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• Salivary Gland Cancer TSO500 dataset

  Salivary gland cancer (SGC) is a rare cancer for which systemic treatment options are limited. Therefore, it is important to characterize its genetic landscape in search for actionable aberrations. This research aimed to identify these actionable aberrations by NGS-based analysis of DNA (single and multiple nucleotide variants, copy number variants, microsatellite instability and tumor mutational burden) in a large cohort of SGC patients. DNA was extracted from archival tissue of 119 patients with various SGC subtypes and sequenced using a targeted NGS panel encompassing 523 cancer related genes (TruSight Oncology 500, TSO500). The 119 patients included 46 AdCC patients, 43 SDC patients, 15 MEC patients, 9 AciCC patients and 6 patients with other subtypes (1 secretory carcinoma, 1 polymorphic adenocarcinoma (PAC), 1 adenocarcinoma NOS, 1 myoepithelial carcinoma, 1 epithelial/myoepithelial carcinoma and 1 mixed PAC/myoepithelial carcinoma). Median exon coverage ranged from 80-904 (median 308) unique reads and the median percentage of exon coverage with at least 100 unique reads was median 96.6% in these 119 samples.

  Study EGAS00001006232

• Clinical Implications of Genomic Alterations in the Tumor and Circulation of Pancreatic Cancer Patients

  Pancreatic adenocarcinoma has the worst mortality of any solid cancer. To evaluate the clinical implications of genomic alterations in this tumor type, we performed whole-exome analyses of 24 tumors, targeted genomic analyses of 77 tumors, and used non-invasive approaches to examine tumor-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin regulating genes MLL, MLL2, MLL3, and ARID1A in 20% of patients that were associated with improved survival. We observe alterations in genes with potential clinical utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumor DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, and recurrence by ctDNA is detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.

  Study EGAS00001001257

• miR-200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers

  High-grade serous epithelial ovarian cancer (HGSOC) has been recently subdivided into molecular subgroups, including the mesenchymal HGSOC associated with partial tumor-debulking surgery and poor patient survival. Consistent with stromal-related genes signatures defining mesenchymal HGSOC, we show here that stroma plays a key function in this HGSOC molecular subtype. We first highlight stromal heterogeneity in HGSOC by identifying 4 subsets of Carcinoma-Associated Fibroblast (CAF-S1-4). Mesenchymal HGSOC significantly accumulate the activated CAF-S1 subset, which exhibits immunosuppressive functions by promoting attraction, survival and activation of regulatory T-lymphocytes. The CXCL12β chemokine reliably characterizes mesenchymal HGSOC and specifically accumulates in the CAF-S1 subset through a regulation mediated by the miR-141/200a. CXCL12β promotes attraction of T-lymphocytes and is thus a key actor in CAF-S1-mediated immunosuppressive functions. In conclusion, we highlight here for the first time stromal heterogeneity and immunosuppression in mesenchymal HGSOC that could participate in the poor patient prognosis.

  Study EGAS00001002184

• DONSON encodes a novel replication fork protection factor mutated in microcephalic dwarfism.

  To ensure efficient genome duplication, cells have evolved a multitude of factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

  Study EGAS00001002224

• Exome-sequencing identifies new oncogenes and tumor suppressor genes recurrently altered in hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. High-resolution copy number analysis of 125 tumors of which 24 were subjected to whole-exome sequencing identified 135 homozygous deletions and 994 somatic gene mutations with predicted functional consequences. We identified new recurrent alterations in 4 genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses demonstrated tumor suppressor properties for IRF2 whose inactivation, exclusively found in hepatitis B virus related tumors, leads to impaired TP53 function. Alternatively, inactivation of proteins involved in chromatin remodeling was frequent and predominant in alcohol related tumors. Moreover, activation of the oxidative stress metabolism and inactivation of RPS6KA3 were new pathways associated with WNT/beta-catenin activation, thereby suggesting a cooperative effect in tumorigenesis. This study shows the dramatic somatic genetic diversity in HCC, it reveals interactions between oncogene and tumor suppressor gene mutations markedly related to specific risk factors.

