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• Metastases of a cancer of unknown primary (CUP)

  RNA seq analysis of 6 CUP metastases (each in triplicate), analysed by paired sequencing with NextSeq 500. Whole exome sequencing of 15 CUP metastases, analysed by paired sequencing with NextSeq 500.

  Dataset EGAD00001005963

• Illumina genome sequencing data for HICF2 craniosynostosis families (Genome Medicine)

  BAM files for two families recruited to the HICF2 genome sequencing project due to craniosynostosis. One family is a singleton and the other is an affected mother-daughter duo.

  Dataset EGAD00001011373

• Whole exome sequencing

  reference whole exome sequence serving as a reference of individuals. Includes the fastq files of each individual (labelled S1-S5) and the called variants in vcf format merge for all individuals.

  Dataset EGAD00001008728

• A study of the immune system in patients with peripheral inflammatory neuropathy (CIDP): RNA adult (2025-10-02)

  Leveraging single-cell sequencing technologies to shed light on the immune aetiology of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) . This dataset contains all the data available for this study on 2025-10-02.

  Dataset EGAD00001015725

• Towards standardized whole exome sequencing (WES) for cancer patients: lessons from a multicentric pilot study

  ZPM WES Pilot consisting of 30 samples paired tumor/normal analyzed with WES at four different laboratories in Germany.

  Dataset EGAD00001011087

• Neuroblastoma deep-sequencing dataset part 1

  Dataset including paired tumor-normal whole-genome deep-sequenced samples from 18 neuroblastoma patients (part1 of a total of 36 patients).

  Dataset EGAD00001010059

• IVF Retrospective Study

  This dataset contains BAM files for 9 samples from individuals involved in a retrospective IVF trial. The BAM files were derived from whole genome sequencing. The 9 individuals consist of three trios containing mother, father and child samples.

  Dataset EGAD00001008147

• RaCHseq data

  Captured single-cell long-read data of a cohort of CLL patients receiving VEN treatment for resistance study

  Dataset EGAD00001008365

• Identification of drug resistance genes in melanoma by Exome Sequencing

  The cell lines in this study are a combination of internally sequenced (cosmic) and externally sequenced cell lines known to be “double-wild-type” (lacking BRAF and NRAS somatic mutations). These sequences were realigned in this data set for consistency.

  Dataset EGAD00001003260

• Cancer Cell Line Exome Sequencing

  Genomic characterisation of a large series of cancer cell lines.

  Dataset EGAD00001001039

• 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

• Exome sequencing files for "Minimal functional driver gene heterogeneity among untreated metastases"

  Files from whole exome sequencing of 14 tumors from two cancer patients (endometrial and lung cancer) along with a matched normal tissue per patient.

  Dataset EGAD00001004212

• Whole exome sequencing of melanomas from a Braf mutant mouse model UV radiation study

  Whole exome sequencing of 41 melanomas and normal DNA from Braf mutant mice: 15 tumours from UV exposed mice, 15 tumours from non-exposed mice and 11 from UV exposed, sunscreen-protected mice.

  Dataset EGAD00001000775

• Whole Genome (WG) sequencing data files for H_NO-JB001

  DNA was derived from the primary tumour, lung metastasis, and peri-aortic lymph node metastasis. DNA from the spleen was used as a normal control.WG sequencing produced ~30-fold (primary tumour, spleen normal)-50-fold (lung metastasis) coverage

  Dataset EGAD00001001253

• Whole exome sequencing of SU- DIPG-XIII from different sites

  Whole exome sequencing of diffuse intrinsic pontine glioma (DIPG) cells isolated from the pons and from a sub-ventricular zone site of spread within the frontal lobe from the same individual (SU- DIPG-XIII)

  Dataset EGAD00001003563

• Balanced Ependymoma

  We propose to definitively characterise the somatic genetics of a number of pediatric malignant tumours including ependymoma, high grade glioma and central nervous system primitive neurectodermal tumours through generation of comprehensive catalogues of somatic mutations by high coverage genome sequencing.

  Dataset EGAD00001000350

• mFAST-SeqS of plasma-DNA

  Sequence data from L1-amplicon libraries prepared from plasma-DNA from a set of 24 female controls and 18 male controls without malignant disease and samples from patients breast (n= 28) and prostate cancer patients (n=61).

