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• CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Summary Results from Genomic Studies

  GWAS have successfully identified genetic loci associated with a variety of conditions such as type 2 diabetes and coronary disease. The large number of statistical tests required in GWAS has posed a special challenge because few studies that have DNA and high-quality phenotype data are sufficiently large to provide adequate statistical power for detecting small to modest effect sizes. Even before the era of GWAS, the requirement for large sample sizes and the importance of replication have served as powerful incentives for collaboration. Meta-analyses combining summary data from multiple sources have improved the ability to detect new loci. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was formed to facilitate GWAS meta-analyses and replication among multiple large and well-phenotyped cohort studies. The design of the CHARGE Consortium was formed initially from 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility (AGES) - Reykjavik Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). Additional studies have expanded the CHARGE consortium based upon the phenotypes and willingness to share information across the research community. In order to facilitate investigators across the world to examine relationships between phenotypes and genetic markers within CHARGE published reports, an open site is made available on dbGaP that provides the rsID and the p-value for inspection. Access to detailed summary statistics (including minor allele frequency, odds ratio/effect size) requires approval of a Data Access Request (DAR).

  Study phs000930

• Efficacy and Immune Effects of Anakinra Prophylaxis for Neurologic Toxicity and Cytokine Release Syndrome in Patients with Lymphoma Receiving Axicabtagene Ciloleucel

  Chimeric antigen receptor T cells have transformed the treatment of multiple hematologic malignancies, but are limited in application due to treatment-related toxicities. Cytokine release syndrome (CRS) and neurotoxicity (NT) are the primary toxicities associated with these therapies and are thought to be mediated by broad immune activation due to robust T-cell expansion. Current treatment of these toxicities utilize anti-IL-6 directed therapy and/or systemic glucocorticoids to mitigate the consequences of this complex inflammatory cascade. We sought to use anakinra, an IL-1R antagonist, as a prophylactic strategy to prevent clinically meaningful CRS/NT, defined as grade 2 or higher toxicity necessitating clinical intervention. Although our study, in line with others, demonstrated that IL-1R antagonism is insufficient to prevent such toxicities entirely, we were able to gain insight into the molecular immune signaling associated with breakthrough CRS & NT in the presence of anakinra prophylaxis using our scRNA dataset of patients treated with and without IL-1R antagonism. We demonstrate that IL-4 and IL-10 anti-inflammatory pathways in infused CAR-T products of both anakinra and non-anakinra cohorts were negatively associated with grade 2+ toxicities. We also found that expression of IFN-gamma pathways and ligand-receptor activities, as well as cytokine levels of IFN-gamma and CXCL10 in CD14+ monocytes, were significantly enriched in patients with breakthrough toxicity in the anakinra cohort. This correlated with an increase in IFN-gamma in the peripheral blood of patients with breakthrough toxicities, among other cytokines. These data identify IFN-gamma as a potential key mechanism in the development of CAR-T cell-associated toxcities and suggest that this pathway is also targetable and not inhibited by anakinra alone.

  Study phs003655

• Clonal Lineage Tracing of Primary Human Cortical Progenitors, Cell Type Profiles in the Brain Vasculature and Genotyping Data for 22q11DS and Control iPS Lines

  We sought to characterize the cell types produced by individual human cortical progenitors and describe their lineage relationships. We labeled individual human cortical cells with a massively complex lentivirus library encoding a GFP reporter gene and a molecular barcode that could be captured by standard 3' scRNA-seq methodologies. We then cultured the labeled human cells for 6 weeks in either a 1) mouse cortical astrocyte co-culture system or 2) in the mouse cortex as a xenograft. In a separate experiment, we maintained human cortical tissue slices in organotypic slice culture for 12 days. GFP+ cells were then isolated by FACS and then captured on the 10x chromium scRNA-seq platform. An additional sample was labeled by lentivirus and briefly cultured for 3 days prior to being mixed with mouse 3T3 cells in order to perform a cell mixing experiment ("barnyard") to benchmark our methodologies. We found that human individual cortical progenitors gave rise to both excitatory and inhibitory neurons as well as glia.We also sought to characterize the adult brain vasculature in both vascular malformations and non-malformed tissue. We use the 10x chromium scRNA-seq platform across 10 individuals (5 control and 5 arteriovenous malformations). We find broad disregulation across multiple cell types including the immune cells and find a specific monocyte subtype to contribute to a rupture phenotype. We also find a novel population of fibromyocytes in both conditions.Finally, we confirmed the genotype status of iPS lines that were derived from either karyotypically normal control individuals or from DiGeorge Syndrome patients carrying the 22q11.2 deletion using the Illumina Infinium Global Screening Array v3.0.

