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• The Chinese University of Hong Kong Hereditary Spastic Paraplegia Data

  The dataset contains the whole genome sequencing data of a family with two unaffected parents and two probands that showed Hereditary spastic paraplegias symptoms. Sequencing reads were aligned to human genome (GRCh38) using BWA-MEM, followed by indel-realignment and PCR-duplicates marking. Alignment results are available for download in BAM format.

  Dataset EGAD00001002146

• ERDERA WES reanalysis - DPF1 Batch 6

  This dataset comprises processed genomic data from 682 samples, corresponding to 682 whole-exome sequencing experiments. Data files include CRAM, gVCF (containing short variants, copy number variants, and structural variants), RoH (BED), B-allele frequencies (BW), and variant IGV visualizations (XML). Associated phenotypic and pedigree information for all samples is also included.

  Dataset EGAD50000002464

• Resuscitation Outcomes Consortium (ROC) Amiodarone, Lidocaine or Neither for Out-Of-Hospital Cardiac Arrest Due to Ventricular Fibrillation or Ventricular Tachycardia (ALPS)(ROC-ALPS-BioLINCC)

  Accessing Data Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Objective To compare the effects of amiodarone, lidocaine, and placebo on survival to hospital discharge after out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. Background Ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) are common causes of out-of-hospital cardiac arrest, but are considered the most responsive to shock and therefore the most treatable. Nonetheless, most defibrillation attempts do not result in sustained return of spontaneous circulation, and VF or VT may persist or recur after shock. There is also evidence that longer durations of VF or VT are associated with decreases in the likelihood of resuscitation. Amiodarone and lidocaine are commonly used to promote successful defibrillation of shock-refractory VF or VT and prevent recurrences. Previous trials have shown amiodarone to be more effective than placebo or lidocaine for return of spontaneous circulation and survival at hospital admittance. This study sought to further extend the research and examine whether amiodarone would improve survival to hospital discharge and neurologic outcomes, as compared to placebo or lidocaine. Participants 3,026 eligible participants were enrolled, with 974 assigned to amiodarone, 993 assigned to lidocaine, and 1,059 assigned to placebo. An additional 1,627 participants that received a study intervention, but did not meet eligibility criteria, were included in analysis of the intention-to-treat population. Design The study interventions (amiodarone, lidocaine, and saline) were packaged in indistinguishable sealed kits and randomly distributed in to Emergency Medical Services (EMS) providers in a 1:1:1 ratio, stratified by participating site and agency. Each kit contained three syringes, and each syringe held 3 ml of colorless fluid containing 150 mg of amiodarone, 60 mg of lidocaine, or normal saline. Participants with out-of-hospital cardiac arrest were treated in accordance with local EMS protocols, in compliance with American Heart Association (AHA) guidelines. If VF or VT persisted or recurred after one or more shocks, eligible participants received a vasopressor and the masked kit containing amiodarone, lidocaine, or placebo. Approximating current clinical practice, the initial dose consisted of two syringes administered by rapid bolus. If the estimated body weight of the patient was less than 100 lbs., then one syringe was used. If VF or VT persisted, standard resuscitation measures, additional shocks, and an additional syringe of the study drug were administered. At that point the trial interventions were completed and standard interventions for advanced life support were employed. Upon arrival at the hospital, providers were notified of the patient's enrollment in the trial and encouraged to provide usual care in accordance with AHA guidelines, including open-label amiodarone or lidocaine if necessary. Components of hospital care were monitored but not standardized by the trial protocol. Participants, providers, and trial personnel were blinded to the trial drug assignments, with the exception of treating physicians if emergency un-blinding was required for care. Data from pre-hospital patient care records, CPR process measures, and hospital medical records were collected. The primary outcome of the trial was survival to hospital discharge, and the secondary outcome was survival with favorable neurologic status at discharge, defined as a score on the modified Rankin scale of 3 or less. Conclusions Neither amiodarone nor lidocaine resulted in a significantly higher rate of survival to hospital discharge or favorable neurologic outcome, as compared to placebo, among participants with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

  Study phs003784

• National Cancer Institute (NCI) Adding Hispanics to Ongoing GWAS in Colorectal Cancer