  Dataset EGAD00001001314

• Whole Exome Data of RFWD3 Fanconi anemia patient

  Dataset contains one sample derived from gDNA of human fibroblasts. Files are in FASTQ format and were generated using the Agilent SureSelect Human All Exon 50Mb Kit and followed by Next Generation Sequencing on a HighSeq2000 instrument (Illumina).

  Dataset EGAD00001003311

• SLC9A3R1 variant associated with age-related hearing loss

  The dataset contains one BAM file that includes a SLC9A3R1 variant identified in two Italian patients affected by age-related hearing loss. Data have been produced by targeted re-sequencing, using Ion Torrent PGM platform.

  Dataset EGAD00001004171

• Longitudinal RNA-seq in a twin cohort

  The dataset consists of 232 RNA-seq samples (whole blood) obtained from healthy female from the TwinsUK adult registry cohort. The samples were obtained at two time points separated on average by 22 months.

  Dataset EGAD00001002068

• Cram files for study entitled Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia

  This dataset contains three cram files for paired end sequencing of a trio, sequenced with Illumina Hiseq 2500

  Dataset EGAD00001006578

• RNAseq data

  Whole genome transcriptome poly-A selected strand specific 100bp paired-end RNA sequencing of post-mortem brain tissue from prefrontal cortex and orbitofrontal cortex were performed. Brain tissue samples were collected from four different biobanks in England and USA.

  Dataset EGAD00001005948

• Epigenetic subtypes of neuroblastoma - ChIPseq

  In the absence of recurrent gene mutations, evidence accumulates that epigenetic deregulation plays a prominent role in neuroblastoma biology. Here we provide genome wide H3K27ac profiles in 60 primary neuroblastoma samples.

  Dataset EGAD00001006285

• Cam_121 RNA-Seq data

  This dataset contains RNA-Seq data from 204 primary melanomas and 177 regional lymph nodes. More details can be found in the manuscript: "Tumour gene expression signature in primary melanoma predicts long-term outcomes: A prospective multicentre study"

  Dataset EGAD00001006401

• Dataset of whole-exome sequencing of clonally related neuroblastoma and teratoma

  This dataset includes bam files of WES of clonally related neuroblastoma and teratoma as well as peripheral blood samples as a control. Neuroblastoma and teratoma samples were formalin-fixed paraffin embedded.

  Dataset EGAD00001007039

• 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

• Nicotine dependence GWAS meta-analysis across European and African American ancestries

  Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 13 other smoking traits (rg=0.40-0.95) and co-morbid diseases. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

  Study phs001532

• Evaluation of Nuclear DNA from Rootless Hairs for Forensic Purposes

  The study aims to overcome current limitations in the recovery of DNA from small, difficult forensic samples. Particularly, our goal is to produce a robust laboratory protocol and the accompanying software to accelerate adoption, as well as to evaluate the reliability and robustness of both the laboratory and computational aspects of generating genotype files from minute and/or degraded DNA samples, such as single, rootless hairs.The data accompanying this study includes raw, paired-end reads from high-throughput sequencing of two panels of saliva, head hair, and pubic hair samples collected from anonymous volunteers at the University of California, Santa Cruz. The smaller set (Hair1.0) comprises 8 individuals, while the larger (Hair2.0) comprises 50 individuals, with 3 overlapping individuals between the two panels identified in post-collection analysis. We did not collect phenotype data or personally identifying information from the participants. For the Hair2.0 panel, only a subset of volunteers provided pubic hairs for DNA extraction and sequencing. Also included are saliva-derived genotype array data for all 8 individuals in the Hair1.0 panel and 44 of 50 individuals in the Hair2.0 panel.

  Study phs002979

• Next Generation Mendelian Genetics: Neonatal Diabetes

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained. We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.