  Study phs002624

• National Emphysema Treatment Trial (NETT-BioLINCC)

  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. Available Data: The current release of the NETT study dataset includes follow-up data through May of 2013.Objectives: To compare lung-volume-reduction surgery with medical therapy for severe emphysema, and to identify participant selection criteria for lung volume reduction surgery.Background: Lung-volume-reduction surgery has been proposed as a palliative treatment for severe emphysema. Effects on mortality, the magnitude and durability of benefits, and criteria for the selection of participants have not been established.Participants: A total of 1,218 participants with severe emphysema underwent pulmonary rehabilitation and were randomly assigned at 17 centers to undergo lung-volume-reduction surgery (bilateral stapled wedge resection) or to receive continued medical treatment. Participants were randomized after a 6-10 week pulmonary rehabilitation period and participants with a forced expiratory volume in one second (FEV1) that was 20 percent or less of predicted and a homogeneous distribution of emphysema or carbon monoxide diffusing capacity 20 percent or less of predicted were not eligible for randomization due to poor post-surgery prognosis for death or functional improvement.Conclusions: Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for participants with both predominantly upper-lobe emphysema and low base-line exercise capacity. Participants previously reported to be at high risk and those with non-upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume-reduction surgery, because of increased mortality and negligible functional gain. (NEJM 2003;348:2059-2073).

  Study phs004077

• Out with the Java, in with the Python - new EGA data download client unveiled

  We will shortly be deprecating the Java-based download client also known as API V2. The Java client began its life at the back end of 2014, and during its time has seen many developments that have served our users well. During its tenure, the Java client enabled distribution of over 6.5 million files totalling nearly 15 petabytes of data to researchers around the globe. Recent increases in genomic and phenotypic data file sizes, the number of datasets archived in the EGA, the number of users downloading data, and the diversity of download locations has meant that at times the Java client struggled to distribute data efficiently. In response, our team of developers have built a new download client with more robust features and better functionality and reliability. Enter stage left our shiny new API V3.1! The new API V3.1 will replace both API V2 and API V3. The download client for the new API V3.1 is written in Python, and the code is openly available on Github. This Python client makes https calls to the EGA AAI (https://ega.ebi.ac.uk:8443/) and to the EGA Data API (https://ega.ebi.ac.uk:8052), both of which must be accessible from the client location. In addition to general updates to improve performance, the API V3.1 has three new features enhancing the EGA distributions services. First, requested data are now downloaded over secure https connections rather than http, meaning that data can be delivered unencrypted. Instead of separately requesting, downloading, and decrypting data using the Java client, data can now be requested and downloaded using a single command without the need for decrypting. The API V3.1 also automatically verifies each file’s unencrypted md5 after download to ensure the file has downloaded correctly. Second, the new API supports segmenting and automatic resuming. To enable quicker download speeds, the API breaks files into up to four segments and downloads them in parallel. With the new resume feature, downloads - both segmented and continuous stream - will automatically resume if they encounter any errors or the connection is interrupted. These features result in both a faster and more reliable download experience. Finally, the new API V3.1 implements the GA4GH-compliant htsget protocol for supporting requests over genomic ranges. This exciting new feature means that for data files with accompanying index files (e.g. .crai for CRAM files) users can download specific regions of interest rather than the entire file saving both time and storage space. The new features of the Python-based API V3.1 represent significant improvements in security, speed, reliability, and flexibility that are sure to provide a better data download experience. To take full advantage of these features, users must update to Python 3.X. Considering the changes in the data structures with the new API, the upgrade to a new version of the Python client is also mandatory. Updating the client to the latest version can be achieved by running the following command: pip3 install pyega3 -U We are excited for users to try out the new features and take advantage of the multifariously growing EGA distribution services for human biomedical omics data. If you have any questions or feedback, please email the EGA Helpdesk team. We'd love to hear from you!

  Blog new-ega-data-download-client

• Integrated Genomic, Epigenetic, and Expression Analyses of Ovarian Cancer Cell Lines

  Epithelial ovarian carcinoma of all subtypes has one of the worst outcomes of any human cancer. To improve our understanding of underlying biology and therapeutic possibilities in this disease, we performed whole genome sequencing, methylation, and expression analyses of a comprehensive set of 47 ovarian cancer cell lines representing different histologic tumor subtypes. Given the challenges of genomic analyses in tumors without matched normal samples, we developed novel approaches for detection of somatic alterations and used these to identify sequence, copy number, and rearrangement changes and integrated these with genome-wide epigenetic and expression alterations. Ovarian cancer cell lines had molecular changes in genes involved in cell cycle, PI3K, RAS, BRCA, chromatin regulating, and p53 pathways, and displayed global mutation and methylation changes similar to primary ovarian carcinoma. We identified alterations not previously implicated in ovarian cancer including amplification or overexpression of ASXL1 and H3F3B, deletion or underexpression of CDC73 and members of the TGF beta receptor pathway, including TGFBR2, SMAD3 and SMAD4, in-frame rearrangements of YAP1-MAML2 and IKZF2-ERBB4, and fusions involving MET, NF1, FBXW7 and CCND1. Integrating cell line alterations with dose-response data using three targeted therapies revealed novel molecular dependencies, including increased sensitivity of tumors with PIK3CA and PPP2R1A alterations to PI3K inhibitor GNE-493, those with MYC amplifications to PARP inhibitor BMN673, and SMAD4 alterations to MEK inhibitor MEK162. Genome-wide analyses revealed intrachromosomal rearrangements as an improved measure of sensitivity to PARP inhibition compared to the homologous recombination defect (HRD) score. This study provides a comprehensive resource of molecular information for ovarian cancer cell line models and a pharmacogenomic platform for developing rational cancer therapeutic strategies.