  Study EGAS00001000217

• Mutations in the RAS/MAPK pathway drive replication repair deficient hypermutated tumors and confer sensitivity to MEK inhibition

  The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors which harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair deficient (RRD) cancers which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (p=10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient derived RRD tumors and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveal durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways resulting in favorable response to targeted therapies.

  Study EGAS00001005008

• Tubulointerstitial fibrosis is the histological hallmark of chronic kidney disease (CKD). Hypoxia and inflammation (i.e., interleukin (IL)-1β signalling) are independent mediators of tubulointerstitial fibrosis. However, the physiological response of human kidney tubular cells to IL-1β/IL-1RI signalling under the hypoxic conditions of CKD is poorly understood and remains a clinical imperative for therapeutic targeting. This study reports that hypoxia and IL-1β act in synergy to trigger cell cycle arrest/cellular senescence of ex vivo patient-derived primary proximal tubular epithelial cells (PTECs).

  Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia. Hypoxia+IL-1β-treated PTECs had 692 ‘unique’ differentially expressed genes (DEGs) compared to normoxic PTECs, with ‘cell cycle’ the most significantly enriched KEGG pathway based on ‘unique’ down-regulated DEGs (including CCNA2, CCNB1 and CCNB2). Hypoxia+IL-1β-treated PTECs displayed signatures of cellular senescence, with reduced proliferation, G2/M cell cycle arrest, elevated senescence-associated β-galactosidase (SA-β-gal) activity and increased production of pro-inflammatory/fibrotic senescence-associated secretory phenotype (SASP) factors compared to normoxic conditions. Treatment of Hypoxia+IL-1β-treated PTECs with either a senolytic drug combination, quercetin+dasatinib, or a type I IL-1 receptor (IL-1RI) neutralizing antibody attenuated senescent cell burden. Our data identify a mechanism whereby hypoxia in combination with IL-1β/IL-1RI signalling trigger PTEC senescence, providing novel therapeutic and diagnostic check-points for restoring tubular regeneration in human CKD.

  Study EGAS00001007904

• Cell-type eQTLs for single-cell Mendelian Randomisation

  The following study mapped eQTLs in the post-mortem human brain from snRNA-seq generated on 391 individuals. Following eQTL discovery and identification of state-specific eQTLs (dynamic associations interacting with disease), colocalisation and MR was performed integrating GWAS from 42 traits, for the identification of putatively causal genes with cell-type specific context. This study contains raw sequencing data and genotype for two datasets used in this work; - The MRC 60 dataset, which contains snRNA-seq generated on post-mortem brain from 60 control individuals (104 samples total, split across prefrontal cortex and hippocampus). Samples were pooled into 27 distinct pools, each of which was split across 4 lanes. Following sequencing and mapping using cellranger, demultiplexing was done using Demuxlet using the pool-specific genotype data (which contain sample IDs). - The Roche PD dataset, which is 10X multiome data generated on on 70 PD and 22 control individuals.

  Study EGAS50000000687

• Trans-ethnic genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

  We carried out a trans-ethnic genome-wide association and replication study of blood pressure phenotypes amongst up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 novel loci to be associated with blood pressure (P=3.9x10-11 to P=5.0x10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that at some of the loci identified DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 novel loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7, TBX2) function. The novel and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, cardiovascular and all-cause mortality (P=0.04 to 8.6x10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

  Study EGAS00001001427

• We describe a method to culture organoids from adult human kidney tissue and describe applications for the culture system.