  Study phs000542

• Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

  ​​Multiple Myeloma (MM) develops from well-defined precursor stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering MM (SMM); however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. In this study, we enumerated circulating tumor cells (CTCs) from patients with precursor and overt diseases, and developed a novel approach, MinimuMM-seq, which enables detection of translocations and copy number abnormalities through whole-genome sequencing of highly pure CTCs. In a cohort of 51 patients, 24 with paired BM, we applied our method MinimuMM-seq and detected 100% of clinically reported BM biopsy events. The next-generation sequencing (NGS) assay could replace molecular cytogenetics by Fluorescence In Situ Hybridization (FISH) for diagnostic yield and risk classification. In 8 patients we could apply MinimuMM-seq on serially collected samples to track and monitor major clones in peripheral blood. We describe clonal evolution and shifting dynamics of subclones over time, as well as in between blood and marrow compartments. All whole-genome sequencing (WGS) data generated in this study will be made accessible through dbGaP.

  Study phs003084

• Urethral Microbiome of Adolescent Males

  Urethral microbiome of adolescent males is designed to characterize the microbial communities resident in the urethra of young men, to identify differences in these communities as a function of race/ethnicity, circumcision status, sexual exposures, and uro-genital symptoms. We collect detailed sexual behavior and symptoms data using cellular telephones with Internet access. Specimens are routinely collected at monthly intervals, and intermittently following reported symptoms, specific sexual exposures, or identification of a sexually transmitted infection. We also collect periodic samples from the penile coronal sulcus to better characterize its relationship to the urethral micriobial communities. Participants are ages 14 - 17 at enrollment, and prior history of sexual exposure is not required for participation. Parental permission is obtained for each participant. The planned duration of followup is up to 4 years allowing for prospective observation of both physical and behavioral maturation from middle adolescence into young adulthood. The overall objectives of the project are to better characterize the healthy male urethral microbiome, and to use this information to better understand acquisition of urethritis and sexually transmitted infections, as well as chronic genital pain and prostatitis syndromes that become common among young adults.

  Study phs000259

• Transcriptomic Characterization of Human Innate T Cells

  We performed low input RNA-seq and single-cell RNA-seq on 7 lymphocyte populations with the objective of finding the common transcriptional programs shared among innate T cells. In brief, we drew blood from healthy donors and isolated CD4+ T cells, CD8+ T cells, Natural Killer cells, invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and two γδ T cell populations: Vδ1 and Vδ2. We performed low input RNA-seq on samples with 1000 cells each, for 6 healthy individuals, in duplicate. We performed single-cell RNA-seq with DNA-barcoded hashing antibodies to identify the cell type of origin for each cell. We found a common transcriptional program across lymphocytes that is gradually turned on as lymphocytes have a more "innateness" state, promoting effector functions and sacrificing proliferative capacity. Additionally, we performed low input RNA-seq for Vδ3-expressing γδ T cells and δ/αβ T cells for one healthy individual in duplicate (1000 cells per sample). This revealed δ/αβ T cells are transcriptionally more adaptive-like and Vδ3 more innate-like.

  Study phs002007

• Development of CMT Peds Scale for Children with CMT

  Information about how different forms of CMT affect children is not readily available because there are not good methods to measure impairment of children with CMT. The purpose of this project is to develop and test such a method and to then test this scale to ensure that it is an effective measurement of impairment of CMT in children, that the children tolerate it well, that different investigators using this method obtain similar results and that changes over time with the scale allow measurement of progression of CMT in the children. Primary Objective: To develop and test the CMT Peds scale (CMTPedS) in children with CMT in order to refine the scoring for future natural history and therapeutic trials. Secondary Objective: We propose to test the sensitivity of the CMT Peds Scale in a longitudinal study and compare the CMT Peds Scale with the Children's Quality of Life scale CHQ-PF50. 2000 patients <21 years of age with various forms of CMT will be evaluated at baseline and at subsequent annual follow up visits when possible. This first study release makes available data of n=208 study participants.

  Study phs001553

• An APOBEC Cytidine Deaminase Mutagenesis in Human Cancers

  Reprinted from Roberts et al. "An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers", Nature Genetics, 45:970-976, 2013, with permission of Nature Publishing Group: Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas (TCGA), showed a significant presence of the APOBEC mutation pattern in bladder, cervical, breast, head and neck, and lung cancers, reaching 68% of all mutations in some samples. Within breast cancer, the HER2-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.