  Study EGAS00001002998

• Confronting historical legacies of biological anthropology in South Africa—Restitution, redress and community-centered science: The Sutherland Nine

  We describe a process of restitution of nine unethically acquired human skeletons to their families, together with attempts at redress. Between 1925–1927 C.E., the skeletonised remains of nine San or Khoekhoe people, eight of them known-in-life, were removed from their graves on the farm Kruisrivier, near Sutherland in the Northern Cape Province of South Africa. They were donated to the Anatomy Department at the University of Cape Town. This was done without the knowledge or permission of their families. The donor was a medical student who removed the remains from the labourers’ cemetery on his family farm. Nearly 100 years later, the remains are being returned to their community, accompanied by a range of community-driven interdisciplinary historical, archaeological and analytical (osteobiographic, craniofacial, ancient DNA, stable isotope) studies to document, as far as possible, their lives and deaths. The restitution process began by contacting families living in the same area with the same surnames as the deceased. The restitution and redress process prioritises the descendant families’ memories, wishes and desire to understand the situation, and learn more about their ancestors. The descendant families have described the process as helping them to reconnect with their ancestors. A richer appreciation of their ancestors’ lives, gained in part from scientific analyses, culminating with reburial, is hoped to aid the descendant families and wider community in [re-]connecting with their heritage and culture, and contribute to restorative justice, reconciliation and healing while confronting a traumatic historical moment. While these nine individuals were exhumed as specimens, they will be reburied as people.

  Study EGAS50000000971

• The University of Hong Kong Gastric Cancer Organoids RHO Signaling Study

  Objective: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. Design: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix, or both, to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA, and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. Results: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to 3 public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to re-sensitization to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype, and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. Conclusions: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

  Study EGAS00001006252

• Intra-tumor heterogeneity and clonal evolution patterns towards platinum-resistant high-grade serous ovarian cancer

  Although many high-grade serous ovarian carcinoma (HGSOC) patients are initially sensitive to the standard-of-care platinum-based therapy, intra-tumor heterogeneity may fuel selection towards platinum-resistant clones over subsequent lines of therapy. We performed whole-exome coupled to ultra-deep re-sequencing and copy number alteration (CNA) profiling on 31 matched diagnosis and relapse tumors from HGSOC patients treated with platinum. Genetic heterogeneity within tumor pairs varied extremely, with some recurrent tumors being identical and others completely different from the primary tumor. All primary tumors showed evidence of homologous recombination (HR)-deficiency, but none of them carried reactivating mutations in the HR pathway at relapse, also not when becoming resistant to subsequent lines of platinum. We did also not identify other mutations, CNAs or pathways that were enriched in platinum-resistant clones. However, a platinum score consisting of 13 CNAs correlated significantly with platinum-free interval (PFI) after first-line therapy in multiple cohorts of >450 primary HGSOCs. A relative increase of this score in the relapsed tumor correlated with a change in PFI during subsequent therapy. Clonal evolution under platinum therapy contributes to genetic heterogeneity within tumor pairs, implicating that genetic tests linked to targeted treatment options for recurrent HGSOC need to be performed on biopsies collected at relapse. Platinum resistance of an initially platinum-sensitive HR-deficient HGSOC at relapse is not caused by reactivation of the HR pathway, suggesting that these tumors are still responsive to PARP inhibitors, instead, several chromosomal aberrations contribute to a score predictive of disease outcome under platinum therapy, both in first and subsequent lines of platinum therapy.

  Study EGAS00001001244

• Altered oligodendrocyte heterogeneity in Multiple sclerosis revealed by single nuclei RNA sequencing

  This study is currently hosted by the European Nucleotide Archive. To access the data contained within the Study please follow the link below: https://www.ebi.ac.uk/ena/browser/view/PRJEB39323 Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes to disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these cell states. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. We found a lack of OL precursor cells (OPCs) and an OL subcluster in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new putative markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

  Study EGAS00001003412

• Post_Mortem_Tissue_COVID19_RNA

  Single cell analysis of post mortem tissue samples from SARS-CoV2-infected patients We aim to directly identify the human cell types infected by SARS-CoV-2 and measure the cellular response to COVID19 infection across 20 different tissues from infected patient autopsies. We have examined the expression pattern of viral entry receptors across healthy human tissues to predict several candidate target cell types across the airway and heart. In addition, high prevalence of cardiac failure and abnormal renal function in COVID19 patients implicates heart and kidney involvement, but the pathogenesis of organ specific damage - whether via a direct cytopathic mechanism or an indirect inflammatory response - remains unknown . Currently, we lack confirmation of target cell types and cellular processes in infected tissues as autopsies are discouraged in most countries due to health and safety risks. Our collaborators Drs Michael Osborn and Brian Hanley (Imperial College) have outlined guidelines to perform post-mortem in COVID19 patients (Hanley et al., 2020) and have established a programme of autopsies for research to be performed in a high-risk facility at Westminster Public Mortuary. Here, we propose to identify infected cell types and aberrant molecular pathologies in this precious tissue resource using single cell and spatial genomics. We will prioritise three organ systems: the human airway, heart and the kidney. We will directly examine the cellular identities of SARS-CoV-2 infected cell types and identify the cellular responses to infection across these organs. This fundamental knowledge will help guide future treatment choices for COVID19. 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/

