oral 16S), PRJEB22895 (Murine 16S), PRJEB22893 (Fecal WGS).

  Study EGAS00001002698

• Single cell and spatial transcriptomics of adult human adrenal glands

  The data set is composed of single cell transcriptomics data for adrenal glands from 11 deceased organ donors (10x 3') and spatial transcriptomic data for adrenal glands from 4 deceased organ donors (10x Visium).

  Dataset EGAD50000000394

• Oncoprint GSCCs

  This dataset contains DNA sequencing data from 7 GSCCs (data for BT569 is not available). We performed focused exome sequencing (43 most mutated genes in GBM), combined with OneSeq analysis (Agilent) on the GSCCs and identified both shared and GSCC-specific mutations. For CME038, whole genome sequencing was performed.

  Dataset EGAD00001011276

• Genotyping of GM samples

  This dataset contains a vcf file for 99 GM individuals genotyped on the Illumina HumanOmni2.5 array . The vcf file is originated after imputation (IMPUTE2) and filtering for minor allele frequency MAF≥0.05, imputation confidence score INFO of >0.4 and Hardy-Weinberg Equilibrium (HWE) p>1e-06, yielding ~6.3 million variants.

  Dataset EGAD00001010255

• Wisconsin Longitudinal Study on Aging

  The Wisconsin Longitudinal Study (WLS) is a long-term study of a random sample of men and women, who graduated from Wisconsin high schools in 1957, and their siblings. The WLS panel started out with a panel of 10,317 members from the class of 1957. Over time a second panel of 8,734 randomly selected siblings of the original graduate panel were recruited for the study. Of these combined panel members, 9,027 survived and contributed saliva for genetic analysis. Survey data were collected from the original respondents or their parents in 1957, 1964, 1975, 1992, 2004, and 2011, and from a selected sibling in 1977, 1994, 2005, and 2011. WLS data provide a detailed record of educational, social, psychological, economic, mental and physical health characteristics of a relatively homogeneous population that is almost entirely of Northern and Western European ancestry. Saliva was first collected in 2007-2008 by mail. Additional samples were collected in the course of home interviews that began in March 2010.

  Study phs001157

• NHLBI TOPMed: The Cleveland Family Study (CFS)

  The Cleveland Family Study (CFS) is one cohort involved in the WGS project. The CFS was designed to provide fundamental epidemiological data on genetic and non-genetic risk factors for sleep disordered breathing (SDB). In brief, the CFS is a family-based study that enrolled a total of 2284 individuals from 361 families between 1990 and 2006. The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first degree relatives, spouses and available second degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first degree relatives. Each exam, occurring at approximately 4 year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in the participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. The GCRC exam (n=735 selected individuals) included more comprehensive phenotype data on a focused subsample of the larger cohort, to permit linking SDB phenotypes with cardio-metabolic phenotypes, with an interest in identifying genetic loci that are associated with these related phenotypes. In this last round of data collection, a subset of 735 individuals was selected based on expected genetic informativity by choosing pedigrees where siblings had extremes of the apnea hypopnea index (AHI). Participants underwent detailed phenotyping including laboratory polysomnography (PSG), ECG, spirometry, nasal and oral acoustic reflectometry, vigilance testing, and blood and urine collection before and after sleep and after an oral glucose tolerance test. A wide range of biochemical measures of inflammation and metabolism were assayed by a Core Laboratory at the University of Vermont. 994 individuals were sequenced as part of TOPMed Phase 1, including 507 African-Americans and 487 European-Americans. Among the sequenced individuals, 156 were probands with diagnosed sleep apnea, an additional 706 were members of families with probands, and 132 were from neighborhood control families. 298 individuals were sequenced as part of TOPMed Phase 3.5, including 169 African-Americans and 129 European-Americans. Among the newly sequenced individuals, 33 were probands with diagnosed sleep apnea, an additional 214 were members of families with probands, and 51 were from neighborhood control families. Please note: Phenotype and pedigree data are available through "NHLBI Cleveland Family Study (CFS) Candidate Gene Association Resource (CARe)", phs000284.

  Study phs000954

• The Environmental Determinants of Diabetes in the Young Study (TEDDY)

  The Environmental Determinants of Diabetes in the Young (TEDDY) Study investigates genetic and genetic-environmental interactions, including gestational infection or other gestational events, childhood infections and other environmental factors after birth, in relation to the development of pre-diabetic islet autoimmunity and type 1 diabetes (T1D). Beginning in 2002, a consortium of six centers assembled to participate in the development and implementation of studies to identify environmental factors that trigger the development of islet autoimmunity and T1D in genetically susceptible individuals. The TEDDY study screened around 400,000 newborns and recruited 7,749 neonates from the general population with a pre-determined T1D risk of 3% and 919 neonates with first degree relatives who have T1D and who have a pre-determined T1D risk of 10%. Thus, TEDDY proposes to follow over 8,000 participants across six clinical centers worldwide (Finland, Germany, Sweden and three in the United States) until the age of 15. Participants are followed every three months for islet autoantibody measurements with blood sampling until four years of age and then at least every six months until the age of 15. After the age of four, autoantibody positive subjects continue to be followed at 3 month intervals and autoantibody negative subjects are followed at six month intervals. In addition to the analysis of autoantibodies, additional data and sample collection is performed at each visit. The parents collect monthly stool samples in early childhood. The parents also fill out questionnaires at regular intervals in connection with study visits and record information about diet and health status in the child's TEDDY Book between visits. Continued long-term follow-up of the currently active TEDDY participants will provide important scientific information on early childhood diet, reported and measured infections, vaccinations, and psychosocial stressors that may contribute to the development of type 1 diabetes and islet autoimmunity. DNA extracted from the 9-month TEDDY blood sample was used for SNP genotyping. Samples were available for 7,082 participants. SNPs were genotyped by the Center for Public Health Genomics at the University of Virginia, using the Illumina ImmunoChip SNP microarray of around 196,000 SNPs selected from 186 regions associated with 12 autoimmune diseases (including T1D) (Hadley et al., 2015). "Data quality control (QC) steps included eliminating subjects with a low call rate (> 5% SNPs missing) and discrepancies between reported gender and prior genotyping at the HLA laboratory. Secondly, SNPs were removed from analysis due to low call rate, Hardy-Weinberg equilibrium P value < 10-6, except for chromosome 6 due to HLA eligibility requirements)" (Törn et al., 2015). QC resulted in a total of 7,023 subjects with data on 176,586 SNPs. Additional information on the TEDDY study are available in the following articles: The Environmental Determinants of Diabetes in the Young (TEDDY) Study. TEDDY Study Group. Annals of the New York Academy of Science, 2008 and TEDDY - The Environmental Determinants of Diabetes in the Young - An Observational Clinical Trial. Annals of the New York Academy of Science, 2006 Details of the TEDDY protocol can be found in The Environmental Determinants of Diabetes in the Young (TEDDY): Genetic Criteria and International Diabetes Risk Screening of 421,000 infants. Pediatric Diabetes, 2011

  Study phs001037

• Bone marrow breakout lesions act as key sites for tumor-immune cell diversification and exhaustion in multiple myeloma

  Multiple myeloma is a disease characterized by the expansion of cancerous plasma cells in the bone marrow. The bone marrow microenvironment plays a pivotal role in supporting myeloma growth and modulating tumor immunity. As the disease progresses, myeloma cells may become independent of the bone marrow environment, leading to extramedullary disease associated with poor prognosis. However, the early processes associated with bone marrow independence and its implications for disease and immune control remain poorly understood. Here, we employed comprehensive single-cell and spatial mapping to identify the disruption of the cortical bone and subsequent expansion of myeloma cells in breakout lesions as a key event in multiple myeloma pathogenesis and tumor immunity. Breakout lesions harbor an adapted niche and a unique immune microenvironment conferred by sustained immune-tumor interactions. In particular, tumor-reactive T cells with a highly exhausted phenotype, alongside unique NK cell and macrophage subtypes, specifically expanded in breakout lesions. Spatially-resolved genomic, transcriptomic and cellular analyses uncovered extensive intra-lesion heterogeneity, suggesting a divergent co-evolution of genomic variation and locally confined T cell responses in distinct subregions. Ultra-high plex imaging revealed that tumor-reactive T cells, together with other immune-regulatory cells and dendritic cells, co-expand and exhaust upon sustained tumor interactions in locally confined immune islands. In contrast, immune-regulatory macrophage and NK cell subsets operate spatially separated within myeloma cell deserts. Jointly, our analyses uncover bone marrow breakout lesions as a hotspot for tumor-immune cell interactions, diversification and exhaustion, representing a key event in myeloma pathogenesis with significant therapeutic implications.