  Genome-wide association studies (GWAS) of colorectal cancer (CRC) have been instrumental in identifying a number of common susceptibility loci in Non Hispanic (NH)-White populations, and a NCI priority is to extend GWAS findings to other populations to address racial/ethnic disparities in cancer susceptibility. Currently, GWA studies of CRC in NH-Whites, Japanese and African-Americans are ongoing. We propose a complementary study to address this critical research area in Hispanics. Hispanics represent the fastest growing ethnic population in the U.S. and have been largely understudied in terms of genetic susceptibility to cancer. There are noted differences in incidence, survival and mortality in CRC by ethnic/racial groups. Hispanics often present with CRC at a younger age and have a significantly greater incidence of stage IV tumors or metastatic disease compared to NH-Whites. We propose to conduct a large, cost-efficient, population-based GWAS in Hispanics by building upon existing NIH-funded resources, the Colon Cancer Family Registry (Colon CFR) and the Multiethnic Cohort Study (MEC). We plan to recruit 2,500 Hispanic men and women diagnosed with CRC between 01/2008 to present using cancer registries in California, physican referrals and familial referrals. Risk factor/diet questionnaires, pathology reports, Oragene saliva samples (for genotyping), optional blood samples (for genotyping and biometric analysis) and tumor blocks (for MSI testing) will be collected using methodologies developed in the Colon CFR/MEC. Cases of CRC in the MEC (currently 473; anticipated 600 at end) will also be included. Population-based Hispanic individuals without a diagnosis of CRC participating in other GWA studies in the MEC (n=3,900, U01HG004726, Haiman) will be used as controls. We will genotype all 3,100 cases using the Illumina 1M array and use available genotype and epidemiologic data collected on 3,900 controls. Our statistical analyses will include: single-SNP and haplotype effects, gene-environment interactions and heterogeneity by MSI, tumor subtype and family history of CRC. We will replicate findings in a second-stage using CRC cases and controls from Mexico (1,000 cases and 1,000 controls, EU FP7 funding, CHIBCHA, Carvajal-Carmona/Tomlinson). We will also examine heterogeneity of the risk estimates by ethnicity/race by leveraging GWA data on NH-Whites (2,142 cases, 1,909 controls, U01 CA122839, Casey), (4,000 cases, 6,000 NH-White controls, UK-CHIBCHA, Tomlinson), Colombians (2,000 cases and 2,000 controls, CHIBCHA), Japanese (1,000 cases and 1,000 controls) and African-Americans (1,500 cases and 1,500 controls, R01CA126895, Le Marchand). We will genotype replicated significant SNPs in our main and combined analysis in several Hispanic populations (note: studies funded by EU or NIH for data collection but not GWAS), including 800 Puerto Ricans, 2,000 Brazilians, 2,000 Argentineans and 3,000 Spanish/Portuguese, to assess generalizability of findings. We will examine the differences in inflammatory gene transcription dynamics in leukocytes (from blood sample collection) by fatigue level (as assessed from study questionnaire data). This study will have a high impact by addressing the key question of racial/ethnic disparities related to genetic susceptibility to CRC, will provide translational guidelines on biological mechanisms during the cancer survivorship period to increase quality of life among cancer survivors, and will enable further growth and investment into research among Hispanics by providing a resource of genetic data and biospecimens, which is lacking.

  Study phs001193

• Genome-Wide Analysis of Diffuse Large B-Cell Lymphoma (De Novo and Derived from the High Grade Transformation of Follicular Lymphoma)