  Study phs000677

• Comprehensive Epigenetic Landscape of Rheumatoid Arthritis Fibroblast-Like Synoviocytes

  We characterized the epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes (FLS) compared with osteoarthritis FLS. Multiple technologies were used, including ChIP-seq to assay H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3, ATAC-seq for chromatin accessibility, the transcriptome by RNA-seq and whole genomic bisulfite sequencing for DNA methylation. Integrative analysis was performed using a novel unbiased method to identify regions of the genome that have similar epigenetic marks. The regions that distinguished RA and osteoarthritis cells were primarily located in active enhancers and promoters. The regions and genes identified included immunological pathways. In addition, some unexpected pathways, most notably "Huntington's Disease Signaling", were discovered. The Huntington's Disease pathway was biologically validated for Huntingtin-interacting protein-1, which regulated invasive behavior of FLS. For a complete description, see R. Ai et al., Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat Commun 9, 1921 (2018). Sequencing data of study participants are available through dbGaP's Authorized Access portal, while analyses of the sequencing data may be obtained through NCBI's GEO portal under GSE112658.

  Study phs001615

• Altered chromosomal topology drives oncogenic programs in gastrointestinal stromal tumors

  Metabolic lesions with pleiotropic effects on epigenetic regulation and other cellular processes are widely implicated in cancer, yet their oncogenic mechanisms remain poorly understood. Succinate dehydrogenase (SDH) deficiency causes a subset of gastrointestinal stromal tumors (GISTs) with DNA hyper-methylation. Here we associate this hyper-methylation with changes in chromosome topology that activate oncogenic programs. To investigate epigenetic alterations in this disease, we systematically mapped DNA methylation, CTCF insulators, enhancers and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes share similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on disrupted insulators that partitions super-enhancers from FGF3, FGF4 and the KIT oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancers and oncogenes. CRISPR-mediated excision of the corresponding CTCF motif in an SDH-intact model disrupted the boundary and up-regulated FGFs and KIT expression. Our findings reveal how a metabolic lesion destabilizes chromatin structure to facilitate the initiation and selection of epigenetic alterations that drive oncogenic programs in the absence of canonical mutations.

  Study phs001906

• eMERGE Phase III Clinical Center at Partners HealthCare

  The Partners HealthCare Biobank is a large research data and sample repository working within the framework of Partners Personalized Medicine. It provides researchers access to high quality, consented samples to help foster research, advance understanding of the causes of common diseases, and advance the practice of medicine. The Partners Biobank provides banked samples (plasma, serum and DNA) collected from consented patients. These samples are available for distribution to Partners HealthCare investigators with appropriate approval from the Partners Institutional Review board (IRB). They are linked to clinical data that originates in the Electronic Medical Record (EMR), as well as additional health information collected in a self-reported survey. The Partners Biobank will be genotyping 25,000 subjects with the Illumina Multiethnic Beadchip 1.6 million SNPs with exome and custom content (> 60,000 LoFs). Of the participants genotyped so far, 4929 of 4962 (99.3%) individuals have genotype data that passed the default quality thresholds for the Infinium array (call rate >= 0.99). We are submitting the genotype data to dbGaP for 4929 subjects with 12 phenotypes (based on icd9 codes). We will do annual releases until we reach the full 25,000 genotyped subjects.

  Study phs000944

• Characterization of Autosomal CNV Among the Negrito from Peninsular Malaysia

  Copy number variation (CNV) has been recognized as a major contributor to human genome diversity. It plays an important role in determining phenotypes and has been associated with a number of common and complex diseases. However the CNV data from diverse populations is rather limited. Here we report the first investigation of copy number variation (CNV) in the indigenous populations from Peninsular Malaysia. We genotyped 34 Negrito genomes from Peninsular Malaysia using the Affymetrix SNP 6.0 microarray and identified 62 putative novel CNVs, consisting of 25 gains and 37 losses. These CNVs appear unique to the Negrito population and were absent in the DGV, HapMap3 and Singapore Genome Variation Project (SGVP) datasets. Analysis of gene ontology revealed that genes within these CNVs were enriched in the immune system (GO:0002376), response to stimulus mechanisms (GO:0050896), as well as the metabolic pathways (GO:0001852). Copy number gains in CNVRs enriched with genes were significantly higher than the losses (P value <0.001). Therefore, in view of the small population size, relative isolation and semi-normadic lifestyles of this community, we speculate that these CNVs may be attributed to recent local adaptation of Negritos from Peninsular Malaysia.

