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• Single-cell RNA-sequencing reveals that glioblastoma recapitulates a normal neurodevetlopmental hierarchy

  Dac EGAC00001001625

• PIK3CA mutation in a case of CTNNB1 mutant sinonasal glomangiopericytoma

  Study EGAS00001005653

• A critical spotlight on the paradigms of FFPE-DNA sequencing

  Study EGAS00001005757

• A multi-center genome-wide association study for nasopharyngeal carcinoma

  Study EGAS00001006062

• The Vaginal Microbiome: Disease, Genetics and the Environment

  The vagina is an interactive interface with the environment, and as such is covered by a protective epithelial surface. This surface is colonized by a biofilm consisting of bacteria and other microorganisms, which through a variety of mechanisms serve to protect the host from invasion by pathogens. Alterations in the normal vaginal microflora; i.e., dysbioses, particularly those associated with bacterial vaginosis, the most common disorder of the female reproductive tract, contribute to risk of sexually transmitted infections, infection by HIV, and are associated with increased risk of adverse pregnancy outcomes including but not limited to spontaneous preterm birth. Physiologic alterations in the host (e.g., menopause and pregnancy), which are beginning to be investigated as potential selective conditions for change in the "normal" vaginal flora, and their impact on disease susceptibility and transmission, remain to be more definitively elucidated. The effects of chronically abnormal physiologic states (e.g., diabetes mellitus) on normal vaginal flora have not been well described or studied. Finally, an almost unexplored area of inquiry is the genetic contribution, including race/ethnicity, to the establishment and maintenance of a "normal" vaginal flora, under normal and physiologically altered circumstances. Our research will shed light on how the vaginal microbiome contributes to adverse obstetrical outcomes and sexually transmitted infections in diverse populations. This project addresses the following questions: First: Do the genes of the host contribute to the composition of the vaginal microbiome? We hypothesize that a woman's genetic composition significantly affects the ability of certain commensal, parasitic and pathogenic microbes to colonize and/or infect the genital tract. Thus, we will compare and quantify the microbial populations inhabiting the vaginas of monozygotic and dizygotic twins from the Mid Atlantic Twin Registry, and, in the process, address the question of whether there is a relationship between the microbiomes of the vagina, mouth and GI tract. Second: What changes in the vaginal microbiome are associated with common physiological perturbations or non-infectious pathological states of the host?We hypothesize that "altered" physiologic (pregnancy, menopause) and pathologic (chronic disease, hysterectomy) conditions, or environmental "exposures" (exogenous hormones, antibiotics, chronic immunosuppressant, smoking; douching) can predictably alter the vaginal microenvironment. These alterations will lead to changes in microbial populations within the vagina. Changes in the microbial populations may have impacts, positive or more likely negative, on the spontaneous and future well-being of the affected individual. We are characterizing the effects of these "altered" physiologic and pathologic conditions, and environmental exposures, on the composition of the vaginal microbiome. Finally, we are examining the impact of the important physiological changes incurred during pregnancy on the composition of the microbiome of the female reproductive tract. Third: What changes in the vaginal microbiome are associated with relevant infectious diseases and conditions? We are testing the hypothesis that infectious diseases predictably alter the vaginal microbiome, and that these changes have an impact on the disease susceptibility, process, and outcome. A predilection for bacterial vaginosis, vaginitis, HIV infection, or other sexually transmitted diseases, is likely associated with a women's vaginal microbial composition. Thus, we will characterize samples from women with a variety of these infectious conditions to determine the contribution of their microbiomes to the disease process and susceptibility. We are addressing these questions using a combination of high throughput 'nextgen' sequencing technologies. Early studies were performed using the Roche 454 FLX and the first generation Illumina Genome Analyzer II instruments and more recently employing Illumina MiSeq and HiSeq 2500 and 4000 platforms, installed in the Genomics Core of the Nucleic Acids Research Facilities at VCU. Thus, segments of the 16S rRNA genes are amplified from the complex samples taken from various target sites in and around the vagina of each study participant. These segments are sequenced and subjected to taxonomic classification protocols to identify and quantify the bacterial taxa present in each sample. Additionally, total DNA isolated from these samples are subjected to shotgun sequence analysis to empirically reconstruct the metabolic potential of these microbiomes. Finally, specific bacterial clones are completely sequenced and analyzed to associate the unavoidable strain and isolate diversity with the clinical phenotypes presented.