  Version 1. Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of the de novo diagnoses and also arising as a frequent clinical evolution of Follicular Lymphoma (FL). The molecular pathogenesis of DLBCL is associated with multiple genetic lesions that in part distinctly segregate with individual phenotypic subtypes, suggesting the involvement of distinct oncogenic pathways. However, the lesions identified so far likely represent only a fraction of those necessary for malignant transformation. In order to characterize the entire set of structural alterations present in the DLBCL genome, we have integrated next generation whole exome sequencing analysis of 6 DLBCL cases and genome-wide high-density SNP array analysis of 72 DLBCL cases. We report here that FL and DLBCL harbor frequent structural alterations inactivating CREBBP and, more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signaling pathways. Overall, ~37% of DLBCL and 36% of FL cases display genomic deletions and/or somatic point mutations that remove or inactivate the HAT coding domain of these two genes. These lesions commonly affect a single allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in the acetylation-mediated inactivation of the BCL6 oncoprotein and activation of the p53 tumor suppressor. These results identify CREBBP/EP300 mutations as a major pathogenic mechanism shared by common forms of B-NHL, and have direct implications for the use of drugs targeting acetylation/deacetylation mechanisms. Version 2. Follicular lymphoma (FL) is an indolent, but incurable disease that, in 30-40% of cases, undergoes transformation to an aggressive diffuse large B cell lymphoma (DLBCL). The history of clonal evolution and the mechanisms that underlie transformation to DLBCL (tFL) remain largely unknown. Using whole exome sequencing and copy number analysis of 39 tFL patients, including 12 with paired sequential FL/tFL biopsies, we show that, in most cases, FL and tFL arise by divergent evolution from a common mutated precursor cell through the acquisition of distinct genetic lesions. Mutations in epigenetic modifiers (e.g., MLL2, CREBBP, EZH2, ARID1A) and anti-apoptotic genes (BCL2, FAS) were observed in 93% (36/39) and 78% (30/39) of cases, respectively, and were invariably shared between the two disease phases, suggesting an early acquisition in the common mutated precursor. Conversely, the development of tFL is associated with deregulation of genes involved in the control of cell proliferation, cell cycle progression and DNA damage responses (CDKN2A/2B, MYC, TP53), as well as with an aberrant activity of the somatic hypermutation mechanism. Finally, we show that the genomic profile of tFL shares significant similarities with that of germinal center B-cell type de novo DLBCL, but also displays unique combinations of altered genes that may explain the dismal clinical course of tFL.Version 3. This version includes thirty-five additional de novo DLBCL samples, newly diagnosed, and their paired normal DNA from previously untreated patients, which were analyzed by whole exome sequencing (n=27T and 25N), whole genome sequencing (8T and 10N), and/or targeted HLA-next generation sequencing (n=26T/N pairs) in order to identify genetic alterations associated with loss of surface MHC-II expression.

  Study phs000328

• Adipose Tissue Omics In Obesity

  This project used a multi-omics approach to study the adipose tissue transcriptome in humans with and without obesity. Our human cohort included males and females between the ages of 18-80 who underwent elective abdominal surgery at the University of Michigan and the Ann Arbor Veterans Affairs Healthcare System.Patients with advanced cancer or immuncompromised status were excluded. Visceral adipose tissue (VAT/omental) and subcutaneous adipose tissue (SAT/abdominal wall) were collected from subjects with obesity (BMI>=35) at the beginning of elective surgical procedures, placed on ice, and transported back to the laboratory for immediate processing. For adipose tissue stromal cells (ASC) isolation, adipose tissue was digested with Type II collagenase (2 mg/mL in PBS/2% BSA) at 37oC, 60min, centrifuged at 250 rcf, and the stromal-vascular cell pellet was retrieved, plated overnight, and the adherent cells passaged three times to enrich for ASC, which were then frozen in DMEM/F12, 15% fetal calf serum, and 10% DMSO in liquid nitrogen until use. Single nuclear sequencing was performed on preparations from intact adipose tissue. Bulk RNA sequencing and single cell sequencing were performed on ASC isolated from intact adipose tissue and cultured in 2D and 3D culture systems. We currently apply bulk, single cell, and single nuclear sequencing analyses to these tissues. One component of this project studies single nuclear sequencing in nuclei isolated from intact adipose tissues from human subjects with obesity, focusing on depot comparisons (VAT vs. SAT). This cohort also permits comparisons of adipose tissue transcriptomes between male and female subjects, controlling for age and BMI. Primary findings to date include identification of multiple ASC, adipocyte, and endothelial cell (EC) subpopulations, T-cell, and macrophage (MAC) populations that are in concordance with and expand upon other published datasets. Of two dominant ASC subpopulations, one (inflammatory-mesothelial, IM- ASC) is present in VAT, but absent in SAT, while the other (fibroadipogenic, FA-ASC) is present in both VAT and SAT. We identified multiple EC subtypes with features of lymphatic, venous, and arterial EC, and a PRDM16 expressing population with features of an EC progenitor. Immune cell populations match recent experimental validation of lipid-activated macrophage (LAM) phenotypes, TIM4 macrophages, and a prominent population of MRC1/CD206+ resident AT macrophages with expression signatures related to glucocorticoid activation. These data support depot-specific differences in ASC subpopulations and previously unrecognized EC heterogeneity within human AT, with the potential to shed light on functional differences in AT depot and disease state. Planned future studies include ATAC-Seq and other omics analyses. Another component of this project studies transcriptional responses of ASC in vitro to various stimuli, including different matrix environments. Current data includes bulk RNA Sequencing of human ASC from VAT and SAT differentiated into mature adipocytes in hydrogels of differing stiffness (3%, 5%, 10%) to define transcriptional responses to matrix environments of different stiffness. Primary findings to date include enrichment of adipogenesis and lipid and oxidative metabolic gene pathways in adipocytes in 5% relative to 3% hydrogels, while fibrotic gene pathways have been enriched in 3% hydrogels. These data demonstrate that intermediate density matrix promotes a more adipogenic, less fibrotic adipocyte phenotype geared towards increased lipid and aerobic metabolism. Planned future studies include expansion of intact tissues from our cohort studied with single nuclear sequencing, as well as further study of ASC responses in vitro to different biologic stimuli, including different matrix environments.