  Study EGAS50000000304

• Atezolizumab Plus Personalized Neoantigen Vaccination in Patients with Urothelial Cancer: a Phase 1 Trial

  This is a phase 1 single center clinical trial evaluating a multi-peptide personalized neoantigen vaccine, PGV001, in combination with atezolizumab for patients with urothelial cancer. Patients were enrolled in either the adjuvant or metastatic setting. Those in the adjuvant setting included patients considered high risk of recurrence (pathological stage ypT2-T4 or ypN+ for those treated with prior neoadjuvant chemotherapy or pT3-T4 or pN+ for those not treated with prior neoadjuvant chemotherapy). Those in the metastatic setting included patients progressing after prior chemotherapy or those with at least stable disease after chemotherapy treated as “switch maintenance” therapy. The primary endpoint was feasibility (including the number of neoantigens identified per patient, vaccine production time, the proportion of patients consenting to the vaccine development phase for whom a vaccine product was prepared, and the proportion of patients eligible for the treatment phase who completed the priming cycle 1 of PGV001 plus atezolizumab) and safety. Secondary endpoints included the objective response rate, progression-free survival or disease-free survival, overall survival, and immunomodulatory effects of treatment. Urothelial tumor tissue and normal tissue or peripheral blood specimens were utilized for DNA sequencing. HLA typing was performed utilizing genomic DNA isolated from whole blood, and RNA sequencing was performed utilizing tumor tissue specimens. Neoantigen prediction and final selection for incorporation into the vaccine was determined by the OpenVax computational pipeline. 12 patients were initially enrolled into the vaccine development phase and 10 patients initiated the treatment phase. PGV001 was administered with poly-ICLC and tetanus peptide on subsequent days for up to 10 doses, including an initial priming cycle 1. Atezolizumab was administered every 3 weeks for up to 1 year in the adjuvant setting or 2 years in the metastatic setting. The vaccine was feasible and safe, the median vaccine production time was 20.3 weeks, and 100% of patients that initiated the treatment phase completed the priming cycle. The most common treatment-related adverse events were local grade 1 injection site reactions, fever, and fatigue. Three of the 4 patients in the adjuvant setting remained disease-free at median follow-up of 39.5 months. There was a 40% objective response rate among patients with measurable disease in the metastatic setting. The single patient treated as “switch maintenance” therapy remained with no evidence of disease at 39.4 month follow-up. All patients demonstrated on-treatment neoantigen-specific T cell reactivity, as measured by ELISPOT and flow cytometry assays. Overall, PGV001 plus atezolizumab was feasible, safe, and warrants further investigation. Whole exome sequencing from tumor tissue and normal tissue or whole blood specimens and RNA sequencing from tumor tissue specimens will be available through dbGaP.

  Study phs003922

• Novel optineurin frameshift insertion causing familial frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis

  Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behaviour, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), progranulin gene (PGRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72), whilst mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with 4 affected members harbouring the same OPTN frameshift insertion, presenting with FTD-related phenotypes, including one sibling with predominant parkinsonism resembling corticobasal syndrome. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.

  Study EGAS00001005220

• Collagen XVII Promotes Pancreatic Cancer Through Regulation of PIK3R5

  Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that promotes the aggressive biology of this disease. While the varied mechanisms by which fibrillar collagens contribute to PDAC have been defined, little is known about the contribution of transmembrane collagens. Among this class of collagens, Collagen XVII uniquely contains an extensive intracellular domain that connects intracellular cytoplasmic components with the extracellular matrix. Collagen XVII is best characterized as the defining component of the type I hemidesmosome, an anchoring complex that attaches epithelial cells to the underlying basement membrane. In this study, we characterize the expression of collagen XVII in PDAC and the mechanisms by which it contributes to PDAC biology. We demonstrate that crosstalk between PDAC cells and cancer associated fibroblasts drive collagen XVII expression in vitro and xenograft tumor models in vivo. Genetic depletion of collagen XVII in low-passage patient derived cell lines diminishes their metastatic potential and ability to form tumors in mice. Whole transcriptome sequencing of tumors formed by cells with diminished collagen XVII levels revealed dramatically lower levels of PIK3R5, a regulatory subunit of class IB phosphatidylinositol-3-kinase (PI3K) that interacts with G protein-coupled receptors. Consistent with this, collagen XVII-deficient tumors exhibited lower levels of phosphorylated AKT, a downstream effector of PI3K. The studies highlight the importance of collagen XVII signaling in PDAC and define a novel mechanism by which collagen XVII mediates activation of PI3K.

  Study phs003641

• PacBio data of de novo assembly individual EGYPT

  This is the PacBio long read data used for performing de novo assembly of the EGYPT individual (mapped against GRCh38).

  Dataset EGAD00001006034

• Study of 5'UTR Mutations in Prostate Cancer

  The 5' untranslated region (5' UTR) of mRNA controls the translation of specific transcripts through encoded cis-regulatory elements. Yet exceedingly little is known about the prevalence and function of 5' UTR mutations in cancer. We have uncovered many 5' UTR mutations in our analysis of localized and castration resistant prostate cancer patients, and hypothesize that systematic mutations in critical 5' UTR regulatory regions perturb gene expression to drive prostate cancer progression. To elucidate the functional 5' UTR regulatory landscape of prostate cancer, we have taken a multi-faceted approach including ribosome profiling, in vitro reporter assays and the development of a novel high throughput method to functionally access the impact of recurrent 5' UTR mutations on both transcription and translation.

  Study phs001825

• Germline Whole-Exome Sequencing of Lung Cancer in EAGLE

  EAGLE is a large population-based case-control study designed and conducted to investigate the genetic and environmental determinants of lung cancer and smoking persistence using an integrative approach that allows combined analysis of genetic, environmental, clinical, and behavioral data. Here, we applied whole exome sequencing (WES) to EAGLE study, in a group of 2,777 Italian subjects (including 1,461 lung cancer cases and 1,316 healthy controls). We derived gene-level burden tests to explore the cumulative effect of deleterious rare variants within protein-coding genes and the lung cancer risk. Additionally, at this site we include WES datasets of 1259 healthy controls from 1054 PLCO (The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) subjects and 205 ACS (The American Cancer Society study) subjects.

  Study phs002496

• Multicenter International Cross-Sectional Evaluation of Pulmonary Alveolar Proteinosis (MICEPAP) Trial

  The purpose of this study is to (1) compare a technically improved assay with an existing assay used to measure serum anti-GM-CSF antibodies in stored serum samples previously obtained from patients diagnosed with either primary, secondary, congenital or idiopathic pulmonary alveolar proteinosis (PAP), other chronic diseases or disease-free, healthy individuals; (2) determine the prevalence and levels of anti-GM-CSF autoantibodies and (3) define the breadth of the autoimmune antibody responses in primary PAP patients from the United States, Japan, Australia, and Europe using previously collected serum samples; and (4) using a chart review approach, compare the clinical, radiologic and laboratory features of primary PAP patients to determine if differences exist among patients in these globally geographically distributed regions.

  Study phs001309

• Combined single-cell transcriptomics and T-cell receptor sequencing reveal heterogeneity of mycosis fungoides between and within patients and identify a CD4+ cytotoxic subtype

  Comprehensive analysis of the malignant cells present in the skin lesions of Mycosis fungoides, the most common subtype of cutaneous T-cell lymphoma, is complicated by the fact that malignant from reactive T cells are challenging to distinguish with certainty. To this end, combined single-cell RNA and TCR sequencing allows unambiguous identification of MF cells, thereby revealing a marked heterogeneity between and within patients with unexpected functional phenotypes. It should be further noted, that mRNA expression of established CTCL protein markers in single-cell transcriptomics to identify MF cells should be used with caution; however, our study uncovered an exciting gene expression pattern that serves as a beacon separating malignant from reactive T cells.

