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• Organoid drug profiling identifies methotrexate as a therapy for SCCOHT, a rare pediatric cancer

  Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal tumor in adolescent and young adult patients. Currently, there is no standard-of-care treatment for these patients. Reliable models that represent this disease and can be used for translational research are scarce. To model SCCOHTs, we have established eight patient-derived tumoroid lines from tumor lesions of three patients with SCCOHT. The tumoroids recapitulate genomic and transcriptomic characteristics of the corresponding patient tumors and capture intrapatient tumor heterogeneity. Organoid drug profiling using a library of 153 clinical compounds identified methotrexate as an effective and selective drug against SCCOHTs with a clinically relevant IC50 of 35 nmol/L. RNA sequencing demonstrated that methotrexate induced TP53 pathway activation and apoptosis. These data underscore that organoid technology can support the design of therapeutic strategies for rare cancers.

  Study EGAS00001007911

• High-depth whole genome sequencing of 51 premalignant breast lesions

  Ductal carcinoma in situ (DCIS) is a non-obligate precursor lesion of breast cancer, representing 20-25% of newly diagnosed breast cancer lesions. It is currently not possible to predict which DCIS patients will progress to invasive breast cancer. The samples deposited here are part of a larger study using high-depth whole-genome sequencing (WGS) to investigate the somatic mutation genomic landscape of DCIS. Comprehensive evaluation of DCIS genomes aims to uncover biological insights into breast cancer progression and potential opportunities to stratify DCIS patients for personalised treatment options or active surveillance.

  Study EGAS50000001436

• Genomics of Kidney Transplantation

  We have an established consortium consisting of 5 clinical centers which do a total of >800 kidney transplants/year. We have developed a quality-controlled multicenter database with high quality data, and obtained DNA samples and clinical data on 962 recipients and 442 donors. Using our developed infrastructure, we propose to study whether genetic variants are, in part, responsible for the differing outcomes of transplant recipients treated with contemporary immunosuppressive protocols. Our central hypotheses are that the genetic variation is associated with a) kidney transplant outcome, and b) immunosuppressive drug disposition and toxicity. Our long-term goals are to determine whether it is possible to individualize immunosuppressive therapy, based on genetics. At the same time, our studies may elicit new information on pathways important in the immune response or in immunosuppressive drug efficacy, disposition, and toxicity.Our application consists of 3 cores (Genetics Core, Clinical Core, and Administrative Core). We will do a genome wide association study (GWAS). Significant single nucleotide polymorphisms (SNPs) will be identified using the GWAS.Project 1 has 2 specific aims.Aim 1: To identify recipient SNPs that are associated with kidney allograft outcomes, including acute rejection, chronic graft dysfunction, and graft failure. Aim 2: To identify living donor SNPs that are associated with kidney allograft outcomes. Project 2 has 4 specific aims. Aim 1: To identify SNPs that are associated with tacrolimus blood levels.Aim 2: To identify SNPs that are associated with early tacrolimus-related nephrotoxicity and immune suppressant-related new onset diabetes.Aim 3: To identify SNPs that are associated with mycophenolate-related toxicity. Aim 4: To establish the relationships between candidate recipient SNPs, enzyme activity and mRNA expression of the pharmacologic targets of mycophenolate and calcineurin inhibitors. The projects use the genotyping data, which were provided by the Genetics Core, and clinical information, which were collected and entered into the multicenter database by the Clinical Core. Further, biostatistical support (Clinical Core) and administrative oversight and support (Administrative Core) will facilitate data collection, data entry, and data analyses for both projects. The Administrative Core will also facilitate interaction between Sites, Cores, and Projects.Technical note: Regarding to the study design, all transplant recipients should be unrelated. Given the nature of transplantation, some donors may be related to recipients. The donor-recipient relationships are reported in the demographic file under the "related" column. As we did not collect full pedigree information for the related donor-recipient pairs, we have included a IBD file (calculated using PLINK) with the genotype data.