  Study phs000256

• Prematurity and Respiratory Outcomes Program (PROP) Core Database Protocol (PROP-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 Prematurity and Respiratory Outcomes Program (PROP) was performed to identify suitable predictors of respiratory outcomes that may serve as surrogate endpoints in future trials of prevention and therapy of respiratory diseases in preterm infants.Background: Acute and chronic respiratory morbidities are common in premature births, and can pose significant risk to the infant's health, particularly during the first two years of life. One such condition is bronchopulmonary dysplasia (BPD) where infants require oxygen therapy due to abnormal repair and impaired lung development after acute lung injury. BPD poses a high mortality risk, even in infants that survive the initial hospitalization. Regardless of BPD diagnosis, preterm infants frequently return for medical care due to symptoms of post-prematurity respiratory disease (PRD), which includes intermittent or chronic wheezing, cough without cold, poor growth, apnea and cyanosis, and lower respiratory tract infections. Impaired lung function can persist into adulthood, contributing to chronic respiratory diseases including asthma and emphysema.However, at the time of the PROP study, there were no objective measures to predict which preterm infants would have persistent respiratory problems after discharge from the hospital. Furthermore, improved survival rates of premature infants and the high prevalence of lasting respiratory morbidities highlight the need for more comprehensive strategies to address both short-term and long-term respiratory complications. Thus, the Prematurity and Respiratory Outcomes Program (PROP) was formed to investigate multiple research hypotheses on the molecular mechanisms that contribute to respiratory disease risk of premature neonates over the first year of life. Specifically, PROP investigators hypothesized that in survivors of extreme prematurity to 36 weeks postmenstrual age (PMA), specific biologic, physiologic and clinical data obtained during the initial hospitalization will predict respiratory morbidity between discharge and 1 year corrected age. Participants: A total of 835 infants were enrolled.Design: PROP was a collaboratively developed multicenter prospective cohort study of very preterm infants from birth through the time of discharge from the NICU and up to one year corrected age.Clinical data included maternal and infant demographics, co-morbidities, and daily infant respiratory, nutritional, and medication data until discharge. These were prospectively collected from birth using medical record review and family interviews. After discharge, phone interviews were conducted with the infant's main caregiver at 3, 6, 9 and 12 months corrected age to assess domains of respiratory morbidity. At 6 and 12 months corrected age, a survey of environmental respiratory irritant exposures and an assessment for gastroesophageal reflux disease were also completed. A standardized physical exam was performed at 36-40 weeks PMA and again at one year corrected age. The exam focused on anthropometrics, vital signs, and respiratory system signs. At 34-41 weeks PMA and within one week of anticipated discharge based on physiologic stability, a set of non-invasive respiratory assessments were performed to assess physiologic biomarkers in infants that were not mechanically ventilated or receiving non-invasive positive pressure ventilation. Respiratory inductance plethysmography (RIP) was performed before and after inhaled albuterol to assess potential airway reactivity. During the RIP study, continuous pulse oximetry was performed during quiet sleep in order to analyze oxygen desaturations and apneas. Standardized oxygen requirement challenge tests were performed at about 36 weeks PMA, and at about 40 weeks PMA if the infant was still hospitalized and was not eligible for, or failed, the previous challenge. Failure was defined as SpO2 20 seconds at any point in the testing. Infants breathing ambient air or that passed the 36 week challenge test underwent a hypoxia challenge consisting of a 15-minute trial of FiO2 of 0.15. Failure was defined as SpO2 The primary outcome was respiratory morbidity, as measured by the presence or absence of substantial post-prematurity respiratory disease (PRD) up to one year corrected age. PRD was classified as a positive response in at least one of four morbidity domains during at least two separate parental interviews. The domains were respiratory medications, hospitalizations for cardiopulmonary cause, respiratory symptoms, and home technology dependence (oxygen, ventilator, or CPAP/BiPAP). Mortality from a respiratory cause was also incorporated.