  Study EGAS00001004442

• Post_Mortem_Tissue_COVID19_spatial

  Single cell analysis of post mortem tissue samples from SARS-CoV2-infected patients We aim to directly identify the human cell types infected by SARS-CoV-2 and measure the cellular response to COVID19 infection across 20 different tissues from infected patient autopsies. We have examined the expression pattern of viral entry receptors across healthy human tissues to predict several candidate target cell types across the airway and heart. In addition, high prevalence of cardiac failure and abnormal renal function in COVID19 patients implicates heart and kidney involvement, but the pathogenesis of organ specific damage - whether via a direct cytopathic mechanism or an indirect inflammatory response - remains unknown . Currently, we lack confirmation of target cell types and cellular processes in infected tissues as autopsies are discouraged in most countries due to health and safety risks. Our collaborators Drs Michael Osborn and Brian Hanley (Imperial College) have outlined guidelines to perform post-mortem in COVID19 patients (Hanley et al., 2020) and have established a programme of autopsies for research to be performed in a high-risk facility at Westminster Public Mortuary. Here, we propose to identify infected cell types and aberrant molecular pathologies in this precious tissue resource using single cell and spatial genomics. We will prioritise three organ systems: the human airway, heart and the kidney. We will directly examine the cellular identities of SARS-CoV-2 infected cell types and identify the cellular responses to infection across these organs. This fundamental knowledge will help guide future treatment choices for COVID19. 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/

  Study EGAS00001004441

• NHLBI TOPMed: The Jackson Heart Study (JHS)

  Since there is a greater prevalence of cardiovascular disease among African Americans, the purpose of the Jackson Heart Study (JHS) is to explore the reasons for this disparity and to uncover new approaches to reduce it. The JHS is a large, community-based, observational study whose 5306 participants were recruited from among the non-institutionalized African-American adults from urban and rural areas of the three counties (Hinds, Madison, and Rankin) that make up the Jackson, MS, metropolitan statistical area (MSA). Jackson is the capital of Mississippi, the state with the largest percentage (36.3%) of African Americans in the United States. The JHS design included participants from the Jackson ARIC study who had originally been recruited through random selection from a drivers' license registry. Approximately six months before the JHS was to begin, an amendment to the federal Driver's Privacy Protection Act was passed that changed the level of consent for public release of personal information from driver's license lists from an "opt out" to an "opt in" basis. The Mississippi Highway Patrol was no longer able to release a complete listing of all persons with driver's licenses or state identification cards, which prevented its use in the JHS. New JHS participants were chosen randomly from the Accudata America commercial listing, which provides householder name, address, zip code, phone number (if available), age group in decades, and family components. The Accudata list was deemed to provide the most complete count of households for individuals aged 55 years and older in the Jackson MSA. A structured volunteer sample was also included in which demographic cells for recruitment were designed to mirror the eligible population. Enrollment was opened to volunteers who met census-derived age, sex, and socioeconomic status (SES) eligibility criteria for the Jackson MSA. In addition, a family component was included in the JHS. The sampling frame for the family study was a participant in any one of the ARlC, random, or volunteer samples whose family size met eligibility requirements. Eligibility included having at least two full siblings and four first degree relatives (parents, siblings, children over the age of 21) who lived in the Jackson MSA and who were willing to participate in the study. No upper age limit was placed on the family sample. Known contact information was obtained during the baseline clinic examination from the index family member with a verbal pedigree format to identify name(s), age(s), address (es), and telephone number(s). Recruitment was limited to persons 35-84 years old except in the family cohort, where those 21 years old and above were eligible. Only persons who otherwise met study criteria but were deemed to be physically or mentally incompetent by trained recruiters were excluded from study eligibility.1 1 Wyatt SB, Diekelmann N, Henderson F, Andrew ME, Billingsley G, Felder SH et al. A community-driven model of research participation: the Jackson Heart Study Participant Recruitment and Retention Study. Ethn Dis 2003; 13(4):438-455 (PMID: 14632263).

  Study phs000964

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE)

  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 pertains only to the 794 subjects from the CANDLE study for whom placental tissue transcriptomics was performed.

  Study phs003619

• Lipid Research Clinics - Prevalence Study (LRC-PS-BioLINCC)