  Study phs001667

• A panel of reference haplotypes for imputing complement component 4 (C4) gene structural variation

  Neuropsychiatric and autoimmune disorders have substantial epidemiological correlations (Benros et al., JAMA Psychiatry 2013, PMID: 23760347) and broad, genome-wide patterns of shared genetic risk (Pouget et al., Hum Mol Genet, PMID: 31211845; Tylee et al., Am J Med Genet B Neuropsychiatr Genet 2018, PMID: 30325587). Some cases of psychosis involve autoantibodies against the NMDA receptor, AMPA receptor, or other synaptic proteins (reviewed in Dalmau et al, Lancet Neurol 2011, PMID: 21163445). The related autoimmune conditions lupus and Sjogren's Syndrome also involve the development of autoantibodies. The possibility that neuropsychiatric disorders can have molecular mechanisms in common with autoimmune disorders - for example, that psychosis involves an inflammatory or autoimmune component in some patients, or that immune molecules are re-used in the brain to underlie other important biological activities (Stevens et al., Cell 2007, PMID: 18083105) - could open novel therapeutic possibilities for neuropsychiatric disorders. At a genetic level, the strongest genetic associations of schizophrenia, lupus, and Sjogren's Syndrome to common genetic variation involve associations to genetic markers in the Major Histocompatibility Complex (MHC) locus. Bipolar disorder in some studies also associates with variation in or near the MHC locus, though less strongly than schizophrenia does. Intriguingly, the same specific SNPs appear to associate strongly with schizophrenia, lupus, and Sjogren's; these strongly associating SNPs span a genomic segment that includes the HLA class II genes (which have an important role in antibody production) and the complement component 4 (C4) genes. The specific genes and alleles responsible for these associations need to be completely defined, and the extent to which they represent shared or distinct genetic influences in neuropsychiatric and autoimmune illnesses needs to be clarified. The complement component 4 (C4A and C4B) genes are present in the MHC locus, between the class I and class II HLA genes. C4A and C4B commonly vary in genomic copy number and encode complement proteins with distinct affinities for molecular targets. The complex genetic variation at C4 - arising from many alleles with different numbers of C4A and C4B genes - has been challenging to analyze in large cohorts. We recently developed an approach to this problem based on imputation: people share long haplotypes with the same combinations of SNP and C4 alleles, such that C4A and C4B gene copy numbers can be imputed from SNP data (Sekar et al., Nature 2016, PMID: 26814963). In the current work, to analyze C4 in large cohorts, we developed a way to identify C4 alleles from whole-genome sequence (WGS) data, then analyzed WGS data from 1,234 individuals to create a large multi-ancestry panel of 2,530 reference haplotypes of MHC SNPs and C4 alleles that can then be imputed into still-larger cohorts for which SNP data are available. With this dbGaP submission, we make this reference panel available for other studies. Protocols and software for imputing C4 alleles into genome-wide SNP data, and for performing molecular analyses on the C4 genes (such as direct measurement of copy number from genomic DNA), can be found on the McCarroll Lab web site (http://mccarrolllab.org/resources). We are also working to create additional reference panels for imputation of C4 alleles that will be based on still-larger and more diverse population samples; links to these will also be available on the McCarroll Lab web site as we create and validate them.

  Study phs001992

• Center for Common Disease Genomics [CCDG] - Cardiovascular: SWISS-AF/SWISS-AF-PVI/BEAT-AF

  This study is a part of NHGRI's Centers for Common Disease Genomics (CCDG), which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation (AF), congestive heart failure and type 2 diabetes. AF will affect between 6-12 million individuals in the US by 2050. AF is also associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules. Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdf Three collections were brought together to form Swiss atrial fibrillation cases: SWISS-AF, SWISS-AF-PVI, and BEAT-AF. SWISS-AF is a prospective observational, multicentric cohort study in Switzerland to increase our knowledge on structural brain damage and its changes over time in patients with atrial fibrillation. Overall, 2400 patients with documented atrial fibrillation aged >65 years will be included and followed on a yearly basis. SWISS-AF-PVI is a registry of patients with atrial fibrillation undergoing catheter-based ablation of atrial fibrillation (pulmonary vein isolation) to determine long-term success rates of catheter-based ablation of atrial fibrillation (pulmonary vein isolation) and to evaluate factors associated with long-term success of catheter-based ablation of atrial fibrillation (pulmonary vein isolation). BEAT-AF is a prospective observational, multicenter cohort study in Switzerland. Overall, 1550 patients with documented atrial fibrillation were enrolled in seven study centers. The main aim of this study is to investigate the therapy and the medical consequences of patients with atrial fibrillation. Samples from all three collections were sent to The Broad Institute of MIT and Harvard to generate genetic data using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all cases with atrial fibrillation.

  Study phs002242

• Myelodysplastic cells in patients re-program mesenchymal stromal cells to establish a transplantable stem cell-niche disease unit.

  Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms with defects in hematopoietic stem/progenitor cells (HSPCs) and possibly the HSPC niche. Here we show that patient-derived mesenchymal stromal cells (MDS MSCs) display a disturbed differentiation program and are essential for the propagation of MDS-initiating lin-CD34+CD38- stem cells in orthotopic xenografts. Overproduction of niche factors such as N-Cadherin, IGFBP2, VEGFA and LIF is associated with the ability of MDS MSCs to enhance MDS expansion. These factors represent putative therapeutic targets to disrupt critical hematopoietic-stromal interactions in MDS. Finally, healthy MSCs adopt "MDS-MSC like" molecular features when exposed to hematopoietic MDS cells, indicative of an instructive remodeling of their microenvironment. This patient-derived xenograft model therefore provides functional and molecular evidence that MDS is a complex disease involving both the hematopoietic and stromal compartments. The resulting deregulated expression of niche factors may well also be a feature of other hematopoietic malignancies.

  Study EGAS00001000716

• Spit for Science

  Spit for Science™ is a university-wide research opportunity with the scientific goal of understanding how genetic and environmental factors come together to influence substance use and emotional health across the college years and beyond. To address this goal, we have comprehensively and longitudinally studied eligible incoming freshmen (18 years or older) from a diverse urban university, assessing a wide range of risk and protective factors, including both biological susceptibility and environmental risk, and a variety of outcome measures, particularly alcohol use and other substances, and difficulties with emotional health. Our goal is to assess how risk and protective factors dynamically interact to contribute to behavior health outcomes over time and plan to use findings from the project to inform prevention and intervention efforts and aid in university policy and programming in ways that can support and promote student success. Methods: In the fall of their freshman year, first-time college students over the age of 18 are invited to complete an online survey containing broad questions about personality and behavior, as well as family, friends, and experiences growing up. Students can also provide a saliva sample and participate in the DNA component of the project (participation in the DNA component is not a requirement for participation in the survey). Each subsequent spring students are asked to complete a follow-up survey, enabling researchers to study patterns of substance use and emotional health across the college years.

  Study phs001754

• Longitudinal Study of Immune Mediated Disorders After Allogenic Hematopoietic Cell Transplantation (HCT)

  Allogeneic hematopoietic cell transplantation (HCT) is the only known curative option for many hematologic disorders. After transplantation, many patients develop immune mediated disorders that may be life-threatening. Post-HCT immune mediated disorders are rare relative to other diseases but the prototype of graft versus host disease (GVHD) develops in 30-70% of patients. The morbidity and mortality associated with these HCT-associated immune mediated disorders are major barriers to successful use of transplantation to cure rare hematologic malignancies such as leukemia, lymphoma, multiple myeloma, myelodysplastic/myeloproliferative syndromes amongst other diseases. The purpose of this study is to characterize and more completely define the onset and course of immune mediated disorders after allogeneic HCT, focusing on participants who develop cutaneous sclerosis, bronchiolitis obliterans syndrome (BOS), late acute graft-vs.-host disease (GVHD), and chronic GVHD. Of the participants undergoing allogeneic hematopoietic cell transplantation (HCT), can we, the researchers better identify who will develop immune-mediated disorders, what types of disorders participants will have, and whether these disorders will be severe or respond to currently available therapies? This is a longitudinal study of 1118 individuals (1081 adults and 100 children). Those participating in this study will be evaluated over a 3 year period at 9 study sites. Participants will be enrolled pre-transplant, or up to day 121 post transplantation. This wide enrollment window will allow sites to use recruitment methods that are most efficient at their institutions. At least 2 years of follow-up will ensure an adequate sample size, and sufficient time for observation of the full spectrum of immune mediated disorders. The data of 1023 individuals have been submitted to dbGaP.

  Study phs001331

• Using human induced pluripotent stem cells (iPSC) and iPSC-derived neurons to explore cellular phenotypes associated with schizophrenia.

  Schizophrenia and major mental illness are common devastating conditions. Whilst partially effective treatments are available, none are disease-modifying. Notwithstanding important insights provided by animal models there is a need for novel models of mental illness to develop more effective therapies. A study of sporadic schizophrenia-derived human induced pluripotent stem cells (hiPS) has demonstrated a neuronal phenotype representing a powerful proof of concept of in vitro disease modeling, even for diseases with complex causation such as schizophrenia. These techniques have been used here to examine the behaviour of neural stem cells and neurons derived from fibroblasts from subjects carrying NDE1 copy number variations (CNVs) associated with increased risk of major mental illness. Using hiPS from individuals with and without disease-associated CNVs we have investigated how disease risk is conferred at a cellular and molecular level through detailed comparative studies of neural progenitor proliferation, neuronal morphology, physiology, cytoskeletal organization, synaptic function, glutamate (NMDA) receptor expression and also RNA sequencing and proteomic studies of these patient-derived cells.