  Study EGAS50000000226

• Characterization of the cellular microenvironment in fibrostenotic Crohn’s disease

  Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibro-stenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate to the mechanisms underlying fibro-stenosis in CD, we analysed the transcriptome of cells isolated from the transmural ileum of CD patients, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from non-CD patients. Our computational analysis revealed that pro-fibrotic signals from a subset of monocyte-derived cells induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibro-stenosis in CD.

  Study EGAS50000000382

• Genome-to-genome analysis highlights the impact of the human innate and adaptive immune systems on the hepatitis C virus

  Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. We use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals chronically infected with HCV, predominately genotype 3. We show that both HLA alleles and interferon lambda innate immune system genes drive viral genome polymorphism, and that IFNL4 genotypes determine HCV viral load through a mechanism that is dependent on a specific polymorphism in the HCV polyprotein. We highlight the interplay between innate immune responses and the viral genome in HCV control.

  Study EGAS00001002324

• Development, maturation and maintenance of human prostate inferred from somatic mutations

  Stem cells within prostate epithelium frequently undergo malignant transformation, but there is limited information on their clonal dynamics and mutation burden in healthy human prostates. We sequenced whole genomes from 409 microdissections of prostate epithelium across 8 donors, using phylogenetic reconstruction with spatial mapping in a 59-year-old man’s prostate to provide high-resolution reconstruction of tissue dynamics across the lifespan. Somatic mutation burden increases linearly with age, at ~16 mutations/year/clone, and is higher in peripheral than peri-urethral regions. The 24-30 independent glandular subunits are established as rudimentary ductal structures during fetal development by 5-10 embryonic cells each. Puberty induces formation of further side branches and terminal acini by local stem cells disseminated through the rudimentary ducts during development. During adult tissue maintenance, clonal expansions are small, with limited geographic scope and minimal migration. Driver mutations are rare in normal ageing prostate epithelium, but the one canonical driver we did observe generated a sizable intraepithelial clonal expansion. By resolving unbiased, continuously occurring lineage-marking mutations, we define stem cell dynamics through embryogenesis, puberty and ageing, with relevance for prostate cancer.

  Dataset EGAD00001006591

• A phase II trial of the aurora kinase A inhibitor alisertib for patients with castration resistant and neuroendocrine prostate cancer: efficacy and biomarker evaluation

  Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth. In this single arm, multi-institutional open label phase 2 clinical trial of alisertib, sixty men were treated with alisertib 50mg twice daily for 7 days every 21-days. Eligibility included metastatic prostate cancer and at least one: small cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; elevated serum neuroendocrine markers. The primary endpoint was six-month radiographic progression free survival. Pre-treatment biopsies were evaluated by whole exome and RNA-seq.

  Study phs001666

• PIEZO1 Loss of Function Compound Heterozygous Mutation in the Rare Congenital Human Disorder Prune Belly Syndrome

  Prune Belly Syndrome (PBS) is a rare congenital myopathy that is incompletely understood genetically. In this IRB approved study, one white Non-Hispanic 35 year-old male PBS proband was prospectively enrolled and phenotyped. Blood lymphocyte DNA from the proband underwent paired-end Whole Exome Sequencing using the Illumina SureSelect kit and HiSeq2500 sequencer with data pipeline analysis. We aligned the subject's sequence against the GRCh38/hg19 assembly and variant calling was performed using data training sets from the 1000 Genomes Project, Omni 2.5 M SNP microarray, and HapMap phase 3.3. These variants were filtered for rare minor allele frequency ( 0.9, CADD score > 20, GERP > 4, MutationTaster = “DC”, Mutation Assessor = “M” or “NE”, and Vest > 3.00. Rare and novel candidate functional variants were screened in the ClinVar database for prior association with smooth muscle myopathy (SMM). Only variants that met these criteria were included for further analysis. Confirmed variants had inheritance analysis performed on available samples. Our WES analysis identified novel compound heterozygous variants in the PIEZO1 gene. We conducted an extensive functional analysis of the PIEZO1 PBS variants that revealed loss-of-function characteristics. Thus, PIEZO1 mutations may be causal for PBS. Our WES data will be available through dbGaP.

  Study phs003475

• DERMATLAS: Hidradenoma papilliferum_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible.For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previously, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles.

  Dataset EGAD00001015480

• DERMATLAS: Hidradenoma papilliferum_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible.For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previously, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles.

  Dataset EGAD00001015481

• Gene expression QTL mapping in stimulated iPSC-derived macrophages

  Immune cells sense and respond to external stimuli, initiating an inflammatory response, with genetic variants potentially altering these responses. Traditional QTL mapping often uses naïve cells, missing condition-specific variants detectable post-stimulation. Our study uses a high-throughput platform to map eQTLs across 24 conditions using iPSC-derived macrophages, identifying that 76% of eQTLs in stimulated conditions were also present in naïve cells. We found response eQTLs (reQTLs) vary widely across conditions, with rare single-condition reQTLs being overrepresented among disease-colocalizing eQTLs. This study nominates 21.7% more disease effector genes at GWAS loci through reQTL colocalization, with 38.6% not found in the GTEx catalogue, highlighting the importance of condition-specific regulatory variation in understanding disease risk alleles. Our findings underscore the value of condition-specific studies in elucidating the genetic mechanisms underlying complex diseases. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001015380

• International Genetics of Parkinson Disease Progression (IGPP) Consortium: EPIPARK and HBS2 Cohorts

  EPIPARK and HBS2 cohorts were analyzed as part of the International Genetics of Parkinson Disease Progression (IGPP) Consortium. EPIPARK is a population-based cohort to study non-motor symptoms in parkinsonism in the city of Lübeck, Germany led by Drs. Meike Kasten and Christine Klein. HBS2 is a recently enrolled subset of participants in the Harvard Biomarkers Study led by Dr. Clemens Scherzer (www.bwhparkinsoncenter.org/biobank) of 89 participants with a diagnosis of Parkinson Disease (PD). Genotyping with Illumina Infinium Multi-Ethnic Genotyping Arrays (MEGA chip) was performed by Dr. Scherzer, Harvard Medical School and Brigham and Women’s Hospital. 179 participants with a diagnosis of PD from EPIPARK and 89 participants with a diagnosis of PD from HBS2 met Q/C criteria were analyzed.

  Study phs002328

• High-Throughput LINE-1 Retrotransposon Discovery in Humans

  The aim of this study is to discover LINE-1 (L1) insertion sites present in humans that are absent from the reference genome sequence. We use the distinguishing nucleotide characteristics of human-specific L1 elements to resequence the L1 3' flanking regions thus locating the L1 insertion sites whether or not they are present in the reference genome assembly. In doing so, we have uncovered a higher than expected number of non-reference L1 insertions, an average of 152 insertions per individual. In addition, we find that any two individuals differ at an average of 285 sites with respect to presence or absence of L1 insertions in those sites, and use this to estimate the rate of retrotransposition in humans at 1 event per 140 live births (95% c.i. 1/95 to 1/270). We show that individual 'L1 profiles' recapitulate genetic ancestry as expected, and find that dimorphic insertions are more frequent in introns relative to fixed insertions.

  Study phs000273

• Single-Cell Sequencing Reveals Distinct Microenvironment Cell Types Associated with Response to High Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma

  The aim of this study is to understand the transcriptome of microenvironment cells in pre- and post- autologous stem cell transplantation (ASCT) samples between patients with complete response and partial response to transplant. Here, we studied immune cells from 40 multiple myeloma patients who have undergone ASCT. Samples were collected from 40 multiple myeloma patients before and after ASCT. Samples were sorted using magnetic activated cell sorting (MACS) and the non-tumor CD138- fraction underwent 3' single cell RNA-sequencing (scRNA-seq) or 5' scRNA-seq + 5' T cell receptor sequencing (TCRseq), to determine the scRNA transcriptome and TCR repertoire. This study includes 24 samples with 3' scRNA-seq, 56 samples with 5' scRNA-seq, and 56 samples with 5' TCRseq data.