  Adult Stem Cell (ASC)-derived organoids are 3D epithelial structures that recapitulate essential aspects of their organ of origin. We have developed conditions for the long-term growth of primary kidney epithelial organoids. Cultures can be established from mouse and human kidney tissue, as well as from urine and can be expanded for at least 20 passages (> 6 months). Chromosome numbers remain normal. Human organoids represent proximal as well as distal nephron segments, as evidenced by gene expression, immunofluorescence and tubular functional analyses. BK virus infection of organoids recapitulates in vivo phenomena. Organoids can be established from Wilms nephroblastoma. Kidney organoids from Cystic Fibrosis (CF) patient’s urine allowed ex vivo assessment of treatment efficacy. Finally, organoids cultured on microfluidic organ-on-a-chip plates adopt a tubular conformation and display active transport function. Adult kidney-derived organoids allow studies of hereditary, infectious and malignant kidney disease in a personalized fashion.

  Study EGAS00001002729

• RNA-seq profiling of NKX6.1 reporter iPSC lines for isolation and analysis of functionally relevant neuronal and pancreas populations

  We generated human induced pluripotent stem cell (iPSC) lines with a GFP reporter inserted in the endogenous NKX6.1 locus. Characterisation of the reporter lines demonstrated faithful GFP labelling of NKX6.1 expression during pancreas and motor neuron differentiation. We performed three independent in vitro differentiations towards the pancreatic endocrine lineage. We FACS-purified GFP positive and negative cells from stage 7 cultures, and generated Smart-Seq2 RNA-sequencing libraries for the pre-sorted cells, as well as the two GFP-sorted cell populations. Gene expression profiling by RNA-sequencing reveals that the NKX6.1-positive population closely resembles mature human beta cells and the functional evaluation of purified populations shows that the glucose-responsive beta-like cells are enriched within the NKX6.1-positive population. These reporter lines provide a valuable resource to the scientific community for the derivation of functional relevant pancreas and neuronal cell subtypes.

  Study EGAS00001002802

• WGS of high grade serous ovarian tumours and matched blood normals

  FASTQ reads for 81 matched tumour-normal WGS pairs for high grade serous ovarian cancer patients. Scottish HGSOC samples were collected via local Bioresource facilities at Edinburgh, Glasgow, Dundee and Aberdeen and stored in liquid Nitrogen until required. HGSOC patients were determined from pathology records and were included in the study where there was matched tumour and whole blood samples. Tumour samples were divided into two for DNA and RNA extraction and slivers of tissue were taken, fixed in formalin and embedded in paraffin wax (FFPE). Samples were only included if they were confirmed as HGSOC and there was greater than 40% tumour cellularity throughout the tumour, determined using H&E staining of the FFPE sections and pathology review. Somatic DNA was extracted from the tumour and germline DNA was extracted from whole blood. Somatic DNA was extracted using the Qiagen DNeasy Blood and tissue kit (cat no 69504). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including RNase digestion step). Germline DNA was extracted from 1-3ml whole blood using the Qiagen FlexiGene kit (cat no 51206) following the manufacturers recommended protocol. The resulting DNA underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as surrogate measures of DNA purity. A260/280 had to be 1.8 or greater and A260/230 had to be 2.0 or greater. Then, DNA was quantified using LifeTechnologies Qubit dsDNA BR kit (cat no Q32850) and we required a minimum of 50ul at 25ng/ul for WGS. Thirdly, DNA was diluted to 25ng/ul and a representative sample was loaded onto a 0.8% TAE gel, ran at 100v for 60mins and then imaged using a BioRad ChemiDoc imaging system to visualise the DNA quality.