  Study EGAS00001002895

• Somatic point mutation data from microsatellite unstable colorectal cancers

  Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI CRCs, however, also contain more point mutations than microsatellite stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome sequenced sporadic MSI CRCs and respective normals, and 12 whole genome sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs.

  Study EGAS00001003101

• Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma

  Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast-cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow-cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose-deprived conditions. Increased fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7-related metabolic pathways is a viable therapeutic strategy.

  Study EGAS00001003251

• Targeted sequencing of head and neck squamous cell carcinomas

  Overall survival remains very poor for patients diagnosed with head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcome. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immune-deficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC we demonstrate that rapid engraftment into immune-compromised mice is highly prognostic, and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, CCND1 and CDKN2A genomic alterations are predictive of response to the CDK4/6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4/6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients, and demonstrates the potential of using PDX models to identify novel targeted therapies for those patients who have the poorest outcomes.

  Study EGAS00001002979

• Mapping genetic variants that underlie gene regulation in intestinal cell types to identify novel, validated, Crohn’s disease drug targets

  Biopsies from the terminal ileum and rectum of healthy individuals and terminal ileum and blood from Crohns disease patients are collected and processed single cells and processed for single-cell RNA-sequencing using 10X Genomics 3' v3 and v3.1 and Illumina sequencing. 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 EGAS00001003647

• A study of the genetic basis of evation by Acute Myeloid Leukaemia of Graft vs Leukaemia effects after allogeneic bone marrow transplantation

  Acute myeloid leukaemia (AML) is an aggressive and molecularly diverse disease with a poor overall survival of 20-25%. With an annual incidence of 2.9 per 100,000, AML is currently the commonest myeloid malignancy in Europe, yet the two main therapeutic options for this disease, anthracyclines and purine analogues, have remained unchanged for over 20 years. Currently patients are stratified at diagnosis according to a series of clinicopathological parameters (e.g. age, white cell count and presence/absence of previous clonal haematological disease) and molecular markers (e.g. chromosomal translocations/deletions, aneuploidy and mutations in genes such as FLT3 and NPM1). Patients with adverse prognostic features, whose prognosis is particularly poor (e.g. <15% long-term survival) are offered treatment with allogeneic bone marrow transplantation (allo-BMT) if a sibling or unrelated donor is available. This can significantly improve survival (e.g. up to 40% long-term survival in some contexts), albeit at the expense of significant toxicity and transplant-related mortality (TRM). Allo-BMT is thought to work in part by allowing the delivery of large doses of chemotherapy followed by haemopoietic "rescue" with donor haemopoietic stem cells (haemopoietic failure would otherwise ensue). However, potentially the most potent effect of allo-BMT is the cytotoxic effect of donor lymphocytes against AML blasts, a phenomenon known as graft-vs-leukaemia (GVL) effect. Increasingly, transplants using reduced chemotherapy intensity (mini-allografts) are being used that partially circumvent the toxicity from chemotherapy and rely on GVL to effect cure. Nevertheless, AML relapse after allo-BMT still occurs at a significant rate of up to 80% depending on the type of transplant. There is accumulating evidence that genetic events in residual leukaemic cells enable them to evade immunodetection and therefore survive the GVL effect and expand to cause relapse. The most striking example of this is the loss of HLA antigens after transplants in which donor and recipient are not fully HLA-matched. In these cases, the leukaemia "deletes" the genomic region containing the disparate HLA antigen which was preferentially targeted as "foreign" by the GVL effect. However, the genetic basis of immune evasion in the majority of transplants, which are fully HLA matched, is not known. One possibility is that loss of genes coding for antigens outside the HLA locus but which are also targets of GVL may operate, alternatively genetic events that affect processes downstream of immunological cytotoxicity may be responsible. The identification of genetic events that mediate immune evasion would not only facilitate the understanding of this process but can help plan therapeutic interventions that improve the outcomes of allogeneic transplantation for AML and other disorders. We intend to study this by conducting exome sequencing on 6 cases of AMLs from patients that attend my clinic at Addenbrooke's hospital and have relapsed after allogeneic transplantation. Samples from AML diagnosis, remission/normal and AML relapse (total n=18) will be studied to identify somatic mutations in the primary AML and those acquired by the relapsed clone. The 18 samples will also be studied by array CGH to detect regions of genomic amplification or deletion.