  Study phs004117

• Neural Systems, Inhibitory Control, and Methamphetamine Dependence

  The Neural Systems, Inhibitory Control, and Methamphetamine Dependence study started in 2011 and is currently finishing data collection for its last participants. The study included methamphetamine abusing individuals and healthy control participants aged 18-55 years. Participants who qualified over the telephone were scheduled to visit the London Laboratory at the UCLA Semel Institute for Neuroscience and Human Behavior for the In-Person Screening Phase. The screening procedures, usually scheduled over two visits, determined if participants were eligible to complete the subsequent study visits. Both groups completed identical screening procedures, with the exception of more in-depth drug use questions for the methamphetamine users. After providing written consent, participants completed questionnaires about their mood, medical, psychiatric and drug use history, personality and life experiences. They also provided a urine sample to determine what drugs they recently used and a breath sample to determine the carbon monoxide levels in their system. The drug screen tested for recent methamphetamine, cocaine, opiates/opioids, benzodiazepines, THC and other amphetamines. Methamphetamine participants needed to test positive for methamphetamine at admission. If methamphetamine participants tested positive for any drugs other than methamphetamine or marijuana, and if healthy control participants tested positive for any drugs other than marijuana, they were excluded from the study. Additionally, the urine samples of female participants were tested for pregnancy; pregnant females were also excluded. If no exclusionary criteria were met during the first screening visit, participants completed a second screening visit to ensure they were mentally and physically healthy enough to participate. The second screening visit included a psychiatric diagnostic interview (DSM-IV (SCID-I) for first 500 participants and the MINI International Neuropsychiatric Interview M.I.N.I for the last 50 participants). Additionally, laboratory tests and procedures were completed by the UCLA General Clinical Research Center and interpreted by a study physician. Laboratory tests included vital signs (heart rate--BPM, blood pressure, and respirations), an electrocardiogram (ECG) to record the electrical activity of the heart, and an 18-cc blood sample to perform laboratory tests which included a complete chemistry and metabolic panel, hepatic panel, Hepatitis-C tests, and HIV test. The laboratory tests from this blood sample ensured that participants' liver and kidneys were functioning normally, and that their standard blood counts (red cell, white cell, and salts) were also normal. If a Hepatitis-C (HCV) or HIV test was positive, participants were not allowed to continue in the study and their results were reported to the California State Health Department. Participants deemed eligible to continue in the methamphetamine group participated on an outpatient basis or were admitted to the UCLA Medical Center to participate on an inpatient basis for up to 10 days. Typically, detectable levels of methamphetamine in urinalysis remain for 2-3 days, therefore inpatient days 0-3 served as a "washout period" and the methamphetamine abusing inpatient participants provided daily urine samples to test for recent drug use and pregnancy (female participants only). Outpatient participants were also required to remain abstinent from all drugs except nicotine and marijuana for at least 4 days prior to study sessions. Self-reported abstinence for outpatients was verified by urine toxicology and saliva screening at every visit to UCLA before completion of study procedures. Neurocognitive assessments, about three hours each, typically took place on two separate days. The purpose of the neurocognitive sessions were to assess participants' intellectual and neurocognitive functioning. On either the same day as the neurocognitive testing or on separate days, both methamphetamine abusers and healthy controls were administered a structural MRI to collect information on brain structure.