  Study phs003219

• Phylogenetic development of childhood tumours

  The aim of this study is to reconstruct the phylogenetic development of childhood tumours

  Dataset EGAD00001005770

• Ewing and Ewing-like-sarcoma tumoroid biobank reveals distinct drug sensitivities: translocation makes the difference

  Ewing sarcoma (ES) and Ewing-like sarcomas (ELS) are highly aggressive tumors found in soft tissues and bone of mostly children and young adults. Despite being different in many aspects, including genetics, possible cell-of-origin, and pathology, patients with any of these entities all receive the same therapeutic regimen. Currently, there is a lack of preclinical cell models that can predict drug response of these entities in vitro. Here, we describe a pediatric ES and ELS tumor organoid (tumoroid) biobank containing tumoroids with different translocations, including EWSR1::FLI1, EWSR1::ERG, CIC::DUX4, and BCOR-rearrangements. Using histology, whole genome sequencing and RNA sequencing, we demonstrate that these tumoroids retain key properties of their matching patient tumors. In addition, we traced tumor subclones in the tumoroids across patient-matched longitudinal samples, which showed that cellular heterogeneity was maintained. We subsequently performed drug screening on the tumoroid models, which unveiled entity-specific drug sensitivity to various cytotoxic compounds and targeted compounds, including MCL-1 inhibitors for CIC::DUX4 sarcomas. Taken together, this newly established ES and ELS patient-derived tumoroid biobank generates a unique source of material for future basic cancer research and drug-screening.

  Study EGAS00001007941

• Childhood Cancer Data Initiative (CCDI): Texas Pediatric Patient Derived Xenograft 

  The DNA/RNA samples of patients for which PDX models were developed were from a population of children, adolescents, and young adults from South Texas. Consent was obtained for collection of malignant and non-malignant tissue samples for genetic analysis and for the development of models to study new ways to treat cancer. For additional details, please refer to these publications: PMID: 37915590; PMID: 37990009.

  Study phs003215

• An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity

  Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn’s disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn’s disease but the functional mechanisms are unknown. Here we show that the isoforms of SBNO2 are differentially regulated by lipopolysaccharide and IL-10. We identify Crohn’s disease associated isoform quantitative trait loci that negatively regulate the expression of the noncanonical isoform 2 corresponding with the methylation signals at the isoform 2 promoter in IBD and CD. The two isoforms of SBNO2 drive differential gene networks with isoform 2 dominantly impacting antimicrobial activity in macrophages. Our data highlight the role of isoform quantitative trait loci to understand disease susceptibility and resolve underlying mechanisms of disease. This dataset contains RNAseq raw data from CD14+ monocyte-derived macrophages and siRNA-mediated knockdown experiments, as well as RNAseq raw data from THP-1 monocytes-derived macrophages following ectopic expression of SBNO2 isoforms.

  Dataset EGAD50000000264

• Gene Expression in an African American Schizophrenia Dataset

  Schizophrenia is a common and severe psychotic disorder. While some common SNPs and rare copy number variants have been identified as being significantly associated with disease risk, the biological mechanisms remain largely undefined. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using RNAseq on lymphoblastoid cell lines from schizophrenia cases and controls of African American ancestry. Genes related to immune processes were enriched in the genes differentially expressed in the schizophrenia cases. Approximately half of the differentially expressed genes in this African American dataset were also differentially expressed by affection status in our previously studied European ancestry dataset (PMID: 28418402).

  Study phs002842

• Whole Exome Sequencing of Colorectal Cancer Patients from the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS)

  Colorectal cancer is a molecularly heterogeneous disease. Whole Exome Sequencing from patients diagnosed with colorectal cancer in the NHS and HPFS cohorts will extend our understanding of the genetic changes occurring in specific clinical contexts in the disease. This effort has the potential to discover novel recurrently mutated genes and pathways in colorectal cancer that can be functionally validated and give further insights to colorectal cancer pathogenesis. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000.

  Study phs000722

• Comprehensive Analysis of the Immunogenomics of Triple Negative Breast Cancer Brain Metastases from LCCC1419

  Triple negative breast cancer (TNBC) is an aggressive subset of breast cancer that lacks expression of the estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immunogenomics of BrM remains largely unknown. Thus, we conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to foster the development of immunotherapy strategies in this aggressive and clinically unmet disease.  

  Study phs002457

• Exploring the Genomic Dark Matter of Neurodevelopmental Disorders

  Neurodevelopmental Disorders (NDDs) are a group of disorders that typically manifest early in development and may give rise to impaired cognition, communication, adaptive behavior, and psychomotor skills. This study aims to take a more comprehensive view into the genomic landscape of structural variants implicated in NDDs with intellectual disability (ID). We have evaluated the genome of families with a genetically unsolved severe NDD via optical genome mapping. This study identified likely pathogenic or pathogenic structural variants in known NDD genes, including BCL11A, OPHN1, PHF8, SON, and NFIA. Data is available in VCF format, following the standard filtering settings in Bionano Access and available as "variants_combine_filters_inMoleRefine1.vcf" files.

  Study phs002937

• My Pediatric and Adult Rare Tumor (MyPART) Natural History Study of Rare Solid Tumors

  The goal of this study is to comprehensively and longitudinally evaluate the natural history of patients with rare solid tumors or tumor predisposition syndromes, estimating and defining their clinical spectrum (e.g. disease course and survival). Clinical data, patient reported outcomes (PROs), and biospecimen associated data are collected. Clinical data includes response to treatment, tumor pathology, and imaging. PROs include measures of pain, depression, anxiety, mobility, and cognitive functioning. Biospecimen data includes next-generation sequencing [RNAseq, whole exome sequencing (WES), whole genome sequencing (WGS), EPIC methylation array data, and TruSight Oncology 500 gene panel sequencing], cytokine analysis of plasma, immune phenotyping of circulating peripheral blood mononuclear cells.

  Study phs003143

• Chromothripsis in Small Cell Lung Carcinoma Associated with Carcinoid Transformation

  Small cell lung carcinoma (SCLC) is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. We performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC in never/light smokers that lacked RB1 and TP53 co-inactivation and found that most cases were associated with chromothripsis – massive, localized chromosome shattering, recurrently involving chromosomes 11 or 12, among other findings. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids. Conversely, SCLC never smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never smokers.

  Study phs003676

• Epigenomic atlas of organoid development

  To investigfate the epigenomic basis of fate decisions in the central nerveous system, we recorded a epigenomic timecourse of human brain organoid development using Cut&Tag with paired scRNA-seq. We further performed perturbation experiment inhibiting EED and profiled the response with scRNA-seq and Cut&Tag. Finally, we profiled a sample of the developing human brain using multiome sequencing and Cut&Tag. In our study, we uncover epigenomic switches during brain region diversification and show that epigenetic activation precedes gene expression during neurogenesis in organoids and in primary tissue. Lastly, we show that transcriptional repression by H3K27me3 is required to stabilize neuroectoderm induction from pluripotency.

  Study EGAS50000000155

• Genetic mutation profiling of lymphomas arising in the uterine cervix and vagina

  Follicle center lymphoma (FCL) of the lower female genital tract (LFGT) is a rare lymphoma, with fewer than 20 cases reported to date. Since the genetic features of FCL of the LFGT have not been well characterized, we aimed to identify genetic alterations in this tumor through whole-exome sequencing or targeted gene panel analysis. Genomic DNA was extracted from a frozen tissue sample obtained from a surgically resected uterine cervical tumor. Whole-exome sequencing was performed using the Illumina NovaSeq X Plus platform. Library preparation was conducted with the SureSelect Human All Exon V6 kit, and sequencing was carried out with 150 bp paired-end reads.

  Study JGAS000823

• North American Brain Expression Consortium (NABEC) Exome Sequencing

  A fundamental challenge in the post-genome era is to understand and annotate the consequences of genetic variation, particularly within the context of human tissues. We describe a set of integrated experiments designed to investigate the effects of common genetic variability on mRNA expression distinct human brain regions. We show that brain tissues may be readily distinguished based on expression profile. We find an abundance of genetic cis regulation mRNA expression. We observe that the largest magnitude effects occur across distinct brain regions. We believe these data, which we have made publicly available, will be useful in understanding the biological effects of genetic variation.