  Dataset EGAD00001009049

• WGS of high grade serous ovarian tumours and matched blood normals

  FASTQ reads for 34 matched tumour-normal WGS pairs for high grade serous ovarian cancer patients. Scottish HGSOC samples were collected via local Bioresource facilities at Edinburgh, Glasgow, Dundee and Aberdeen and stored in liquid Nitrogen until required. HGSOC patients were determined from pathology records and were included in the study where there was matched tumour and whole blood samples. Tumour samples were divided into two for DNA and RNA extraction and slivers of tissue were taken, fixed in formalin and embedded in paraffin wax (FFPE). Samples were only included if they were confirmed as HGSOC and there was greater than 40% tumour cellularity throughout the tumour, determined using H&sE staining of the FFPE sections and pathology review. Somatic DNA was extracted from the tumour and germline DNA was extracted from whole blood. Somatic DNA was extracted using the Qiagen DNeasy Blood and tissue kit (cat no 69504). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including RNase digestion step). Germline DNA was extracted from 1-3ml whole blood using the Qiagen FlexiGene kit (cat no 51206) following the manufacturers recommended protocol. The resulting DNA underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as surrogate measures of DNA purity. A260/280 had to be 1.8 or greater and A260/230 had to be 2.0 or greater. Then, DNA was quantified using LifeTechnologies Qubit dsDNA BR kit (cat no Q32850) and we required a minimum of 50ul at 25ng/ul for WGS. Thirdly, DNA was diluted to 25ng/ul and a representative sample was loaded onto a 0.8% TAE gel, ran at 100v for 60mins and then imaged using a BioRad ChemiDoc imaging system to visualise the DNA quality.

  Dataset EGAD00001010135

• DAC anti-MPO BCR sequences

  DAC for the requests of access to data of anti-MPO BCR sequences in the EGA repository,

  Dac EGAC50000000446

• Liquid biopsy-based minimal residual disease monitoring for early risk stratification and decision-making in advanced non-small cell lung cancer

  Dac EGAC50000000832

• Analysis of circulating miRNAs for the identification of new prognostic and predictive markers in gastro-entero-pancreatic neuroendocrine tumour (GEP-NET)

  Study EGAS00001007227

• University of Miami Udall Center of Excellence Identification of Rare Variants in PD through Whole Exome Sequencing

  The focus of this study is to identify a new level of genetic variation, i.e. rare genetic variants with a population frequency less than 5%, usually less than 1%, which are believed to provide a stronger risk per variant than those studied to date in the large genome wide association studies (GWAS). To do this we are generating whole exome sequencing data on the Illumina HiSeq. Each HiSeq produces at least 600 billion base pairs of DNA sequence in one run. Whole exome sequencing sequence data, about 50 million base pairs, or about 1.5% of the total DNA of each person's genome, is generated. We are using this data to look for new DNA variations that give risk for Parkinson disease, as well as "modifiers", that may lead to having more severe or milder disease or later or earlier ages of onset.

  Study phs000908

• Mitochondrial Abnormalities in Schizophrenia and Bipolar Disorder

  Mitochondrial DNA structural variation is one proposed indicator of mitochondrial dysfunction. The large common deletion of mitochondrial DNA (mtDNA) increases with aging across multiple brain regions. We found other large deletions of mtDNA in brain at levels comparable to the common deletion (PMID: 30869147). Since mtDNA molecules replicate independently of nuclear division, the mtDNA copy number is a measure of mitochondrial health; levels are negatively correlated with age and all-cause morbidity. Complex I activity is another functional measure of mitochondria. We previously published a subset of this data from DLPFC (PMID: 29594135) for three indicators (common deletion, mtDNA copy number, Complex I activity). For this study, four indicators (common deletion, large deletions, mtDNA copy number, Complex I activity) were measured in four brain regions from subjects with schizophrenia (SZ) and bipolar disorder (BD) and compared to controls. The four brain regions were: the dorsolateral prefrontal cortex, superior temporal gyrus, primary visual cortex (V1), and nucleus accumbens.    