  Dataset EGAD00001000404

• PEACE melanoma 14

  Understanding the evolutionary pathways to metastasis and resistance to immune checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here we present the most comprehensive intra-patient metastatic melanoma dataset assembled to date as part of the PEACE research autopsy programme, including exome, panel-sequenced, RNA-seq, and single-cell whole-genome sequencing samples from 14 ICI-treated patients. The main goals of the project are to decipher the evolutionary dynamics of melanoma metastases and to elucidate mechnisms of resistance to therapies.

  Study EGAS00001007081

• Resuscitation Outcomes Consortium Trial of Continuous Compressions Versus Standard CPR in Patients With out-of-Hospital Cardiac Arrest (ROC CCC-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: To compare the rate of survival to hospital discharge after continuous chest compressions versus standard American Heart Association recommended cardiopulmonary resuscitation with interrupted chest compressions in patients with out-of-hospital cardiac arrest.Background: Standard cardiopulmonary resuscitation (CPR) consists of manual chest compressions to maintain blood flow and positive-pressure ventilation to maintain oxygenation until spontaneous circulation is restored. Chest compressions during standard CPR are interrupted frequently by ventilations. These interruptions reduce blood flow and potentially reduce the effectiveness of CPR. In animals with cardiac arrest, the interruption of chest compressions has been associated with decreased survival. Observational studies involving humans with out-of-hospital cardiac arrest of presumed cardiac cause have suggested that continuous compressions are associated with higher rates of survival than interrupted compressions.Participants: Of 35,904 patients with out-of-hospital cardiac arrest who were screened, 26,148 were eligible for participation in the trial and were enrolled in the trial during either the run-in phase or the active-enrollment phase. The active-enrollment phase included 23,711 patients, of whom 12,653 were assigned to the intervention group and 11,058 to the control group.Design: There were 114 participating EMS agencies across the eight participating Resuscitation Outcomes Consortium (ROC) sites, which were grouped into 47 clusters. Clusters of agencies were randomly assigned, in a 1:1 ratio, to perform continuous chest compressions or interrupted chest compressions during all the out-of-hospital cardiac arrests to which they responded. Each cluster was required to begin enrolling patients in a run-in phase to demonstrate adherence to the protocol before entering the active-enrollment phase of the trial. Twice per year, each cluster was crossed over to the other resuscitation strategy.Patients assigned to the group that received continuous chest compressions (intervention group) were to receive continuous chest compressions at a rate of 100 compressions per minute, with asynchronous positive-pressure ventilations delivered at a rate of 10 ventilations per minute. Patients assigned to the group that received interrupted chest compressions (control group) were to receive compressions that were interrupted for ventilations at a ratio of 30 compressions to two ventilations; ventilations were to be given with positive pressure during a pause in compressions of less than 5 seconds in duration. The primary outcome was the rate of survival to hospital discharge. Secondary outcomes included neurologic function at discharge, which was measured with the use of the modified Rankin scale, and adverse events. Conclusions: During the active-enrollment phase, 1129 of 12,613 patients in the continuous chest compression group and 1072 of 11,035 patients in the interrupted chest compressions group survived to hospital discharge.In patients with out-of-hospital cardiac arrest, continuous chest compressions during CPR performed by EMS providers did not result in significantly higher rates of survival or favorable neurologic function than did interrupted chest compressions.