  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. Objectives: The LRC Program began in 1971 under the sponsorship of the National Heart, Lung, and Blood Institute, National Institutes of Health. Part of this program was the Lipid Research Clinics Prevalence Study, a standardized series of cross-sectional surveys of various North American populations designed to determine the prevalence of dyslipidemias and to describe the distributions of lipids and lipoproteins in major ethnic and social groups. In addition to contributing to the aggregate analysis, each independent population-based study was designed with capabilities for separate analyses of lipid and lipoprotein distributions. The participating populations were not selected to be a probability sample representative of the North American population per se, but by virtue of their size and economic and geographical diversity, they provide a useful cross-sectional group. The Family Study was the third phase of the Lipids Research Clinics North American Population Studies. The Family Study was designed to obtain knowledge of the distribution of lipids and lipoproteins among family members and of the association of familial and genetic attributes to dyslipoproteinemias. Background: An association between serum cholesterol and coronary heart disease is well established. A system was developed for classifying hyperlipoproteinemias into six types of patterns, as a basis for characterizing lipoprotein disorders. The Lipid Research Clinics was thus created to improve the detection of and clinical management of hyperlipoproteinemias. The three primary objectives were: 1) to acquire data on the prevalence of different types of hyperlipoproteinemia in various age and ethnic groups, with special emphasis on the nature and frequency of genetic forms; 2) to collect reliable data on the prevalence and incidence of atherosclerosis in different types of hyperlipoproteinemia; and 3) to conduct an intervention trial to determine if lowering plasma lipid levels would reduce the risk of CHD. Participants: There were 60,495 participants. Conclusions: Data from this study confirm findings from earlier studies in developed countries, showing age-related differences in plasma lipid levels. However, for overall distributions, the LRC data showed slightly lower cholesterol and markedly higher trigylceride values than those previously reported for North America. Some variation in plasma lipid values was evident among the clinic populations. The large number of participants within most subgroups permitted a variety of analytic and comparative studies. For example, data from the large pediatric population revealed a drop in plasma cholesterol levels in adolescent males and females. Males aged 20-50 years had higher cholesterol levels than females in the same age group, and higher trigylceride levels between ages 20-70 years. Numbers were also significient for meaningful comparisons between lipid distributions of females who were taking sex hormones and those who were not; in females taking sex hormones, cholesterol and triglyceride levels were higher for subjects younger than 45 years, but slightly lower after age 45, than lipid levels in females not taking hormones (Circulation 1979; 60(2):427-439).

  Study phs003995

• Landscape of Somatic Mutations in B Lymphocytes Across Human Lifespan

  The accumulation of spontaneous mutations in somatic cells has been implicated as a cause of aging since 1950. Yet, attempts to establish a causal relationship between somatic mutations and aging have been constrained by the lack of methods to directly identify mutational events in primary human tissues. Using a highly accurate single-cell whole-genome sequencing method, we analyzed human B lymphocytes from donors varying in age from birth to over 100 years, studying both genome distribution and functional impact of base substitution mutations.

  Study phs001808

• Characterizing Disease-Causing Variants Using Personal Genomes with Large Recurrent Deletions

  Individuals with recurrent genomic deletions are known to present variable clinical phenotypes, despite the apparent identical range of the genomic segments being affected in their genomes. We propose to study the phenotypic variability and the molecular polymorphism in individuals with the recurrent 17q12 deletions or the recurrent 1q21.1 deletions, with the objective to establish causal relationship between the genotypes and the incompletely penetrant clinical phenotypes. Genome sequencing and phenotypic data from individuals with the deletions and their relatives are included in this submission.

  Study phs002613

• Immune Profiling in Patients with High-Risk Smoldering Myeloma

  Single-cell RNA-sequencing identifies immune biomarkers of response to immunotherapy in patients with high-risk Smoldering Multiple Myeloma (SMM). We conducted a Phase II trial of the immunotherapeutic anti-SLAMF7 antibody, Elotuzumab, in combination with Lenalidomide and Dexamethasone (E-PRISM study), to determine the utility and safety of early immunotherapy in patients with high-risk SMM and develop biomarkers for optimal patient selection and monitoring of response to treatment.There is an overlap in subjects between this study and dbGaP accession phs001323.

  Study phs002476

• Disease Severity in Familial Dysautonomia

  Familial Dysautonomia (FD) is a developmental and degenerative genetic disease that manifests in the neural crest cells and peripheral nervous system (PNS). Despite all FD patients having the same mutation in IKBKAP, patients present with varying disease severity, ranging from mild to severe. We used the human pluripotent stem cell technology to recapitulate this varying disease severity in the dish. Further, we found that severe, but not mild patients harbor mutations in candidate modifier genes that may contribute to severe disease presentation.

  Study phs001233

• Bladder Chemotherapy Responders

  Cisplatin-based chemotherapy is the standard of care for patients with muscle invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, and some patients with metastatic disease achieve complete responses to these therapies. However, the molecular determinants of cisplatin response are incompletely understood. We performed whole exome sequencing on tumor and germline DNA from patients with muscle invasive or metastatic urothelial carcinoma who received cisplatin-based chemotherapy to identify somatic mutations that occurred preferentially in cisplatin responders.

  Study phs000771

• Pulmonary Fibrosis and Telomerase Dysfunction

  This study was used to perform an exome-limited analysis of whole genome sequencing data of patients with idiopathic pulmonary fibrosis (IPF) or familial pulmonary fibrosis. Case cohorts were derived from local centers at University of Southwestern or Columbia University, and subjects were from the IPFnet cohort of clinical trial. Rare damaging mutations in the coding regions of cases were compared to healthy controls, and gene burden analysis was performed to identify enrichment of novel risk genes in the development of pulmonary fibrosis. 