  Study EGAS00001002110

• Identification of cis-regulatory mutations generating de novo edges in personalized cancer gene regulatory networks

  The identification of functional non-coding mutations is a key challenge in the field of genomics. Here we introduce μ-cisTarget to filter, annotate and prioritize cis-regulatory mutations based on their putative effect on the underlying ‘personal’ gene regulatory network. We validated μ-cisTarget by re-analyzing the TAL1 and LMO1 enhancer mutations in T-ALL, and the TERT promoter mutation in melanoma. Next, we re-sequenced the full genome of ten cancer cell lines and used matched transcriptome data and motif discovery to identify master regulators with de novo binding sites that result in the up-regulation of nearby oncogenic drivers.

  Study EGAS00001002571

• Exome-wide somatic mutation characterization of small bowel adenocarcinoma

  Small intestinal adenocarcinoma (SIA) is a rare and aggressive form of cancer with limited treatment options. To further characterize the somatic mutation landscape of this tumor type, exome sequencing was conducted on a population-based set of SIA samples from all three parts of the small intestine. Archival tissue from 106 tumors with comprehensive clinical patient information entered exome sequencing from a patient series consisting of SIA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify significantly mutated genes from the exome data. Also mutational signature and pathway enrichment analyses were performed.

  Study EGAS00001002559

• Genome Landscape of Primary Pancreatic Ductal Adenocarcinoma

  The purpose of the Australian ICGC Pancreatic Cancer Genome Sequencing Initiativestudy is to identify the common driving mutations underlying the initiation anddevelopment of Pancreatic Adenocarcinoma in a large cohort of pancreatic cancerpatients (n=350). Matched genome sequences will be generated from normal tissue(duodenum) and resected primary tumour tissue in each patient using exome andwhole genome sequencing. The complete repertoire of somatic mutations will bedetermined (substitutions, indels, copy number changes and structural changes).Where possible, matched transcriptome sequencing will also be carried out todetermine locus activity, which mutations are actively expressed and whichrearrangements give rise to gene-fusion transcripts.

  Study EGAS00001000154

• RNA sequencing in primary inflammatory (TPP) macrophages treated with a MEK1/2 inhibitor

  By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis, we discover that the causal gene, ETS2, is a master regulator of inflammatory responses in human macrophages and delineate how the risk haplotype increases ETS2 expression. Using a database of cellular signatures, we identified drugs that could modulate this pathway. To validate the anti-inflammatory activity of one class of small molecules in vitro, we treated TPP macrophages with vehicle control or a selective, non-ATP competitive MEK inhibitor (PD-0325901) at 2 doses (100nM and 500nM) and performed RNA sequencing.

  Study EGAS00001007552

• MethylationEPIC BeadChip samples of pre- and post-5ZA-treated head and neck cancer patients refractory to anto-PD-1 therapy

  Background Immune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, most patients are refractory. Methods In a non-randomized, open-label phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5’azacytidine (5’aza) daily for either 5- or 10-days in combination with fixed doses of durvalumab and tremelimumab after progression on ICB therapy. The primary objective was to assess the biologically effective dose of 5’aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety. Results Thirty-eight percent (3/8) of participants with evaluable paired tissue samples had a greater than 2-fold increase from baseline in interferon-gamma (IFN-ɣ) signature and CD274 (programmed cell death protein 1 ligand, PD-L1) expression within the tumor microenvironment (TME), which was associated with increased CD8+ T cell infiltration and decreased infiltration of CD4+ T regulatory cells. The mean neutrophil-to-lymphocyte ratio (NLR) decreased by greater than 50%, from 14.2 (SD 22.6) to 6.9 (SD 5.2). Median overall survival (OS) was 16.3 months (95% CI 1.9, NA) and 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%) with 58% (7/12) of treated participants demonstrated prolonged OS of greater than 12 months. Conclusion Our findings suggest that low-dose 5’aza can reprogram systemic host immune responses and the local TME to increase IFN-ɣ and PD-L1 expression. The increased expression of these established biomarkers correlated with prolonged OS upon re-challenge with ICB.

  Study EGAS00001007998

• Family Genomics of Congenital Heart Defects

  The study identified the causal mutation in a five-generation pedigree harboring a cardiac septal defect. The inheritance pattern is consistent with an autosomal dominant mutation with high penetrance. We performed whole-genome sequencing (Complete Genomics) on 21 individuals in the pedigree, of which 11 individuals are affected. We identified a single gene, GATA4, as primarily responsible for this cardiac phenotype in this pedigree.

  Study phs000758

• Whole transcriptome and exome sequencing of childhood ALL

  Gene fusion is a major class of genomic abnormalities in childhood acute lymphoblastic leukemia (ALL) and sentinel chromosomal rearrangements involving EP300 and CREBBP may cause global epigenetic deregulation during leukemogenesis with potentials for therapeutic targeting. This dataset includes whole transcriptome sequencing of 231 children with acute lymphoblastic leukemia from a Singapore-Malaysia frontline clinical treatment protocol.

  Study EGAS00001001858

• Brain transcriptome of hereditary cerebral haemorrhage with amyloidosis–Dutch type (HCHWA-D)

  HCHWA-D is an early onset hereditary form of Cerebral Amyloid Angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the Amyloid Precursor Protein (APP). Post-mortem brain tissue (9 patients and 9 age-related controls; frontal and occipital cortex) was used for next generation sequencing of RNA (RNA-Seq with ribosomal RNA depletion).

  Study EGAS00001002730

• COVID-19 Severity of First Wave of Infection for Severe Patients in Madrid

  Through thorough exclusion criteria and deep phenotypic characterisation for a Madrid-based population we intend to find enrichment of gene mutations associated to severity. In addition we will look for statistically overrepresented annotation of particular phenotypes (a controlled vocabulary specifically developed for this project) that associate them to affected genes in our patient sample.

  Study EGAS00001005931

• An integrated single-cell reference atlas of the human endometrium

  This dataset includes both the anchor scRNA-seq and snRNA-seq datasets used to build the Human Endometrial Cell Atlas (HECA). HECA provides a comprehensive definition of endometrial cell types and states throughout the menstrual cycle in donor with and without endometriosis. It identifies consensus cell types across datasets generated by teams worldwide, as well as previously unreported cell types, all of which are validated and mapped in situ using spatial transcriptomics. Processed data is available from ArrayExpress with accession number E-MTAB-14039. See Marečková, M., Garcia-Alonso, L., Moullet, M. et al. An integrated single-cell reference atlas of the human endometrium. Nat Genet 56, 1925–1937 (2024) https://doi.org/10.1038/s41588-024-01873-w for more information.

  Dataset EGAD00001015446

• Massive Genomic Rearrangment Acquired in a Single Catastrophic Event During Cancer Development

  Cancer is driven by mutation. Using Agilent exome hybridisation capture and Illumina GA massively parallel sequencing technology, we aim to sequence ~1600 microRNAs plus the protein coding genome of 25 matched human renal cancer samples. Bespoke algorithms are being developed to identify the somatically acquired point mutations, insertions and deletions in these samples. This project will give unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with renal cancer development.Agilent whole exome hybridisation capture will be performed on genomic DNA derived from 25 renal cancers and matched normal DNA from the same patients. Three lanes of Illumina GA sequencing will be performed on the resulting 50 exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes.

  Study EGAS00000000029

• Whole Genome and Exon Capture Sequencing of Bladder Cancers

  One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.

  Study phs000535

• SPECTA RP-1759-AYA Sarcoma cohort

  EORTC-SPECTA RP1759 study focuses on cancers in adolescent and young adult (AYA), age 12 to 29 years. This study explicitly recruited AYA patients and therefore collected empirical data to bridge the molecular gap between pediatric and adult oncology. The initial pilot study, activated in February 2019 across Europe, aimed to recruit 100 AYA patients (aged 12-29 years) with newly diagnosed or relapsed high-grade gliomas and high-grade bone and soft tissue sarcomas. The primary objective of the pilot is to determine feasibility and recruitment rates. Here we submit the data from patients with newly diagnosed, recurrent intermediate or high-grade sarcoma that were collected and analyzed during the study. More specifically, we submit raw FASTQ files obtained from whole exome sequencing (WES) of matching tumor and blood samples, tumor RNA sequencing and DNA methylation profiling.