  Study phs003901

• Demographically Diverse Substance Use Disorder Cohorts of Dr. Stanley H. Weiss

  The Demographically Diverse Substance Use Disorder Cohorts of Dr. Stanley H. Weiss, which constitute the Epidemiology of the Weiss Cohort Projects, consist of a series of inter-connected projects, building upon a set of cohort projects of various groups, mainly drug users from medication-assisted treatment programs, that Dr. Stanley H. Weiss first developed in the 1980’s plus several newer initiatives, each with an array of collaborators. Beginning in the 1980’s, Dr. Stanley H. Weiss started several long-term studies of persons who inject drugs (PWID) across the United States, ultimately enrolling over 10,000 participants through the early 1990’s with an average age then in their 30’s. About a quarter were enrolled from sites in New Jersey (NJ). These studies included the first testing of PWID for the human immunodeficiency virus (HIV) and the human T-cell lymphotropic viruses (HTLV I and HTLV II). Cumulative past support (initiation thru ~ 1999) for these cohort studies included ~ $20 million from intramural resources from the National Cancer Institute (NCI) and the National Institute on Drug Abuse (NIDA), plus multiple grants and in-kind support from the New Jersey Department of Health (NJDOH) totaling ~ $1 million. The Weiss Cohort Projects include the first large AIDS-era cohorts to include women at high risk for HIV. A high percentage of subjects in these studies are black or Latino. Thus, this is an ethnically diverse US cohort, with a high proportion of women included. These subjects are at high risk of parenteral and sexual infection from both drug use and sexual practices. Samples from other studies conducted by Dr. Weiss, in which detailed interviews were conducted, are included as controls (persons documented by us not to have a history of opioid drug use). As one of our groups of subjects have many persons of Haitian ancestry, we specifically included some Haitians who had never used opioids as controls. Our documentation includes such ancestry. These cohorts demonstrated high rates of HIV and HTLV-II infection in PWIDs, including one study initiated in 1981 with confirmation in the later cohorts. In the first two decades of these studies, among numerous publications was the first study showing a very high rate of hepatitis C infection among PWIDs. An example of how the studies’ long-time horizon proved essential was that it first became possible to test whether a person had ever been infected with hepatitis C virus (HCV), as well as how much HCV was in each person’s blood, many years after the specimens were collected. This allowed HCV amounts in blood to be compared for subjects who had died of liver disease early in the study versus those who survived. Then a sequence of published papers culminated in demonstrating, using a nested case-control design, that a high baseline HCV titer was predictive of early progression to death from end-stage liver failure. Outcomes related to HCV (end stage liver disease and hepatocellular carcinoma) remain under study. In the original cohort studies, the mean age at enrollment was ~ 33 years old, so that those still alive in 2022 are mainly now ~ 60 - 75 years old. Many participants have already died. The tincture of time has led to subjects reaching ages when many more are dying from a wide array of outcomes, including from many chronic diseases (including cancer) as well as from infectious agents (especially HIV, HCV) or drug overdose. Renewed collaboration with local drug treatment programs has led to new field-based studies, including examination of some currently evolving problems among drug users. Dr. Weiss joined the National Institute on Drug Abuse (NIDA) Genetics Consortium (NGC) in 2017, and through the NIDA project officer has had access to NGC contract resources (see below). NIH Certificate of Confidentiality, CC-DA-16-214 (attached) protects these studies. Past arrangements related to data on our subjects leads to restrictions on the use of data emanating from our study, such as potential commercialization and restrictions on whom may access and use these data. NIDA Genetics Consortium (NGC) resources further support these endeavors and will be used as part of the NGC analyses studying the genetics of substance use. Study participants signed informed consent for the information collected from them to be used with no time limit and for biologic specimens collected from them to be used without restriction in future research. Serum samples were collected from participants, and from many also plasma, white blood cells and/or urine samples. About 100,000 vials were stored. All specimens have been continuously preserved at sufficiently cold temperatures to prevent deterioration, and many subjects separated white blood cells were processed and frozen in such a way as to maintain viability. Detailed data from the participants has been accumulated over time, and in general, linkage has been retained in each sub-study in accordance with the consent forms and protocols. For some participants, specimens were collected at multiple times (that is, sequential specimens). Multiple specimens from a single person exist in this database, and efforts at de-duplication remain ongoing. Dr. Weiss should be contacted if an investigator requires unique individuals since: • Multiple phases of enrollment occurred, and as our prospective follow-up continues; Dr. Weiss may identify new instances of multiple enrollment. • Some persons are related to each other. • In general, in this dataset for dbGaP, only a single specimen/record form a given person is included. Advances in laboratory testing techniques now permit innovative new uses for our linked research biospecimen repository. The ongoing focus of an interdisciplinary research program based on these cohorts relates subjects’ diseases, behaviors, medical history, and outcomes with biological and exposure markers. Participants’ use of various substances was ascertained on study enrollments, many serially over time. Quantitative frequency of use data, also sometimes sequential over time, were ascertained. Active ascertainment of outcomes is being conducted, including matching to mortality and cancer databases. Investigators interested in collaborations on specific outcomes (which is not part of this dbGaP dataset) or in the use of our stored specimens are encouraged to contact the principal investigator, Dr. Weiss. The processing of the genomic data was done in conjunction with NIDA, and in accordance with some longstanding data cleaning steps used by NIDA in the NIDA Genetics Consortium (NGC), a group to which we shall be contributing these data for collaborative analyses. Since there is the potential for these steps to introduce certain types of potential biases, we summarize these here. Under contract from NIDA, cryopreserved sera or plasma (-80 C) or cells (in liquid nitrogen) were used, with most stored having been stored for 30 to 40 years in our biorepository. In the case of serum or plasma, in which only (largely) cell-free DNA fragments were available, DNA was extracted and restored prior to amplification. Industry standard DNA amplification techniques were done on all samples prior to genotyping in accord with established protocols of the NIDA Genetics Consortium. Our genotype data were run and processed on the Illumina Infinium OmniExpress_v_1.3 array. This array has 714,238 SNPs, and was designed many years ago. There were 628 SNPs on the array that do not correspond to any chromosome position, and these were removed. Genotype data were submitted by NIDA’s contracted genotyping laboratory in six batches over time to NIDA’s contracted dbGaP data management group, which conducted quality control (QC) analyses. QC analysis included an assessment of batch effects on for five of the six batches. (One of the batches, with only 12 samples, was too small for QC analysis of batch effects.) Standard NIDA Genetic Consortium cleaning was performed. Samples with a call rate <.85 were removed. Only one sample per person was retained. When more than one specimen was genotyped from one subject, only the sample with the higher call rate was retained (provided, of course, that that call rate was ≥ 0.85). We have retained some people we know are related, including some found to have been related through genotyping; the pedigree file describes those relationships. In summary, key cleaning steps include: 1. Using PLINK to check gender discrepancy. 2. Using PREST-PLUS and KING (Kinship-based Inference for GWAS) to check relatedness. 3. Using PEDCHECK and PLINK to check/zero-out Mendelian error. 4. Using PLINK to perform sample QC, SNP QC, along with KING to perform chromosome X and chromosome Y QC. 5. SNP-QC: Batch-effect: 5 Batches were compared (one batch, with few samples, was not). These five batches were compared to each other in all ten possible pairs, one batch vs. another batch, examining SNP allele frequency discrepancies by population (from GRAF), Fisher Exact Allelic test, with the criterion of p<5e-8 for removal. 6. SNP-QC: discordant SNPs in QC duplicates. Compared 25 QC duplicated samples with call rate > 0.95, removed SNPs with 3+ discordance. 7. There were 1,056 SNPs that were monomorphic; these have been retained so they can be included in analyses in which our dbGaP data are combined with those from other cohorts (in the latter of which those SNPs may not be monomorphic). The final cleaned dataset submitted has 8,898 samples and 606,793 SNPs.