  Study phs003390

• ARDSNet 07-08: Randomized, Blinded, Placebo-Controlled, Multi-Center Trial of Omega-3 Fatty Acid, Gamma-Linolenic Acid, and Antioxidants in Acute Lung Injury or ARDS (OMEGA) (ARDSNet-Omega-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. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-Omega include bronchial lavage, plasma, urine, and DNA. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: To determine if dietary supplementation of omega-3 (n-3) fatty acids, γ-linolenic acid and antioxidants to participants with acute lung injury would increase ventilator-free days to study day 28.Background: Early acute lung injury (ALI) is characterized by neutrophilic lung inflammation, permeability, and intravascular and alveolar fibrin deposition. The type and inflammatory activity of eicosanoids liberated during inflammation depends on the membrane phospholipid composition: omega 6 (n-6) fatty acid arachidonate yields highly reactive and inflammatory dienoic prostaglandins and series 4 leukotrienes, whereas omega-3 (n-3) fatty acids favor production of less active and potentially anti-inflammatory trienoic prostaglandins and series 5 leukotrienes. Participants at risk of developing ALI have n-3 levels approximately 25% of normal and those with established ALI have n-3 levels as low as 6% of normal, suggesting a potential role for n-3 dietary supplementation in participants with ALI.Three randomized controlled studies, conducted in participants with ALI or sepsis-induced respiratory failure, demonstrated an association between the administration of an enteral formula enriched in n-3 fatty acids, GLA, and antioxidants and improved oxygenation and respiratory physiology compared with an unenriched, high-fat formula. However, interpretation of these results is limited by the small sample sizes and as-treated analyses of only those participants who tolerated full enteral nutrition. Participants: The total number of participants in the study was 272.Design: Participants were stratified by hospital and the presence of shock at baseline and then randomized to receive either twice-daily enteral supplementation of n-3 fatty acids, GLA, and antioxidants (n-3 supplement) or an isocaloric-isovolemic carbohydrate-rich control. Participants were also simultaneously randomized to a separate ongoing trial (the EDEN study) comparing low- vs full-calorie enteral nutrition in a 2×2 factorial design.The n-3 or control supplement was administered enterally as twice-daily boluses of 120 mL beginning within 6 hours of randomization. Dosing continued until the earliest of 21 days, 48 hours of unassisted breathing, or extubation. The energy provided by the boluses supplemented that provided by each primary physician's choice of standard continuous non–n-3-enriched enteral formula. The rate of continuous enteral feeding was managed by a protocol with an algorithm for gastrointestinal intolerances. The supplement was administered even if enteral nutrition was interrupted, as long as the patient was tolerating enteral medications. Conclusions: The study was stopped by the DSMB for futility at the first interim analysis after 143 participants had been randomized to receive the n-3 supplement and 129 to receive the isocaloric control. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, participants receiving the n-3 supplement had fewer ventilator-free days, intensive care unit–free days, and nonpulmonary organ failure-free days.