  Study EGAS00001005840

• Whole exome sequencing reveals the mutational spectrum of testicular germ cell tumours

  Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole exome sequencing of 42 TGCTs to comprehensively study the mutational profile of TGCT. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per megabase [Mb]) as compared to the common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.

  Study EGAS00001001084

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

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

  Study EGAS00001007553

• Targeted DNA sequencing on bulk bone marrow and peripheral blood

  Targeted DNA sequencing was performed on 195 bone marrow samples to identify cases of clonal haematopoiesis, and on 99 paired peripheral blood samples. The SeqCap EZ HyperCap protocol was followed, and targeted capture performed against a panel of 97 genes recurrently mutated in myeloid malignancies and clonal hematopoiesis. One BAM file (mapped to the hg38 reference genome) is provided per sample.

  Dataset EGAD00001011083

• NINDS Deep Sequencing for the Detection of Viral Sequences in Primary Progressive Multiple Sclerosis Brains

  Deep sequencing allows for a rapid, accurate characterization of microbial DNA and RNA sequences in many types of samples. Deep sequencing (also called next generation sequencing or NGS) is being developed to assist with the diagnosis of a wide variety of infectious diseases. In this study, seven frozen brain samples (n = 7) from deceased subjects with recent encephalitis were investigated. RNA from each sample was extracted, randomly reverse transcribed, and sequenced. The sequence analysis was performed in a blinded fashion and confirmed with pathogen-specific PCR. This analysis successfully identified measles virus sequences in two brain samples and herpes simplex virus type-1 sequences in three brain samples. No pathogen was identified in the other two brain specimens. These results were concordant with pathogen-specific PCR and partially concordant with prior neuropathological examinations, demonstrating that deep sequencing can accurately identify viral infections in frozen brain tissue (Chan et al., 2014). Data from the primary progressive multiple sclerosis (PPMS) brain specimens (n = 14) and Normal Control brain specimens (n = 14) are also submitted here. All the subjects studied here (encephalitis, PPMS, and controls) were selected from existing collections at the Rocky Mountain and UCLA brain banks. These selections were performed by the directors at the two centers (Dr. Corboy at RM and Nagra at UCLA) based on clinic information provided at the time of collection. All the specimens are from deidentified deceased individuals. The submitting investigators have no identifying information on any of these subjects. To avoid confusion, the dbGaP Subject IDs are identical to the brain bank identifying numbers.

  Study phs000715

• UniKilinikum Wuerzburg MSNZ AGRasche/AG Riedel EMD DAC

  This is a Data access committee for the Data presented in the paper tilted "Spatially resolved transcriptomics reveals profound subclonal heterogeneity and T cell dysfunction in extramedullary myeloma"

  Dac EGAC50000000173

• Res1_HT29_exp1_MC_02.03.22

  1 sample is pure plasmid DNA and 10 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Dataset EGAD00001012230

• Res1_H23_exp1_MC_04.03.22

  1 sample is pure plasmid DNA and 8 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Dataset EGAD00001012229

• Res1_HT29_exp2_MC_03.03.22

  1 sample is pure plasmid DNA and 10 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Dataset EGAD00001012231

• Whole Genome Sequences of 18th century African descended individuals from Charleston, South Carolina.

  This study presents Whole Genome Sequencing results from the Anson Street African Burial Ground Project, which is a community-based initiative aimed at understanding the histories of 37 Ancestors found during construction in Charleston, South Carolina. Here we report fastq files for all 37 Ancestors. DNA was extracted at the University of Tennessee-Knoxville following Dabney et al. 2013, and dual index libraries prepared using a modified NEBNext Ultra II kit with partial USER enzyme digestion. Libraries were then enriched for human genomic DNA (MyBaits) and sequenced on Illumina Platforms.

  Study EGAS00001006693

• Analysis of copy number variation landscape of glioma by shallow coverage whole genome sequencing

  We reported shallow coverage whole genome sequencing (WGS) is an economic method for identification of whole genome somatic copy number variation (SCNV). Combining with a Taqman low density array (TLDA) designed for molecular subtyping of glioma, it enabled classification of glioma into biological entities with different cellular origin and genomic alterations. Further, we also showed shallow-coverage WGS enabled systematic identification of clonal and subclonal SCNV in glioma genomes and the burden and pattern of SCNV can serve as an objective marker of tumor progression and predict risk and relapse.

  Study EGAS00001003690

• Na?ve Treg-specific genomic DNA hypomethylation for autoimmune disease susceptibility

  Naturally occurring regulatory T (Treg) cells, which are specifically expressing the transcription factor FOXP3, CD25 and CTLA-4, are indispensable for the maintenance of immunological self-tolerance and homeostasis. Mutations of the FOXP3, CD25 and CTLA4 genes compromise the function of natural FOXP3+CD25+CD4+ Treg cells and cause severe autoimmune diseases showing Mendelian inheritance. Also, altered Treg-specific epigenetic changes, such as DNA hypomethylation and enhancer activation, impair the expression of these molecules in developing Treg cells, causing autoimmune diseases. It is obscure, however, whether Treg cells significantly contribute to the development of polygenic common autoimmune diseases (such as type 1 diabetes and rheumatoid arthritis), which afflict ~10% of the population. Recent genome-wide association study (GWAS) of common autoimmune diseases has revealed many autoimmune disease-associated single nucleotide polymorphisms (SNPs) in enhancer regions of immune cells, for example, in non-coding regions of T cell activation-associated genes such as CD25 and CTLA4. These findings, especially the involvement of common T-cell genes in the functions of both Treg cells and effector T cells, prompt one to ask whether autoimmune disease-associated causative SNPs impact on the functions of either disease-causing effector T cells or disease-suppressing Treg cells. Here, we have explored epigenetic profiles of human Treg and conventional T (Tconv) cells in na?ve or activated states, and found that autoimmune disease-associated SNPs are predominantly enriched in Treg-specific CpG demethylated regions (Treg-DRs), which were mostly included in Treg-specific super-enhancers. Treg-DRs are developmentally established in na?ve Treg cells before antigenic stimulation, distinct from activation-induced CpG hypomethylation in Treg or Tconv cells, and highly associated with Treg cell-specific transcriptional and epigenetic changes. Taken together, genetic variants affecting endogenous development of natural Treg cells and their Treg-intrinsic functions are causative of common autoimmune diseases, indicating natural Treg cells as a key target for their treatment and prevention.

  Study JGAS000145

• Dataset Rdata segmentations

  This data set contains an .Rdata file for all the processed segmentation profiles from 81 lpWGS samples included used in downstream analyses from Github repository Evo_history_CACRC. Lastly, there is an .Rdata object with 50 segmentations for 50 total samples from 25 sporadic SNP adenomas used in the comparison with colitis samples.

  Dataset EGAD00010001586

• DAC for EGA study: Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer

  This is the Data Access Committee for the EGA study: Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer (temp ID 800).

  Dac EGAC50000000563

• Characterization of iPSC derived macrophages - cardiovascular pilot (2017-05-24)

  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 2017-05-24.

  Dataset EGAD00001003347

• Immune Response to Life-Threatening Respiratory Infections in Children and Young Adults

  This is a cross sectional study describing age-related differences in the nasal mucosal immune response to SARS-CoV-2. We collected nasal mucosal samples from six groups: healthy children, children infected with SARS-CoV-2, children infected with respiratory syncytial virus, children infected with influenza virus, healthy adults, and adults infected with SARS-CoV-2. Samples were obtained by mucosal scrape biopsy of the inferior turbinate using a sterile plastic curette. We performed bulk RNA-sequencing to obtain gene expression data. Clinical data was extracted from the electronic health record including: demographics, medical history, clinical presentation, duration of symptoms, intensive care unit admission, hospital and intensive care unit length of stay, type and duration of respiratory support at sample collection and peak illness. Our analysis described the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compared it to the host response to respiratory syncytial virus and influenza virus.