  Study phs002140

• TARGET-seq+ single-cell transcriptome sequencing

  Single-cell whole transcriptome sequencing data for bone marrow samples from 9 cases with clonal hematopoiesis and 4 control samples. The TARGET-seq+ protocol was used to generate plate-based 3' transcriptome data. For details on cell sorting and the TARGET-seq+ protocol see the methods section of the manuscript. One FASTQ file is provided per cell. Cells are named with their plate and well IDs and the subject ID. Empty wells (no-cell controls) are named "blank". Corresponding genotyping files use the same naming without the "_transcriptome" suffix.

  Dataset EGAD00001011175

• RNA-seq of atypical 3q26 samples

  RNA was isolated using phenol-chloroform extraction followed by DNase digestion or using the Qiagen Allprep DNA/RNA kit and protocol (Qiagen, #80204). cDNA synthesis was done using the SuperScript II Reverse Transcriptase kit (Invitrogen). Quantitative real-time PCR was performed by using primers as described previously13,21 on the 7500 Fast Real-time PCR System (Applied Biosystems). Relative levels of gene expression were calculated using the ΔΔCt method

  Dataset EGAD00001006106

• The Finland-United States Investigation of NIDDM Genetics (FUSION) Study

  The Finland-United States Investigation of NIDDM Genetics (FUSION) study is a long-term effort to identify genetic variants that predispose to type 2 diabetes (T2D) or that impact the variability of T2D-related quantitative traits. The initial effort involved linkage analysis of affected-sibling-pair (ASP) families based on over 5,000 individuals living in Finland, and association fine mapping based on these family members and additional T2D cases and controls. Recently we completed a genome-wide association scan on 1161 T2D cases and 1174 normal glucose tolerant (NGT) controls. Individual-level data is available here for the 919 T2D cases and 787 NGT controls who reconsented to the use of their data or are deceased. Version 3 adds individual-level data for additional phenotypic variables.