  Study phs002692

• Whole exome sequencing and methylation profiling of uveal melanoma

  Uveal melanoma (UM) is the most common primary cancer of the eye and frequently leads to metastatic death. Metastatic risk can be stratified into low, intermediate and high based on the presence of mutually exclusive mutations in EIF1AX, SF3B1 and BAP1, respectively. The purpose of this study was to comprehensively profile the genetic aberrations in a set of primary uveal melanomas using whole exome sequencing, as well as DNA methylation profiling of selected samples, to improve understanding of its pathogenesis.

  Study phs001421

• Genetic Effects on miRNA Expression During Mid-Gestation Neocortical Development

  In this study we aimed to find common genetic variants that influence miRNA expression during mid-gestation neocortical development. Small RNA-sequencing from 212 fetal cortical tissue samples between 14 and 21 weeks gestation were used to profile miRNA expression. Combined with donor genotypes, we were able to find miRNA-eQTLs during neocortical development. The dataset provided here includes 212 Small RNA-sequencing files in FASTQ format from cortical wall samples. Also provided here are 212 donor genotypes in PLINK format (hg19).

  Study phs003106

• Genetics of Cerebral Hemorrhage with Anticoagulation (GOCHA)

  This is a prospective, longitudinal cohort study of spontaneous ICH. Subjects were recruited from among consecutive patients ≥ 55 years old who presented with primary hemorrhage to the Massachusetts General Hospital or one of our off-site collaborators from 1999 to 2010. Potential subjects were identified by screening lists of all admissions to the neurology and neurosurgery inpatient services. All patients underwent routine clinical evaluation, including history taking and physical examination, laboratory testing, and computed tomography of the brain.

  Study phs000416

• Genomics and Modification of Pain: A peripheral component identified using iPSCs with the S241T mutation

  We have capitalized on inherited erythromelalgia (IEM) as a well-characterized genetic model of chronic pain, and studied IEM patients carrying Nav1.7 mutations which affect channel activation and often produce hyperexcitability of DRG neurons. Whole exome sequencing was used to discover multiple gene variants that might contribute to neuronal excitability and that might serve as modifiers of sensory neuron firing, and identified the Kv7.2 channel as a contributor to differences in pain profiles between individuals.

  Study phs001724

• Germline genome-wide association studies in women receiving neoadjuvant chemotherapy with or without bevacizumab on NSABP B-40

  Neoadjuvant chemotherapy (NAC) for breast cancer is widely employed. We performed genome-wide association studies (GWAS) to determine if germline genetic variability was associated with benefits, in terms of pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS), in patients entered on the NSABP B-40 NAC (National Surgical Adjuvant Breast and Bowel Project, B-40, Neoadjuvant Chemotherapy) trial where some patients were randomized to receive bevacizumab, in addition to chemotherapy.

  Study phs001365

• Center for Common Disease Genomics (CCDG)-Cardiovascular: University of Pennsylvania Cohort

  The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases. This study of early onset cardiovascular disease and metabolic risk contains data derived from the whole genome sequence data of individuals participating in Penn Medicine's BioBank.

  Study phs001502

• CCG Multicentric Italian Lung Detection (MILD)

  For the CCG-MILD project, NCI will utilize whole genome sequencing and/or whole exome sequencing in conjunction with transcriptome sequencing to try to identify recurrent genetic alterations (mutations, deletions, amplifications, rearrangements) and/or gene expression signatures that would be important to the hypothesis(es) submitted by the investigators. The samples will be processed and submitted for genomic characterization using the established NCI Genome Characterization Pipeline. Subsequent genomic and clinical data will be hosted at the NCI Genomic Data Commons (GDC).

  Study phs002253

• High-throughput determination of the antigen specificities of T cell receptors in single cells

  High-throughput linking of T cell receptor (TCR) sequences to their binding antigens is vital for immune profiling, yet challenging. We present Tetramer associated TCR Sequencing (TetTCR-Seq) to address this challenge. Binding is determined using a library of DNA-barcoded antigen tetramers that are rapidly and inexpensively generated using an in vitro transcription/translation platform. We included CMV+ donors (CMV seropositive donors who are infected with Cytomegalovirus) to screen for CMV specific TCRs.

  Study phs001678

• Longitudinal Assessment of Methylmercury and Gut Microbes During Pregnancy

  Methylmercury is a potent neurotoxin, and the fetal period is the most vulnerable exposure period. There is significant variability in methylmercury metabolism, which has been attributed to differences in the structure and function of the gut microbiome. Our main objective was to better understand the interplay between gut microorganisms and methylmercury metabolism during pregnancy. To address this aim, associations were investigated between maternal biomarkers (blood, hair, stool) for prenatal methylmercury exposure and maternal gut microbiota during early and late gestation.

  Study phs001768

• Kids First: Whole Genome Sequencing Studies of Multiplex Nonsyndromic Cleft Lip/Palate Families

  Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect that affects approximately 135,000 newborns worldwide, and imposes significant medical, psychosocial and financial burdens to affected individuals and their families. Genetic variation in numerous genes has been associated with NSCLP, however the exact mechanisms by which they contribute to the condition remain largely unknown. Here, we will use whole genome sequencing and robust analytical approaches to systematically evaluate the causes of NSCLP in 923 individuals from large multigenerational families.