  Study phs002395

• Novel Strategies to Eliminate Resistance to B-cell Receptor Inhibitor Therapy in Lymphoid Malignancies

  Ibrutinib and acalabrutinib are BTK inhibitors (BTKi) used as frontline therapies for chronic lymphocytic leukemia (CLL). Clonal evolution during ibrutinib treatment has previously been studied, but limited study of clonal evolution in patients receiving acalabrutinib has been done. Our group analyzed 216 blood samples from 38 CLL patients at multiple time points during their BTKi treatment. Samples were prepared by standard protocols and sequenced using 200x Illumina sequencing. Using the longitudinal data, we reconstructed the clonal evolution of each patient using somatic mutations found within the B-cell populations. Three patterns of clonal evolution were identified: 1) new clone emergence, 2) clonal selection, and 3) clonal replacement. As previously seen in ibrutinib treatment, the evolution of subclones containing CLL-driver mutations was associated with worse clinical outcomes for patients treated with acalabrutinib (Log-rank p=0.04). Understanding clonal evolution during treatment with acalabrutinib can help determine and modify the clinical course of patients with CLL.

  Study phs003042

• Identifying genetic variants that alter TCR usage in the peripheral repertoire

  The relationship between genetic variation and CD8+ T-cell receptor (TCR) repertoire usage in patients receiving Immune Checkpoint Blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)-focused analysis of CD8+ T-cell TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-mer usage from samples taken prior to and after ICB (n=250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, whilst at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with novel implications for understanding factors relating to therapeutic response and patient outcomes.

  Study EGAS00001008189

• Determination of cell specific regulatory enhancers in hematopoetic models

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10, led by NS) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise "experimental noise" and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. Units of 475 ml of AB will be obtained from consenting volunteers of the Cambridge BioResource (CBR), a panel of 10,000 healthy volunteers local to Cambridge who have already consented to participate in biomedical research and of whom biological samples (DNA, plasma, serum) and lifestyle data have been deposited in a repository and database, respectively. We are requesting funding from the Human Diversity project to sequence the genomes of the 200 CBR volunteers at low pass (6x coverage). Nuclei, DNA and RNA will be recovered from the purified cells and made available for RNA-seq, DNA-seq and ChIP-seq and genomic DNA for entire genome sequencing will be recovered from the DNA repository.

  Dataset EGAD00001002205

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-Releasing Hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e., fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e., asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertain only to the 408 subjects from the GAPPS study for whom placental tissue transcriptomics was performed.