  Study phs000664

• Functional Enhancer Elements Drive Subclass-Selective Expression From Mouse to Human Neocortex

  A complete epigenomic map of human brain cell types will be necessary to fully understand their genetic regulation, and to create the next generation of non-species-restricted genetic tools for their functional characterization. Here we performed both bulk and single-nucleus ATAC-seq studies of fresh human neocortical samples excised during neurosurgery, in order to discover the functional genomic elements that discriminate cell types. This dataset contains 78 bulk layer-dissected ATAC-seq samples, and 3660 single-nucleus ATAC-seq samples from fresh acutely isolated human neurosurgical samples. Furthermore, from these data we identified and validated several enhancers for use in AAV context. We also provide validation single cell RNA-seq for 456 human acutely labeled neurosurgical neurons labeled by 3 unique enhancer-AAV vectors, and single cell RNA-seq for 1483 mouse neurons labeled in vivo by 11 unique enhancer-AAV vectors. Together these datasets provide high-resolution maps of single human neocortical cell types, as well as proof of the functional utility of the genomic elements discovered. As a whole these data will be important to furnish the next generation of cell type-specific functional tools and therapies in neuroscience.  

  Study phs002292

• Human Blastocyst 10X Single Cell RNA Sequencing

  Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. One limitation of our first protocol for human blastoid generation was relatively low efficiency. We now report an optimized protocol for the efficient generation of large quantities of high-fidelity human blastoids from naive pluripotent stem cells. This enabled proteomics analysis that identified phosphosite-specific signatures potentially involved in the derivation and/or maintenance of the signaling states in human blastoids. Additionally, we uncovered endometrial stromal effects in promoting trophoblast cell survival, proliferation, and syncytialization during co-culture with blastoids and blastocysts. Side-by-side single-cell RNA sequencing revealed similarities and differences in transcriptome profiles between pre-implantation blastoids and blastocysts, as well as post-implantation cultures, and uncovered a population resembling early migratory trophoblasts during co-culture with endometrial stromal cells. Our optimized protocol will facilitate broader use of human blastoids as an accessible, perturbable, scalable, and tractable model for human blastocysts. In addition, this study is the first to use the 10X Genomics platform for human blastocysts, and we anticipate this resource will be widely used by the community as a reference for future studies.

  Study phs003122

• Somatic Mutations in Single Human Neurons from Patients with Congenital Neurodegenerative Diseases

  It has been hypothesized that accumulating DNA lesions in neurons contribute to aging and neurodegeneration. Despite their pathophysiological importance, the DNA lesions have not been systematically examined with effective methods. In this study, we developed a computational method for detecting genomic deletions in single-cell whole-genome sequencing (scWGS) data, and analyzed the whole genome of human single neurons. Single neurons were obtained from neurotypical individuals of various ages and from patients with three different congenital neurodegenerative diseases: Ataxia telangiectasia (AT), Cockayne syndrome (CS), and Xeroderma pigmentosum (XP). Single-neuron WGS data of AT brains are released here, and the data of other two diseases are released in a separate dbGaP study (phs001485).To understand the molecular mechanisms underlying AT, we performed single-nucleus RNA-sequencing (snRNA-seq) of postmortem cerebellar vermis and prefrontal cortex from individuals with AT and controls. To genetically confirm the diagnosis of AT, we also performed WGS on postmortem brain tissue from each individual with AT. Induced pluripotent stem cells (iPSCs) from individuals with AT and controls were differentiated into microglia, and the transcriptomes were profiled with bulk RNA-sequencing (RNA-seq).