  Study phs002626

• Transcriptome and epigenomic landscape of cytotrophoblasts from normal and HDP placentas

  Hypertensive isorders of pregnancy (HDP) is a severe pregnancy-related disorder that poses significant risks to both maternal and fetal health. Dysfunctional placental development is one of the major contributors to the onset of HDP. In this study, we investigated the gene expression and epigenomic modifications in cytotrophoblasts from normal and HDP placentas. The information obtained in this study contributes to the growing body of knowledge aimed at improving the diagnosis, management, and treatment of HDP.

  Study JGAS000667

• genetic analysis of carcinogenesis in GAPPS

  Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal dominant syndrome characterized by polyposis localized in the gastric body and fundus with a strong tendency for adenocarcinoma. The genetic mutations that accumulate during the progression from normal mucosa through fundic gland polyps (FGPs) to carcinoma in GAPPS remain unclear.We investigated the evolutionary process from normal mucosa to FGPs and carcinoma in GAPPS. Through comprehensive mutational and transcriptome analyses, we aimed to provide insights into the biology of this disease.

  Study JGAS000843

• Filtered variants including SLC12A2 in patients with hearing loss

  Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss.

  Study JGAS000379

• Comprehensive molecular profiling of pulmonary pleomorphic carcinoma

  Information regarding the molecular features of pulmonary pleomorphic carcinoma (PPC) is insufficient. Here, we performed next-generation sequencing to determine the genomic and transcriptomic profiles of PPC. Whole exome sequencing (WES) of fresh-frozen tissue samples and target-capture sequencing of formalin-fixed-paraffin-embedded (FFPE) samples were performed. Fresh-frozen tissue samples and FFPE samples were subjected to WES and target-capture sequencing as normal control, respectively. Fresh-frozen tissue samples and 56 FFPE samples were subjected to RNA-seq.

  Study JGAS000297

• Mutational Spectrums and Clinical Features of Patients with LOXHD1 Variants Identified in a 8,074 Hearing Loss Patient Cohort.

  Variants of LOXHD1 gene, which are expressed in hair cells of the cochlea and vestibule, have been reported to cause a progressive form of autosomal recessive non-syndromic hereditary hearing loss, DFNB77. In this study, genetic screening was conducted on 8,074 Japanese hearing loss patients utilizing the massively parallel DNA sequencing, to identify individuals with LOXHD1 variants and to assess their phenotypes. 28 affected individuals and 21 LOXHD1 variants were identified, among which 13 were novel variants.

  Study JGAS000192

• Longitudinal Transcriptomic Profiling of Endothelial Progenitor Cells in Post-COVID-19 Patients: Insights at 3 and 6-Months Post-SARS-CoV-2 Infection

  Bulk RNA-sequencing analysis of endothelial cells isolated from post-COVID patients at 3 and 6 months post-infection, alongside healthy controls. This study aims to identify differentially expressed genes in endothelial cells from post-COVID patients—at both 3- and 6-month time points—compared to those from healthy individuals. The objective is to uncover upregulated and downregulated pathways potentially associated with long-term consequences of SARS-CoV-2 infection.

  Study EGAS50000000993

• cfDNAme allows early prediction of PE

  Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis to prevent PE, it is essential that pregnancies at risk of PE are identified early, in the first trimester. To identify patients at risk, we profiled methylomes of plasma-derived cell-free DNA (cfDNA) from pregnant women. We detected DNA methylation differences between control and PE pregnancies that enable risk stratification of patients, at PE diagnosis but also presymptomatically, around 12 weeks of gestation.

  Study EGAS00001007071

• Whole_genome_sequence_of__third_generation_family_member__SFHS_

  Previously we performed deep WGS on 6 parents and 13 children from 3 large families from the Scottish Family Health Study to identify de novo mutations. This prelim is cover the additional sequencing of one grandchild from one of these three families. The inclusion of a third generation individual will provide additional experimental validation for the de novo mutations found in the initial trio. As in the previous study, the DNA will be WGS to a depth of approximately 25X to achieve this purpose.

  Study EGAS00001000429

• AML_targeted_resequencing_study

  Genomic libraries will be generated from whole genome amplified genomic DNA derived from 3,000 myeloid neoplasms. Targeted capture will be performed by multiplexing 16 barcoded samples in each library. Pools of 96 DNA samples will be subjected to 1-2 lanes of HiSeq 75bp sequencing. Reads will be mapped to the current build of the human reference genome to facilitate the generation of a comprehensive catalog of somatic mutations associated with 116 known myeloid and cancer driver genes.

  Study EGAS00001000275

• Variability in immune response genes and prediction of severe SARS-CoV-2 infection (INMUNGEN-Cov2 project)

  Genetic factors may contribute to explain the variable clinical response to SARS-CoV-2 infection. To this end we sequenced the DNA of 392 COVID-19 patients from Spain. Whole Exome Sequencing (WES) was performed at two different sequencing centers. Half of the samples were sequenced at a commercial service, NIMGenetics, whereas the other half were sequenced by the EASI-Genomics consortium. Finally, Variant Call Format (VCF) files for each sample was also obtained.