  Study phs002579

• Evolution of Chromatin Architecture and Transcriptional Regulation in Mammals

  Changes in gene expression are a critical force driving the evolution of form and function. As a result, the mechanisms by which gene expression evolves have become a subject of intense interest. A number of investigators have measured evolutionary changes in gene expression at the chromatin, mRNA, and protein levels, leading to new insights about how species evolve. However, studies of different stages in gene expression have not always been in agreement. For example, the extremely rapid rates of evolutionary changes that have been widely observed at enhancers appear to conflict with the slower rates observed in mRNA abundance. We recently completed a major comparative study in primates showing that this disparity between enhancer and mRNA evolution, in part, reflects extensive compensation at enhancers that jointly determine transcription at target genes. Likewise, related findings have demonstrated that post-transcriptional changes buffer protein abundance to relatively more common differences in mRNA expression. Together, these recent findings demonstrate that evolutionary changes affecting multiple stages of transcriptional regulation often have interdependent effects on gene expression. Here we propose to determine how stages early during transcriptional regulation work in concert, either to conserve gene expression through compensatory changes across stages, or, in rare cases, to change mRNA in ways that alter organism phenotypes. Our central hypothesis is that interactions between stages are common, especially at long evolutionary time-scales. To test this hypothesis we propose an ambitious plan to collect rich genomic data profiling distinct stages of gene expression in two cell types and three tissues from nine mammalian species. We have focused our study on several early rate-limiting steps in mRNA production, using molecular assays selected to provide orthogonal sources of information about chromatin architecture (Hi-C/Hi-ChIP), accessibility (ATAC-seq), transcription (PRO-seq), and mRNA levels (RNA-seq). This project will produce the largest resource of genomic data uniformly collected across mammals to date. We will integrate genomic data using a suite of new computational tools, which together will provide a new understanding of how distinct regulatory stages work in concert during regulatory evolution.

  Study phs002146

• Clean sequence of LUAD in young never-smoker

  we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never-smoker Chinese patients with lung adenocarcinomas (LUADs). This dataset is containing clean fastq files of 36 never-smoker Chinese patients with lung adenocarcinomas (LUADs)

  Dataset EGAD00001003890

• A neoadjuvant, phase II trial demonstrates efficacy and tolerability of Talimogene laherparepvec in cutaneous basal cell carcinoma (NeoBCC trial)

  This dataset is related to the NeoBCC trial and includes 12 human tissue samples

  Dataset EGAD50000000371

• ChIP sequencing in Cancer Cell Lines

  The project is to evaluate the genomic binding sites of the histone demethylase JARID1C. This gene was recently identified in CGP as a novel recessive cancer gene in human renal cell carcinoma.

  Dataset EGAD00001001453

• Non-ADT METs ICGC Prostate UK

  To characterize the subclonal genomic architecture of non-androgen-deprived metastatic prostate cancer, we performed whole-genome sequencing (WGS) of pelvic lymph node metastases and matching noncancerous blood from 10 patients to an average sequencing depth of 55x. The patients are part of PELICAN (Project to ELIminate Lethal Cancer) study led by G. Steven Bova at Johns Hopkins University (USA) and Tampere University (Finland). As of September 2020, study using these data is: Wedge et al, Nature Genetics 2018 (PMID: 29662167)

  Dataset EGAD00001002002

• Whole exome sequencing of young onset Primary Sclerosing Cholangitis

  Primary sclerosing chloangitis is a rare autoimmune disease of the liver (prevalence =10/100,000) with a mean age of onset of 40 years. We are currently undertaking GWASand immunochip experiments to identify loci underlying PSC susceptibility. Through ourcollaborators at the University of Calgary we have access to DNA from three parent-offspringtrios where the children required liver transplants due to PSC before the age of 9. These areextremely rare cases indeed and we believe that exome-sequencing represents a powerfulmeans of identifying the causal mutation underlying this severe phenotype.

  Dataset EGAD00001000671

• Batches 1-3 prostatectomy analysis

  Whole Genome Sequencing Illumina HiSeq data from 95 men with prostate cancer. Samples were taken from primary tissue obtained at prostatectomy (target sequencing depth 50X) with matched blood control (target sequencing depth 30X). This data is from batches 1 to 3 and is the bulk of the data used in Wedge et al, Nature Genetics 2018 (PMID: 29662167). As of September 2020, some of the studies using these data include: Wedge et al, Nature Genetics 2018 (PMID: 29662167) Pan-Cancer Analysis of Whole Genomes, Nature 2020 (PMID: 32025007)

  Dataset EGAD00001001116

• Exome Sequencing of Statin-Induced Myopathy Cases

  Severe myopathic events occur in 0.1-0.5% of patients taking statins. Although genetic association studies have identified some possibly associated gene loci, these have not been reproducible in additional studies with independent patient cohorts. A more reasonable explanation for susceptibility to statin-induced myopathy is the presence of rare pathogenic variants in genes important for skeletal muscle structure and function. In support of this, we have previously reported an increased incidence of pathogenic variants in genes causing metabolic myopathies in patients with statin-induced myopathy (Vladutiu et al.,2006). We also reported a patient with statin myopathy who had an RYR1 variant known to be causative of malignant hyperthermia susceptibility (MHS) (Vladutiu et al., 2011). There are a number of genes associated with metabolic myopathies triggered by various factors such as extreme exercise, fasting, extremes in temperature, viral infection and exposure to volatile anesthetics. In addition, many of the genes causing congenital myopathies, myofibrillar myopathies and muscular dystrophies have overlapping phenotypes with these genes. We propose that statins act as an additional trigger inducing myopathic symptoms and many patients with severe statin-induced myopathy have causative genetic variants within similar genes associated with MHS and congenital myopathy. We have analyzed the resultant data using a disease model in which rare pathogenic variants, possibly within multiple genes, are causative of statin-induced myopathy. In this study, we have identified potentially causative genetic variants in greater than 50% of the statin-induced myopathy cases and in particular, rare and possibly pathogenic in the RYR1 and CACNA1S genes were present in 25% of the patient samples studied. Vladutiu, G. D., Simmons, Z., Isackson, P.J., Tarnopolsky, M., Peltier, W.L., Barboi, A.C., Sripathi, N., Wortmann, R.L., Phillips, P.S., (2006). "Genetic risk factors associated with lipid-lowering drug-induced myopathies." Muscle Nerve 34: 153-162. Vladutiu, G. D., Isackson, P.J., Kaufman, K., Harley, J.B., Cobb, B., Christopher-Stine, L., Wortmann, R.L, (2011). "Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies." Mol Genet Metab 104: 167-173.

  Study phs001342

• TIRE-seq: an Integrated Sample Extraction and Transcriptomics Workflow for High Throughput Perturbation Studies

  TIRE-seq is a novel RNA sequencing method that integrates mRNA purification directly into library preparation, eliminating separate RNA extraction. The technique demonstrated utility across three biological applications, including capturing transcriptional changes in human T cells, identifying genes driving murine dendritic cell differentiation, and analyzing the dose-response effects of temozolomide on patient-derived neurospheres. With its simplified approach and high sequencing efficiency, TIRE-seq offers a cost-effective solution for large-scale gene expression studies.

  Study EGAS50000000867

• Whole genome sequencing in myasthenia gravis

  This dataset contains whole genome sequencing data on 25 individuals with myasthenia gravis. The data was generated using Illumina sequencing technology and is presented as BAM files for each sample.

  Dataset EGAD00001005262

• 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

• sWGS data from 362 tumor with non muscle invasive bladder cancer and 30 blood samples (15 males and 15 females)

  A better understanding of the molecular landscape of non-muscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and identify potential therapeutic targets. Here, we perform a comprehensive genomic analysis of patients diagnosed with NMIBC based on whole-exome- (n=438), shallow whole-genome- (n=362), and total RNA-sequencing (n=414). This dataset contains 876 BAM files corresponding to the full WES dataset. This dataset contains 392 BAM files corresponding to the full sWGS dataset. Tumor samples were sequenced to median coverage of 2.14x (1.24-9.01).