  Study phs003005

• Adipocytes Regulate Fibroblast Function and Their Loss Contributes to Fibroblast Dysfunction in Inflammatory Diseases

  We profiled live synovial cells from 16 individuals with no diagnosed arthritis using single-cell RNA sequencing. Our study was designed to provide a reference single cell RNA sequencing dataset for researchers interested in studying arthritic synovium, providing sequencing data on healthy synovial cells for comparison to cells from diseased synovial tissues. Synovial tissue was collected post-mortem from three different sources between 2019-2021: the National Disease Research Interchange, a collaboration with Rush University and the Gift of Hope, and the Brigham and Women's Hospital Autopsy Department. To be included in the study, patients had to be between the ages of 18 to 72 and have no diagnosed arthritis or autoimmune diseases. Additionally, this study includes bulk RNA sequencing data of cultured primary synovial fibroblasts isolated from three rheumatoid arthritis patents. Cells were stimulated with either cortisol, fat conditioned media, TGFβ, TNFα, fat conditioned media with mifepristone, TGFβ with fat conditioned media, or TNFα with fat conditioned media. Cells were harvested 4 or 22 hours later and lysates collected for sequencing. Data from this study submitted to the Gene Expression Omnibus (GEO) may be accessed via accession number GSE233504.

  Study phs003304

• HuBMAP: Single-Cell Multiplex Chromatin and RNA Interactions in Aging Human Brain

  The study employs the Multi-Nucleic Acid Interaction Mapping in Single Cell (MUSIC) technique to concurrently profile multiplex chromatin interactions, gene expression, and RNA-chromatin associations within individual nuclei, revealing dynamically organized chromatin complexes in human frontal cortex samples from elderly donors. The MUSIC technique allows for the exploration of chromatin architecture and transcription at cellular resolution in complex tissues. The study includes 14 human cortex tissues and employs MUSIC to delineate diverse cortical cell types and states, revealing that nuclei with fewer short-range chromatin interactions correlate with an "older" transcriptomic signature and Alzheimer's pathology. Additionally, the study elucidates that specific cell types, characterized by chromatin contacts between cis expression quantitative trait loci (cis eQTLs) and a promoter, are particularly susceptible to the regulatory impact of these cis eQTLs on target gene expression. Furthermore, the female cortical cells exhibit highly heterogeneous interactions between the X-inactive specific transcript (XIST) non-coding RNA and Chromosome X, along with diverse spatial organizations of the X chromosomes. MUSIC presents a potent tool for exploring chromatin architecture and transcription at cellular resolution in complex tissues.

  Study phs003568

• CONNECTS Master Protocol for Clinical Trials targeting Macro- and Micro-Immuno-Thrombosis, Vascular Hyperinflammation, and Hypercoagulability and Renin-Angiotensin-Aldosterone System (RAAS) in Hospitalized Patients with COVID-19 (ACTIV-4 Host Tissue)

  ACTIV 4 Host Tissue is a shared-placebo clinical trial platform evaluating therapies targeting the host response to COVID-19 in hospitalized patients. The overarching goal of the platform was to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. Three trials were implemented to investigate three agents: TXA-127, TRV-027, and Fostamatinib. These agents all impact the host tissue response in COVID-19 via a number of unique mechanisms, including potential beneficial effects on the RAAS system and formation of neutrophil extracellular traps (NETs). Each trial evaluated the efficacy of these agents' ability to impact the host tissue response and improve outcomes in patients hospitalized with COVID-19. We found no evidence that any of the three agents significantly improved clinical outcomes as measured by the primary outcome, oxygen free days through day 28.

  Study phs003708

• Prediction of homologous recombination deficiency identifies colorectal tumors sensitive to PARP inhibition

  BRCAness is a well-established feature in breast, ovarian, prostate and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HRD from reference-free tumor samples. We validated HRDirect using matched breast cancer and CRC patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology (TSO) _500 HRD panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose integrating HRDirect scoring with ATM immunohistochemical analysis as part of our "composite biomarker approach" to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.