  Study phs001197

• Genome-Wide Association Study of Hypertriglyceridemia in Mexicans

  Coronary artery disease (CAD) is the number one cause of death and mortality world-wide. High levels of serum triglycerides (TGs) and low levels of serum high-density lipoprotein cholesterol (HDL-C) are major risk factors for CAD. Previous epidemiological studies have shown that these two lipid disturbances are highly common dyslipidemias in Mexicans. However, the genetic factors underlying high serum TGs and low HDL-C are underinvestigated and poorly identified in Mexicans. As the Mexican-American and the genetically related Latin-American populations represent the fastest growing minority in the United States, elucidation of the unknown genetic factors influencing the increased susceptibility of Mexicans to these common dyslipidemias is of great relevance to these U.S. minorities and the American healthcare system. This study is a research collaboration between investigators at the University of California, Los Angeles (UCLA) and Instituto Nacional de Ciencias Médicas y Nutrición (INCMN), Mexico City, to perform a two-stage genome-wide association study (GWAS) for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (Weissglas-Volkov et al. 2013, PMID: 23505323). This study was funded by an RO1 grant from NIH/NHLBI (PI Paivi Pajukanta; PI of the subaward Teresa Tusie-Luna). In stage 1 of the GWAS, we tested all GWAS SNPs from the Illumina Infinium Human610-Quad platform that passed quality control for association in ~2,200 hypertriglyceridemia cases and controls. In stage 2, we genotyped the ~1,200 positive signals of stage 1 in additional ~2,200 hypertriglyceridemia cases and controls, and performed a combined analysis of the two stages to identify genome-wide significant variants. The subjects were recruited at the INCMN. The DNA isolation and clinical laboratory measurements of the case-control study samples were performed at INCMN using standardized procedures. Genotyping and statistical analyses of the data were performed at UCLA. A summary of this GWAS can be found in Weissglas-Volkov et al. 2013 Journal of Medical Genetics, PMID: 23505323. Briefly, using the two-stage GWAS design, we identified a novel Mexican-specific genome-wide significant locus for serum TG levels close to the Niemann-Pick type C1 protein (NPC1) gene (Weissglas-Volkov et al. 2013, PMID: 23505323). Of the European lipid GWAS loci, three TG loci (APOA5, GCKR, and LPL) and four HDL-C loci (ABCA1, CETP, LIPC and LOC55908) resulted in genome-wide significant signals in Mexicans. Furthermore, our cross-ethnic mapping narrowed three European TG GWAS loci, APOA5, MLXIPL, and CILP2 that exhibited long range LD and a large number of candidate SNPs in the European GWAS scan. In the apolipoprotein A1C3A4A5 gene cluster region, the cross-ethnic fine mapping and LD comparisons reduced the number of candidate variants to one SNP, rs964184. We also found that although 52% of the associations from European lipid GWAS meta-analysis could be generalized to Mexicans, in 82% of the European GWAS loci, a different variant other than the European lead SNP provided the statistically strongest evidence of association in the Mexican scan (Weissglas-Volkov et al. 2013, PMID: 23505323). Taken together, our Mexican GWAS for lipids identified a novel Mexican-specific locus for high serum TGs; restricted three European GWAS loci; and investigated which European lipid GWAS variants extend to the Mexican population (Weissglas-Volkov et al. 2013, PMID: 23505323). This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to serum lipid levels in Mexicans. In addition to de-identified genome wide genotypic data, a selected list of de-identified phenotypic data related to hypertriglyceridemia and related metabolic traits are also available in dbGaP.

  Study phs000618

• ProHealth: Kaiser Permanente Genome-wide Association Study of Prostate Cancer

  A genome-wide association study (GWAS) of prostate cancer (PCa) was conducted in Kaiser Permanente (KP) Northern California health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) [PMID: 26034056]. The data for these members were drawn from three KP cohort studies: Research Program in Genes, Environment and Health (RPGEH) ProHealth, and California Men's Health Study (CMHS) (described further under Study History). Four custom arrays were designed for genotyping, one for each of the four major race-ethnicity groups in the RPGEH cohort: African Americans, East Asians, Latinos, and Non-Hispanic Whites. The number of SNPs and SNP content varied by array, with SNP content designed to maximize the genome-wide coverage of low frequency and more common variants specific to the different race-ethnicity groups, including newly identified SNPs from sequencing projects, and SNPs with established associations with disease phenotypes and risk factors [PMIDs: 21565264, 21903159]. Within the total study cohort, n=34,736 completed a consent which permitted deposition of data to NIH. Genotyping followed the same general procedure described in [PMIDs: 26092718, plus additional quality control (QC) steps for the additional men, in order to control for potential batch and kit effects, described in [PMID: 26034056. Briefly, we first repeated the filters described in [PMID: 26092718] for all four arrays (EUR, LAT, EAS, AFR). Then, on an array-wise basis, we removed SNPs with MAF<0.01, with a call rate<95%, or with Hardy-Weinberg Equilibrium (HWE) p-value in homogeneous groups<1x10ˆ-5. Furthermore, on the EUR array, to adjust for potential kit effect, we conducted a GWAS of kit, and removed those kit associated SNPs with p<1x10ˆ-6; we also re-genotyped each of the new samples (those not genotyped with the original GERA data) with some of the original GERA data, and removed SNPs with >13/1,268 (1%) mismatches. For the AFR array, to adjust potential plate batch issues, we conducted a GWAS of whether an individual was in the original GERA data vs. in the newly genotyped data and removed those batch-associated SNPs with p<0.05 (we used a stronger threshold than that used for the EUR array because there were fewer individuals on the AFR array); we also re-genotyped each of the new samples with the original GERA data and removed SNPs with >2/78 (2.6%). After the QC described above, imputation was performed as described in [PMID: 26034056]. Imputation was performed on an array-wise basis, pre-phasing with SHAPE-IT v2.5 [PMID: 22138821], and imputing from the 1000 Genomes Project October 2014 release as a cosmopolitan reference panel with IMPUTE2 [PMID: 22384356]. In addition to the GWAS described above, a nested exome-wide association study (EWAS) of PCa was also conducted (7,489 cases, 7,323 controls; 78% non-Hispanic white, 9% African-American, 3% East Asian, 6% Latino, 4% Other). A custom EWAS array primarily focused on rare variants was designed for genotyping that complemented the GWAS arrays [PMID: 26034056]. The EWAS array content included missense and loss-of-function mutations, and rare exonic mutations from The Cancer Genome Atlas (TCGA) and dbGaP prostate cancer tumor exomes [PMID: 26544944; PMID: 26544944]. Much of the EWAS array design content overlapped with the probesets on the UK Biobank Affymetrix Axiom array [PMID: 30305743]. Genotyping and QC steps taken to filter out samples exhibiting low quality and variants with low call rates are described in Emami et al., 2020 [biorXiv]. The resulting EWAS array genotypes are provided here.