  Study phs000100

• Peripheral blood DNA transcriptomics of ustekinumab treatment response in patients with Crohn's disease

  Data pertains longitudinal transcriptomic data measured from blood obtained from patients with Crohn's disease that were starting treatment with ustekinumab. Samples were obtained prior to treatment and approximately 26 weeks into treatment during response assessment. At response assessment, patients were classified as responders (R) or non-responders (NR) based on a strict combination of endoscopic, biochemical and clinical criteria: ≥50% reduction in the endoscopic SES-CD score, corticosteroid-free clinical remission (≥3 point drop98 in HBI or HBI ≤4 and no systemic steroids) and/or biochemical response (C-reactive protein (CRP) and fecal calprotectin reduction ≥50% or ≤5 mg/L and fecal calprotectin ≤250 µg/g). Modified response was defined as a combination of corticosteroid-free clinical- (HBI ≤4) and biochemical (CRP ≤5 mg/L and/or fecal calprotectin ≤250 µg/g) remission between week 26-52 without treatment change through week 52. Transcriptomic analyses was conducted through RNA sequencing, wherein mRNA was extracted utilizing the QIAsymphony system, converted into cDNA and sequenced in a paired-end format on the Illumina NovaSeq6000 at the Amsterdam UMC Core Facility Genomics, generating a dataset comprising 40 million 150 bp-reads.

  Dataset EGAD50000000386

• Peripheral blood DNA transcriptomics of vedolizumab treatment response in patients with Crohn's disease

  Data pertains longitudinal transcriptomic data measured from blood obtained from patients with Crohn's disease that were starting treatment with vedolizumab. Samples were obtained prior to treatment and approximately 26 weeks into treatment during response assessment. At response assessment, patients were classified as responders (R) or non-responders (NR) based on a strict combination of endoscopic, biochemical and clinical criteria: ≥50% reduction in the endoscopic SES-CD score, corticosteroid-free clinical remission (≥3 point drop98 in HBI or HBI ≤4 and no systemic steroids) and/or biochemical response (C-reactive protein (CRP) and fecal calprotectin reduction ≥50% or ≤5 mg/L and fecal calprotectin ≤250 µg/g). Modified response was defined as a combination of corticosteroid-free clinical- (HBI ≤4) and biochemical (CRP ≤5 mg/L and/or fecal calprotectin ≤250 µg/g) remission between week 26-52 without treatment change through week 52. Transcriptomic analyses was conducted through RNA sequencing, wherein mRNA was extracted utilizing the QIAsymphony system, converted into cDNA and sequenced in a paired-end format on the Illumina NovaSeq6000 at the Amsterdam UMC Core Facility Genomics, generating a dataset comprising 40 million 150 bp-reads.

  Dataset EGAD50000000385

• Genetics and Functional Studies of Autosomal Recessive Neurological Disorders

  Neurological conditions account for over 6% of the global disease burden. There are more than 600 neurological disorders, and cognitive dysfunction, also referred to as intellectual disability (ID), occupies a prominent position in this list. Cognitive dysfunction arises from the failure of neuronal cells to organize into a complex network and remodel this network in response to learning and experience. It is manifested by deficits in adaptive behaviors in everyday social and practical skills. Due to its high prevalence and the lifetime cost of care per individual, in the range of $1-2 million in United Sates (CDC), it presents a significant health burden. Genetic and functional studies of the genes and protein determinants of ID have helped to elucidate the molecular pathways of human brain development in health and disease. However, the identity of a large number of essential molecular and cellular components still remain elusive. The objectives of our study are to expand the genetic repertoire of causal ID genes and characterize their role in neuronal structure and cognitive function. The rationale is that identification and functional elucidation of causative gene variants that lead to cognitive dysfunction will be essential for understanding brain function and for developing improved diagnostic tools and efficacious preventive and therapeutic agents for neurological disorders, including ID. There are 3 aims of our comprehensive research program: 1) Ascertain and clinically phenotype members of extended families segregating autosomal recessive intellectual disability (ARID); 2) identify new ARID genes and gene products; and 3) determine the functions of prioritized novel ARID genes using multifaceted approaches, including analysis of spatiotemporal expression patterns in mouse brain, targeting in cultured rat hippocampal neurons, effects on cell morphology and synapse abundance, synaptic transmission and plasticity in neuronal cells by electrophysiology and live-cell imaging assays. The project will advantageously combine human clinical assessment, genetic and functional analyses relevant to brain development and function. Impact: Execution of the proposed studies will generate new knowledge that is clinically relevant, with high potential to impact ID molecular diagnosis, prognoses, and identify novel therapeutic targets to slow progression, delay onset, and possibly devising precision medicine approaches for ID.

  Study phs003298

• DHODH is a synthetic-lethal vulnerability in BCOR-deficient acute myeloid leukemia

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co- repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

  Study EGAS50000001060

• DHODH is a synthetic-lethal vulnerability in BCOR-deficient acute myeloid leukemia

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co- repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

  Study EGAS50000001108