  Study EGAS50000000426

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

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

  Study phs003756

• Somatic Mutations in Individual Skin Cells

  Ultraviolet (UV) radiation is the primary cause of melanoma through the acquisition of driver mutations in melanocytes. It also plays a significant role in oncogenesis in other skin cells, such as keratinocytes. However, the mutational profiles vary widely among different skin cancers, and the early mutational processes in different cell types from the same skin, is not well understood. Additionally, our preliminary studies also suggest that the mutation burden in different skin cells vary significantly based on risk factors such as the anatomical site and the use of tanning beds. To explore this, we employed innovative Next Generation Sequencing (NGS) tools to perform a site-matched comparison of the genomic landscapes of melanocytes, keratinocytes, and fibroblasts. From 20 biopsies of physiologically normal skin, collected from various anatomical sites across 16 donors, we have performed DNA-sequencing on 106 melanocytes, 78 keratinocytes and 13 fibroblasts. Of these samples, we have also simultaneously performed RNA-sequencing on 78 melanocytes, 46 keratinocytes and 9 fibroblasts. For normal bulk DNA, we also performed targeted (UCSF500; n=9) or exome sequencing (n=8) of skin or saliva samples from the donors.

  Study phs003683

• Chicago Infant Mortality Study

  The Chicago Infant Mortality Study (CIMS) was a population-based, prospective, case-control study conducted in metropolitan Chicago, Cook County, Illinois, to examine the risk factors for sudden infant death syndrome (SIDS) among a primarily Black population. Eligible case infants were aged birth to one year where the cause of death was determined to be SIDS while eligible control infants were aged one month to one year who died of other sudden unexpected infant death (SUID) causes. Recruitment occurred between November 1993 and April 1996. The goal of this ancillary multiomics study was to evaluate possible genetic and epigenetic determinates of SIDS and together with metabolomic profiles, identify novel clinical diagnostic tools to enable molecular autopsies and biomarkers to proactively identify and intervene in infants at greater risk of death from SIDS. The multiomics data was generated from medical examiner autopsy specimens and includes: whole exome sequencing genotypes; RNA-seq transcriptome and methylome profiles from autopsy heart tissue; and serum metabolomics profiles. The sample size available varies with the modality of the omics assay, but the total number of unique infants included is about 400.

  Study phs003790

• Effective screening strategy for deafness using a new-genetation sequencing platform: a consecutive analysis

  The diagnosis of the genetic etiology of deafness contributes to the clinical management of patients. We performed the following four genetic tests in three stages for 52 consecutive deafness subjects in one facility. We used the Invade assay and Sanger sequencing for the GJB2 gene or SLC26A4 gene in the first stage test, TaqMan genotyping assay in second stage test, and targeted exon sequencing using the massively parallel DNA sequencing in third stage test. Overall, we identified the genetic cause in 40% (21/52) of patients. The diagnostic rates of the first-, second- and third-stage genetic testing were 17%(9/52), 9%(4/43) and 21% (8/39), respectively. The combination approach using these genetic tests appears to be useful as a diagnostic tool for deafness patients. We recommended that genetic testing for the screening of common mutations in deafness genes using the Invader assay or TaqMan genotyping assay be performed as the initial evaluation. For the remaining undiagnosed cases, targeted exon sequencing using MPS is clinically and economically beneficial. This data set was MPS reads data (fastq) for 39 sensorineural hearing loss patients.

  Study JGAS000032

• Adaptive Therapy Exploits Fitness Deficits in Chemotherapy-Resistant Ovarian Cancer to Achieve Long-Term Tumor Control Open Access

  Drug resistance results in poor outcomes for cancer patients. Adaptive therapy is a potential strategy to address drug resistance that exploits competitive interactions between sensitive and resistant subclones. Here, we showed that adapting carboplatin dose according to tumor response (adaptive therapy) significantly prolonged survival of murine ovarian cancer models compared to standard carboplatin dosing, without increasing mean daily drug dose or toxicity. Platinum resistant ovarian cancer cells exhibited diminished fitness when drug was absent in vitro and in vivo, which caused selective decline of resistant populations due to reduced proliferation and increased apoptosis. Conversely fitter, sensitive cells re-grew when drug was withdrawn. Using a bioinformatics pipeline that exploits copy number changes to quantify the emergence of treatment resistance, analysis of cell‐free DNA obtained longitudinally from ovarian cancer patients during treatment showed subclonal selection through therapy, and measurements of resistant population growth correlated strongly with disease burden. These preclinical findings pave the way for future clinical testing of personalized adaptive therapy regimens tailored to the evolution of carboplatin resistance in individual ovarian cancer patients.

  Study EGAS50000001142