  Study phs001221

• Multiple Myeloma Genomic Study (MMGS)

  Multiple Myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow (BM) infiltration and lytic bone lesions. Recent studies of massive parallel sequencing of tumor cells obtained from the BM of patients with MM have demonstrated significant clonal heterogeneity in MM. Despite this remarkable clonal heterogeneity, it could be envisioned that such clonal diversity may be even higher since single BM samples only represent a small fraction of the whole BM compartment, and the pattern of BM infiltration in MM is typically patchy. In addition, BM biopsies are painful and cannot be repeated multiple times during the course of therapy, indicating a need for less invasive methods to molecularly characterize MM patients and monitor disease progression during the therapy. Thus, optimal characterization of circulating tumor cells (CTCs) may represent a non-invasive method to capture relevant mutations present in PC clones. In addition, MM almost always progresses from precursor states of monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) to overt MM. However, some patients rapidly progress from MGUS/SMM to overt MM (progressors) with a rate of progression of up to 70% over 5 years, while others remain indolent with minimal progression over the same time period (non-progressors). Although many patients are diagnosed with earlier phases of disease, most patients do not receive treatment until their disease progresses, at which time they have overt end-organ damage. This concept of initiating therapy at the time of symptomatic disease is analogous to initiating therapy in patients with solid tumors only after the development of measurable metastatic disease. It is therefore not surprising that cure is not achieved for most patients with MM. Interestingly, studies have demonstrated that MGUS/SMM clones may already harbor chromosomal alterations (Ig loci or hyperdiploidy) and that progression to MM is mainly due to expansion of clones that were already present in the early stages of MGUS/SMM. However, the biological factors that discriminate progressors from non-progressors in MGUS/SMM are not well known. Therefore, our overarching hypothesis is that an effective therapeutic intervention will result from defining genomic and transcriptomic markers that are associated with disease progression. We believe, therefore, that focused research studies that define molecular mechanisms of clonal evolution in MGUS/SMM/MM will identify novel biomarkers of disease progression and help develop therapeutic agents that prevent or delay progression from MGUS to overt MM. Indeed, by eradicating the disease at the precursor stages, MM may become a preventable disease. Recently, a new term called Clonal Hematopoiesis of Indeterminate Potential (CHIP) has been proposed to describe asymptomatic individuals with hematologic malignancy-associated somatic mutations. Those individuals do not fulfill any diagnostic criteria for any hematological malignancy yet they have a tendency to progress into myelodysplastic syndrome (MDS) or myeloid or lymphoid neoplasia at a rate of around 0.5-1% per year, similar to MGUS. The frequency of CHIP and role of HSCs mutations in enhancing acquisition of somatic mutations in MM plasma cells, allowing progression following treatment, has not been studied. Investigating the dysregulated pathways in early progenitor cells would allow us to understand the reasons of progression and establish novel therapeutic and potentially preventive strategies. This study dissects genomic and transcriptomic characteristics of clonal evolution from MGUS/SMM to MM as well as the characteristics of the tumor microenvironment/immune cells/peripheral blood. Our hypothesis is that molecular biomarkers will be strong predictors of progression from MGUS/SMM to MM and will allow for the development of novel therapeutic agents that prevent or delay this progression. We aim to define genomic and transcriptomic markers that lead to progression from MGUS/SMM to MM in tumor cells, blood biopsies (cell free DNA and circulating tumor cells), and the tumor microenvironment.

  Study phs001323