  Study phs003620

• HeartShare - Extant Datasets - Harmonized Clinical Trials Collection

  Heart failure with preserved ejection fraction (HFpEF) prevalence is rising with an aging population and contributing comorbidities, such as obesity and diabetes. The Get With The Guidelines - Heart Failure (GWTG-HF) study showed that the proportion of hospitalized HFpEF patients rose from 2005 to 2010, and this trajectory continued to increase through 2020. HFpEF patients have a poor 5-year outcome with a 75% mortality rate. Taken together, these data suggest that HFpEF may be the dominant HF subtype in the future, affecting approximately 1 in 10 adults during their lifetime.In addition to its increasing prevalence, HFpEF is a heterogeneous syndrome with multiple pathophysiological processes and varied clinical presentations. There is an urgent need to improve understanding of different HFpEF phenotypes to match patients with interventions based on their unique subtype. Phenomapping studies have identified between two and six HFpEF clusters/phenogroups with shared features. Of these, three overlapping phenotypes repeatedly arise: an 'older, vascular aging' phenotype, 'metabolic, obese' phenotype, and 'relatively younger, natriuretic peptide (NP) deficiency' phenotype. Continued refinement of these HFpEF subtypes is needed to identify distinct characteristics and underlying biologic and molecular mechanisms towards therapeutic development and future precision trials with improved diagnostic criteria and treatment including prevention.The HeartShare extant datasets collection consists of selected completed trials on HFpEF which have been harmonized for the purpose identifying and defining subtypes. The goal is to identify HFpEF subtypes that have a common pathophysiology. Through the HeartShare extant datasets collection, users can request access to both the harmonized data and the individual trial datasets.To request access to this study collection, select phs003989 in the dbGaP when submitting a data access request. The following clinical trials and harmonized data is available through this collection:Study NameHandleAccessionConsent GroupsSurgical Treatment for Ischemic Heart FailureBioLINCC_STICHphs003493.v1.p1GRUHeart Failure Network Aldosterone Targeted Neurohormonal Combined with Natriuresis TherapyBioLINCC_HFN_ATHENAphs003506.v1.p1GRUHeart Failure Network - Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal SyndromeBioLINCC_HFN_CARRESSphs003510.v1.p1GRUHeart Failure Network: Diuretic Optimization Strategies Evaluation in Acute Heart FailureBioLINCC_HFN_DOSEphs003524.v1.p1GRUHeart Failure Network - Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure PatientsBioLINCC_EXACT_HFphs003533.v1.p1GRUHeart Failure Network: Functional Impact of GLP-1 for Heart Failure TreatmentBioLINCC_HFN_FIGHTphs003542.v1.p1GRUHeart Failure Network - Nitrate's Effect on Activity Tolerance in Heart Failure with Preserved Ejection FractionBioLINCC_HFN_NEATphs003548.v1.p1GRUHeart Failure Network - Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart FailureBioLINCC_HFN_RELAXphs003565.v1.p1GRUHeart Failure Network - Renal Optimization Strategies Evaluation in Acute Heart Failure and Reliable Evaluation of DyspneaBioLINCC_HFN_ROSEphs003589.v1.p1GRUHeart Failure: A Controlled Trial Investigating Outcomes of Exercise TrainingBioLINCC_HF_ACTIONphs003599.v1.p1HMBHeart Failure: A Controlled Trial Investigating Outcomes of Exercise TrainingBioLINCC_HF_ACTIONphs003599.v1.p1HMB-NPUGuiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart FailureBioLINCC_GUIDE_ITphs003621.v1.p1GRUSudden Cardiac Death in Heart Failure TrialBioLINCC_SCD_HeFTphs003654.v1.p1GRUTreatment of Preserved Cardiac Function Heart Failure With an Aldosterone AntagonistBioLINCC_TOPCATphs003665.v1.p1HMB-MDSHeart Failure Network - Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEFBioLINCC_HFN_INDIEphs003667.v1.p1GRUStudies of Left Ventricular DysfunctionBioLINCC_SOLVDphs003668.v1.p1GRUEvaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization EffectivenessBioLINCC_ESCAPEphs003782.v1.p1GRU

  Study phs003989

• Dataset developed for use with EOSC4Cancer of synthetic colorectal cancer tumor/normal pairs.