  Dataset EGAD50000000732

• Whole-exome sequencing of 20 samples of actinic keratosis (10s) and cutaneous squamous cell carcinoma (10s)

  Whole-exome sequencing of 20 samples of actinic keratosis (10) and cutaneous squamous cell carcinoma (10) was performed to investigate a potential relationship between DNA methylation-based subtypes and genetic mutation patterns. 7 samples were shown to belong to the stem cell-like subclass (4 AK and 2 SCC), 12 - to the keratinocyte-like subtype (6 AK and 6 SCC) and one SCC sample is unclassified (was not included in the methylation analysis). Exome regions were captured using Agilent Low Input Exome-Seq Human v5 kit and sequenced on Illumina Hiseq4000 with paired-end 100-nucleotide reads.

  Dataset EGAD00001003765

• Genomic Evolution of Breast Cancer Metastasis and Relapse

  Recurrent breast cancer is almost universally fatal. We characterize 170 patients locally relapsed or distant metastatic cancers using massively parallel sequencing. We identify that the relapse-seeding clone disseminates late from the primary tumor. TP53 and AKT1 appear to be enriched in ER-positive cancers predisposed to relapse. Mutation acquisition continues at relapse as the same mutation signatures continue to operate and new signatures, such as that caused by radiotherapy appear de novo. In 49% of cases we identify drivers mutations private to the relapse and these are sampled from a wider range of cancer genes, including SWI-SNF complex and JAK-STAT signaling.

  Dataset EGAD00001002697

• The spectrum of somatic mutations in high-risk acute myeloid leukemia with -7/del(7q)

  Patients with myeloid malignancies bearing high-risk cytogenetic abnormalities lack effective therapies and have a poor overall survival. -7/del(7q) is identified in half of high-risk myeloid neoplasms. We recently identified CUX1 to be a haploinsufficient myeloid tumor suppressor gene located within the commonly deleted segment of 7q22. Here we identify the spectrum of somatic mutations that co-occur with loss of CUX1 and chromosome 7 in patients with de novo acute myeloid leukemia (AML) or a therapy-related myeloid neoplasm. -7/del(7q) leukemias have a distinct mutational profile characterized by low frequencies of alterations in major leukemogenic pathways, including genes encoding transcription factors, cohesin, and DNA-methylation-related proteins. In contrast, RAS pathway activating mutations occurred in 40% of -7/del(7q) samples, a significantly higher frequency than other AMLs and higher than previously reported. As targeted therapeutics advance, our data provide guidance for which pathways are most relevant in the treatment of adverse-risk myeloid leukemia.

  Study phs000759

• Long-read-transcriptome-sequencing of CLL and MDS patients uncovers common molecular effects of SF3B1 mutations

  Mutations in SF3B1 occur frequently in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS), and a full-length transcriptome approach can expand our current knowledge on SF3B1 mutation effects on RNA splicing. We applied long-read-transcriptome-sequencing (LRTS) to 44 MDS and CLL patients with and without SF3B1 mutations and found a large fraction (>60%) of novel isoforms. Furthermore, we revealed that mutation effects on alternative splicing were largely common in both cancer types and specifically altered the usage of introns as well as 3’-splice-sites. We combined the LRTS with genome-wide SF3B1-RNA binding maps and show multimodal binding at 3’-splice-sites highlighting a window of 12-21nt upstream of the canonical 3’-splice-site in which a dynamic switch in splice site usage is observable in patients carrying SF3B1 mutations. Our work presents the hitherto most complete LRTS study in CLL and MDS and provides a resource for further research on aberrant splicing in cancer.

  Study EGAS50000000053

• Analysis of translatome, truncating mutations, lncRNA, circRNA and microproteins of 80 human DCM cases and controls

  The regulation of gene expression in healthy and diseased human tissues is incompletely understood and has primarily been studied on the transcriptional level. Here, we quantify the impact of translation on gene expression and annotate novel translational events in 80 human hearts. These include 65 tissues from patients with dilated cardiomyopathy (DCM) - the most common cause of heart transplantation – and 15 unaffected controls. We show that translational regulation modulates disease-associated molecular processes. Further, we evaluate ribosome dynamics at protein truncating variants revealing incomplete termination of translation at titin-truncating variants (TTNtv) that commonly cause DCM. Finally, we identify dozens of unknown microproteins translated from lncRNAs and circRNAs and link these to mitochondrial processes. Several microproteins are expressed from lncRNAs with previously demonstrated function, suggesting a dual coding and noncoding role. This resource will stimulate novel functional investigations into cardiac biology in health and disease and may serve as a blueprint for characterizing the translational landscape of other human tissues.

  Study EGAS00001003263

• Description and determinants of the faecal resistome and microbiome of farmers and slaughterhouse workers: a metagenome-wide cross-sectional study.

  Within this study, we extracted DNA of 194 stool samples of persons living or working on pig and broiler farms (54 pig farmers, 24 broiler farmers), 70 pig slaughterhouse workers and 46 control subjects (Lifelines population living in the Northern parts of the Netherlands, and without recent antimicrobial use and occupational livestock contact). Total DNA was sequenced and metagenomic analysis was performed. Subsequently, the faecal resistomes and microbiomes were described and analysed (doi: 10.1016/j.envint.2020.105939). Highlights study: • Food chain workers are exposed to antimicrobial resistant (AMR) bacteria in livestock. • We describe faecal resistomes and microbiomes of farmers and slaughterhouse workers. • Faecal AMR gene loads in pork exposed workers exceed those in broiler farmers/controls. • Resistome and microbiome differences are shown between and within occupational groups. • On-farm working hours and working/living on a pig farm determine the faecal resistome. • Contact with livestock may be a determinant for human AMR gene carriage. This study is part of the EFFORT project: http://www.effort-against-amr.eu/.

  Study EGAS00001003944

• A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

  Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.

  Study EGAS00001005493

• Multi-focal genomic dissection of synchronous primary and metastatic tissue from de novo metastatic prostate cancer

  De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely-collected tissue in this setting has hindered genomic stratification and jeopardizes precision oncology efforts. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotype across 607 synchronous primary and metastatic tissue foci plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically-relevant genes, resulting in frequent discordance between select primary-restricted foci and synchronous metastases. Additional complexity was driven in several instances by polyclonal metastatic seeding from the reservoir of phylogenetically-related primary populations. When simulating standard clinical practice relying on a single tissue focus, genomic heterogeneity plus highly variable per-sample tumor fraction caused false genotyping of dominant disease. However, in silico modeling demonstrated that analysis of multiple biopsy cores can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-naive primary and metastatic lesions in de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.

  Study EGAS00001006466

• Sequencing of Coding and Non-coding Regions in Primary Breast Cancers and Patient-matched Controls

  Genomic analysis of tumor samples has led to the identification of hundreds of cancer genes based on the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here, we performed deep sequencing in 360 primary breast cancers and developed computational methods to identify significantly mutated promoters. Clear signals were found in the promoters of four genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbors a mutational hotspot in its promoter that leads to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that alter protein binding to the promoter and impact expression levels. Overall, our study shows that recurrent mutations in or near gene promoters in cancers have functional consequences. Power analyses indicate that more such genes remain to be discovered through deep sequencing of adequately sized patient cohorts.

  Study phs001250

• A single-chain derivative of the integrin β1-activating TS2/16 antibody potentiates organoid growth in Matrigel and Collagen hydrogels.

  Culturing epithelial organoids from Adult Stem Cells (ASCs) requires interaction of their β1-integrins with extracellular matrix (ECM) components such as laminin or collagen. Matrigel and BME® (extracts from Engelbreth-Holm-Swarm tumor cells grown in the mouse abdomen) are a popular source of ECM proteins. Yet, these preparations are costly and subject to batch-to-batch variation due to animal-derived contaminations. Here, we describe a single chain version (scFv) of antibody TS2/16, allosterically activating integrin β1 function in organoids. Addition of 5 nM of monomeric scFv to organoid medium results in up to 5-fold higher yields of organoids in Matrigel/BME®. In addition, scTS2/16 generates 6-7-fold higher yields of intestinal organoids in collagen-I hydrogel, when grown both in 3D and in 2D. Collagen is well-defined, available at clinical grade, and in combination with scTS2/16, will enable the clinical use of gastrointestinal organoids.

  Study EGAS50000001113