  Study EGAS50000000066

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Cancer_Mastectomy__Exome_

  Sequencing of LCM-derived microbiopsies from 30 women who underwent mastectomies due to a breast cancer diagnosis. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Exome data will be used as a driver and clonality screen, highly clonal or driver-containing samples will subsequently be sent for whole-genome sequencing. Results from this portion of the study will be compared to women who had cosmetic breast reduction surgeries and those with germline BRCA 1/2 mutations.

  Study EGAS00001003319

• Comprehensive single-cell genome analysis at nucleotide resolution using the PTA Analysis Toolbox

  We developed a comprehensive bioinformatic workflow, called the PTA Analysis Toolbox (PTATO), to accurately detect single base substitutions, insertions-deletions (indels) and structural variants in PTA-based WGS data. PTATO includes a machine learning approach and filtering based on recurrency to distinguish PTA-artefacts from true mutations with high sensitivity (up to 90%), outperforming existing bioinformatic approaches. Our results show that PTATO enables studying somatic mutagenesis in the genomes of single cells with unprecedented sensitivity and accuracy.

  Study EGAS00001007288

• Investigation of different library preparation and tissue of origin deconvolution methods for urine and plasma cfDNA methylome analysis

  In this study, a single- and a double-stranded library preparation approach was evaluated with respect to their technical biases when applied on cfDNA from plasma and urine. This study thus outlines potential limitations of double-stranded library preparation for methylation analysis of cfDNA especially for urinary cfDNA. While the double-stranded method allows jagged end analysis in addition to TOO analysis, it leads to significant methylation bias in urinary cfDNA, which single-stranded methods can overcome.

  Study EGAS00001007314

• Exome_Sequencing__to_Identify_Causes_of_Leukaemia_Predisposing_Congenital_Neutropenias

  The objective of this study is to identify the causative genes in two unrelated congenital neutropenia families. We aim to whole exome sequence the affected individuals, unaffected siblings and parents in both cases in an effort to idenitfy the causative genetic mutation. Exome capture will be performed using Agilent SureSelect system. Subsequently, exome libraries will sequenced using the Illumina HiSeq platform. Sequence variant calling will be done in house and common variants excluded using public databases and data from unaffected family members.

  Study EGAS00001000100

• Efficacy of asciminib in acute lymphoblastic leukaemia (ALL) patient derived NUP214::ABL1 xenografts.

  Study to assess the activity of the STAMP inhibitor asciminib against NUP214::ABL1 acute lymphoblastic leukaemia (ALL). mRNA-sequencing was performed on ALL patient samples to identify the NUP214::ABL1 gene fusion, determine the genomic breakpoint of the fusion and identify co-occurring mutations. Patient-derived xenografts (PDX) were established from three ALL patients (one T-cell ALL and two B-cell ALL) with NUP214::ABL1 disease and used to assess asciminib activity in vivo.

  Study EGAS50000000957

• CARE idiopathic subglottic stenosis bulk transcriptomics.

  Idiopathic subglottic stenosis (iSGS) is a severe chronic orphan disease characterised by recurrent scarring of the subglottis, predominantly affecting Caucasian females in their fourth to sixth decade of life. Due to its rarity, understanding the clinical trajectory and molecular factors involved in iSGS disease development and prognosis has been challenging. In this study, we prospectively enrolled patients with iSGS, trauma-induced subglottic stenosis, and controls to investigate the clinical, transcriptional, and genetic features that may be associated with disease pathogenesis and treatment outcomes.

  Study EGAS50000000879

• Targeted sequencing of brain expressed miRNA genes

  As regulators of gene expression, microRNAs (miRNAs) are likely to play an important role in the development of disease. In this study we present a large-scale strategy to identify miRNAs with a role in the regulation of neuronal processes by screening 289 brain expressed miRNAs. Thereby we found variant rs7861254 located near the MIR204 gene to be significantly associated with schizophrenia. This variant resulted in reduced expression of miR-204 in neuronal-like SH-SY5Y cells.

  Study EGAS00001001607

• Effects of interferon-gamma treatment on human small intestinal organoids generated from healthy donors

  The intestine is vulnerable to interferon-gamma as intestinal epithelial stem cells undergo cell death when exposed to interferon-gamma. Here, we developed a novel human intestinal organoid-based 3D model system to study the effects of interferon-gamma-induced intestinal epithelial damage at the RNA level. We treated organoids with 10 ng/mL for either 6 or 18h. Knowledge generated with this dataset is relevant for a variaty of intestinal pathologies with an immune component, for instance graft-versus-host disease.

  Study EGAS50000000083

• Whole Exome Sequencing of Waldenström Macroglobulinemia (WM) Precursor Conditions

  In this study we aimed to comprehensively characterize the genomic landscape of WM precursor conditions and identify potential biomarkers of progression to symptomatic WM by means of Whole Exome Sequencing (WES) of CD19-selected samples from 139 patients, primarily with IgM-MGUS and asymptomatic WM. Overall, our study shows that genomic profiling of patients’ tumor at the time of aWM diagnosis might represent an improved strategy for identifying patients at high risk to progression who could benefit from earlier intervention.

  Study EGAS50000001249