  This dataset contains 10 tumor and normal pairs synthetic WGS data of colorectal cancer that were simulated in a standard format of Illumina paired-end reads. The NEAT read simulator (version 3.0, https://github.com/zstephens/neat-genreads) was utilized to synthetize these 10 pairs of tumor and normal WGS data. In the procedure of data generation, simulated parameters (i.e., sequencing error statistics, read fragment length distribution and GC% coverage bias) were learned from data models provided by NEAT. The average sequencing depth for tumor and normal samples aimed to reach around 110X and 60X, respectively. For generation of synthetic normal WGS data per each sample, a germline variant profile from a real patient was down-sampled randomly, representing 50% germline variants of a given patient. These were mixed with the other 50% in silico germline variants that were modelled randomly using an average mutation rate (0.001), finally constituting a full germline profile for normal synthetic WGS data. For generation of synthetic tumor WGS data per each sample, a pre-defined somatic short variant profile (SNVs+Indels) learnt from a real CRC patient was added to the germline variant profile used for creating the normal synthetic WGS data of the same patient, consisting of the variants for tumor sample. Neither copy number profile nor structural variation profile was introduced into the tumor synthetic WGS data. Tumor content and ploidy were assumed to be 100% and 2, respectively. For mapping/variant detection, the Sarek pipeline v3.1.2 (https://nf-co.re/sarek/3.1.2) was used, specifically: 1. BWA v0.7.17-r1188 for read mapping 2. GATK v4.3.0.0 for pre-processing BAM file (including markduplicates and recalibration). 2. Mutect2 (GATK v4.3.0.0) for somatic variant calling 3. Strelka2 v2.9.10 for germline and somatic variant calling Metadata information of 10 CRC patients used for the generation of synthetic normal and tumor WGS data: Patient_id Tumor_barcode Normal_barcode Age Sex Tissue Cancer SIM007 SIM007_T SIM007_N 71 F Rectal Primary CRC SIM008 SIM008_T SIM008_N 45 F Colon Neuroendocrine Metastasis CRC SIM010 SIM010_T SIM010_N 62 M Colon Metastasis CRC SIM011 SIM011_T SIM011_N 55 M Colon Neuroendocrine Metastasis CRC SIM012 SIM012_T SIM012_N 57 M Rectal Metastasis CRC SIM013 SIM013_T SIM013_N 69 M Colon Metastasis CRC SIM014 SIM014_T SIM014_N 68 M Colon Neuroendocrine primary CRC SIM015 SIM015_T SIM015_N 58 F Colon Primary CRC SIM016 SIM016_T SIM016_N 49 M Colon/Rectal Primary CRC SIM017 SIM017_T SIM017_N 78 M Colon Neuroendocrine primary CRC

  Dataset EGAD50000000564

• Sickle Cell Disease Natural History Data Resource (SCD NHDR)

  Data Access NOTE Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. BackgroundThe NHLBI initiated the Sickle Cell Disease Natural History Data Resource (SCD NHDR) to leverage existing SCD studies to build a data resource to provide phenotypic data on contemporaneous control cohorts for gene therapy trials and other studies. The potential uses of the NHDR are broad, including providing matched controls for clinical trials, observing a cohort of untreated patients as part of a natural history study, or conducting comparative effectiveness research on a subpopulation with selected co-morbidities or drug treatment profiles. The SCD NHDR includes two multi-center SCD longitudinal cohort studies with extensive annual clinical data and patient surveys, the Sickle Cell Disease Implementation Consortium (SCDIC-I and SCDIC-II) and the Globin Research Network for Data and Discovery (GRNDaD). The SCDIC-I, initiated in 2017 and concluded in June 2022, enrolled over 2400 patients with SCD from 8 US treatment centers. The SCDIC-II reconsented 1220 of the SCDIC-I patients as well as enrolling an additional 450 new patients from the same 8 centers between September 2022 and October 2023, for a total of 1670 in SCDIC-II. Only two of the many GRNDaD centers are submitting data to the SCD NHDR for deposit into BDC (approximately 122 patients). Data submissions from the SCD NHDR to BDC will be annually starting in early 2024. Description of the Study Data All data obtained for the SCD NHDR are considered common data elements (CDEs) important for studies of SCD. These CDEs were identified from several workgroups of SCD experts convened under the NHLBI's Cure-SC Initiative (https://curesickle.org/cde-catalog). The following types of data elements were abstracted from the medical record – variables that describe the SCD diagnosis, SCD co-morbidities and other clinical complications, elements from the physical examination, medications and transfusions, insurance type, laboratory measurements, healthcare utilization, history of SCD-related procedures, and measurements from cardiac procedures. The following types of data were self-reported on the patient survey – demographics, diagnosis information, pain experience, social and mental health information, other patient reported outcome domains (e.g., sleep, fatigue), and alcohol and smoking history. Standard PRO measures were used from ASCQ-Me, PROMIS and Neuro-QoL. Patient surveys were completed approximately annually. Under SCDIC-I, two medical record abstractions and labs were reported at enrollment and approximately 3 years later. Under SCDIC-II and GRNDaD, all data are collected annually. Patients may refuse to complete the survey.

  Study phs003529