  Study phs003744

• Asthma in the Lives of Families Today (ALOFT)

  Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here we investigated the effect of psychosocial experiences on gene expression in peripheral blood immune cells of 251 children with asthma in Metro Detroit. Participants were included from an ongoing longitudinal study Asthma in the Lives of Families Today (ALOFT; recruited from November 2010-July 2018. The ALOFT project was established to identify the behavioral and biological pathways through which family social environments impact youth with asthma.In version 1 we used RNA-sequencing and a new machine learning approach to identify transcriptional signatures of 19 variables including psychosocial factors, blood cell composition and asthma symptoms. Using longitudinal data collected from a subset of the participants we showed that transcriptional signatures track the longitudinal changes in measured phenotypes. Importantly, we found 169 genes associated with asthma that are regulated by psychosocial factors, and 344 significant gene-environment interactions for gene expression levels. These results demonstrate that immune gene expression mediates the link between negative psychosocial experiences and asthma risk.In version 2, we focused on pubertal development. We identified substantial gene expression changes associated with age and pubertal development. We showed that genetic effects on gene expression change dynamically during pubertal development. Gene expression changes during puberty are correlated with gene expression changes associated with asthma and may explain sex differences in prevalence. Our results show that molecular data used to study the genetics of early onset diseases should consider pubertal development as an important factor that modifies the transcriptome.Version 3 uses single cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated Peripheral Blood Mononuclear Cells from 96 African American children. We employed novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we demonstrated that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and demonstrated widespread genetic regulation of the transcriptional dynamics of the gene expression response.Version 4 adds scATAC-seq in activated peripheral blood mononuclear cells (PBMC) from 16 children with asthma with phytohemagglutinin (PHA) or lipopolysaccharide (LPS), and treated with dexamethasone (DEX), an anti-inflammatory glucocorticoid. We analyzed changes in chromatin accessibility, measured transcription factor motif activity, and identified treatment and cell-type specific transcription factors that drive changes in both gene expression mean and variability. We observed strong positive linear dependence between motif response and their target gene expression changes, but negative in variability changes. This result suggests that an increase of transcription factor binding tightens the variability of gene expression around the mean. We then annotated genetic variants in chromatin accessibility peaks and response motifs followed by computational fine-mapping of eQTL signals from a pediatric asthma cohort. We found that eQTLs were 5-fold enriched in peaks with response motifs and refined the credible set for 410 asthma risk genes, with 191 having the causal variant in response motifs. These results enhance the understanding of molecular mechanisms for asthma risk variants mediated by gene expression.

  Study phs002182

• Evolution of an adenomacarcinoma in response to selection by targeted kinase inhibitors

  Background - Adenocarcinomas of the tongue are rare and represent the minority (20-25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment. Results - In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. 1,078 genes exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumours and 9 new somatic protein coding mutations. The observed mutations and amplif ications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways. Conclusions - We conclude that complete genomic characterization of a rare tumour has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in-vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual.

  Study EGAS00000000074

• STAMPEED: Whole Genome Association Analysis of Hematopoietic Cell Transplant (HCT) Outcomes

  This retrospective cohort study was designed to identify single nucleotide polymorphisms (SNPs) that are associated with complications after allogeneic hematopoietic cell transplantation (HCT). Validated discoveries provide information to improve risk assessment, counseling and treatment planning and to direct future mechanistic studies of the genes and pathways that influence outcomes, thereby providing insight and rationale for new targeted therapies. The study was conducted with the use of 3 different approaches. (1) We used GWAS discovery and replication analyses to identify SNPs variants associated with outcomes after HCT. (2) We tested SNP alleles in HLA-matched sibling donors and recipients to determine whether mismatching in the recipient is associated with graft-versus-host disease (GVHD) or the risk of recurrent malignancy after HCT. Such associations would suggest that the peptide encoded by the SNP allele functions as a minor histocompatibility antigen. (3) We performed in silico candidate SNP studies to determine the validity of previously published results showing associations with outcomes after HCT. The study population represents a large cohort from the Fred Hutchinson Cancer Research Center and consists of 4,471 recipients and 4,628 donors containing 4,258 recipient-donor pairs. Recipients suffered from a hematologic malignancy or myelodysplastic syndrome and were treated in a highly structured clinical research environment with comprehensive monitoring and systematic data recording. We used proportional hazards analyses to test for associations with acute and chronic GVHD, acute kidney injury, gram-negative bacteremia, invasive fungal disease, CMV infection and disease, recurrent malignancy, death not attributable to recurrent malignancy, and death after recurrent or progressive malignancy.

  Study phs001918