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• RNA sequencing data of in vitro differentiated megakaryocyte cells transduced with E527K and WT SRC

  For RNA sequencing (RNAseq), CD34+ hematopoietic stem cells (HSC) were isolated from healthy controls before transduction with WT-SRC and E527K-SRC lentiviral vectors in triplicate and differentiation to MK. RNA was extracted from the complete cell population as the aim was to detect differences in genes regulating MK maturation and differentiation. A total of six WT-SRC and six E527K-SRC RNA samples were used for RNAseq to identify differentially expressed genes.

  Study EGAS00001005808

• NHLBI GO-ESP Family Studies: Pulmonary Arterial Hypertension

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. Pulmonary arterial hypertension (PAH) is a progressive disease characterized by widespread occlusion of the smallest arteries of the lungs. Pulmonary vascular obstruction leads to increased pulmonary vascular resistance, which subsequently causes heart failure with mean survival of 3 years. PAH occurs at all ages and affects women more than twice as frequently as men. Sporadic Idiopathic pulmonary arterial hypertension (IPAH), comprises 94% of what was formerly known as primary pulmonary hypertension, and is clinically and pathologically indistinguishable from familial PAH (FPAH). Most FPAH is due to mutation in BMPR2, including more than 120 families in the US. Our goal here is to find other genes that are a basis for FPAH, so we selected for exome sequencing 5 families among 40 who do not have mutation in BMPR2, or other known genes (ACVRL1, SMAD8, ENG) that rarely are the basis for FPAH.

  Study phs000354

• The EVE Asthma Genetics Consortium: Building Upon GWAS

  The EVE Asthma Genetics Consortium comprises U.S. investigators who have conducted genome-wide association studies (GWAS) of asthma; the main objective is to combine results of individual studies to increase the overall power to identify loci for asthma and asthma-associated traits. The consortium includes investigators at 9 U.S. institutions with GWAS results for >10,000 individuals representing European American, African American, African Caribbean, U.S. Hispanic, and Mexican populations and includes the following studies: The Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) The Genetic Research on Asthma in the African Diaspora (GRAAD) Study The Genetics of Asthma in Latino Americans (GALA 1) Study The Childhood Asthma Management Program (CAMP) The Childhood Asthma Research and Education (CARE) Network The Children's Health Study (CHS) Mexico City Childhood Asthma Study (MCCAS) The Chicago Asthma Genetics Study (CAG)* The National Heart, Lung, and Blood Institute Collaborative Studies of the Genetics of Asthma (CSGA)* The Severe Asthma Research Program (SARP)* (*CAG, CSGA, and SARP are part of the NHLBI-supported SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) consortium.) For the GWAS, we developed a common set of >1 million genotyped and imputed SNPs from the EVE Asthma Genetics Consortium to be tested for association with asthma and associated phenotypes in all samples and combined p-values for a grand meta-analysis for asthma gene discovery. A subset of 296 individuals representing African American, European American, and Latino ancestry were selected for whole genome sequencing. The broad goals of this project were to characterize the genetic architecture of asthma and associated quantitative phenotypes (e.g., lung function, total serum IgE) in ethnically diverse populations from the U.S., Mexico, Puerto Rico, and Barbados.

  Study phs001156

• Modifier Genes in 21-hydroxylase Deficiency

  CAH is a genetic steroidogenesis disorder. The most common form, 21OHD, leads to cortisol deficiency and, in turn, an excess of androgen, a hormone that promotes the development and maintenance of male sex characteristics. As a result of this androgen excess, prepubescent males and newborn, prepubescent, and grown females exhibit mature masculine characteristics. The symptoms and severity of 21OHD vary among individuals with the disease and in adults versus children. The reasons for these differences are not yet known. Current therapy for 21OHD consists of administration of glucocorticoids to replace cortisol and suppress excessive pituitary function. With more information about what genes or factors contribute to the severity of 21OHD, researchers may be able to better treat children and adults with the disease. This study will examine participants' DNA to determine what other genes may affect the severity of 21OHD and may make the disease milder in adults than in children This is a 3-day inpatient study. Once eligibility is confirmed through physical exam and blood analysis, eligible participants are admitted to the study site in the morning on the first study day. A blood sample is taken and participants receive one 10-mg pill of hydrocortisone. Heart rates and blood pressures are taken every 4 hours throughout the day. In the morning of Day 2, a blood sample will be obtained and a 24 hour urine collection will begin. On the morning of Day 3, another blood sample is obtained. Participants then receive intravenous cosyntropin, a synthetic form of a hormone that the body makes. About 1 hour after this, participants provide a final blood sample. Participants receive a pill of hydrocortisone prior to the end of the study.

  Study phs001313

• Genome-Wide Association Study of Preterm Birth

  Preterm birth (PTB, born before 37 weeks of gestation) is a leading cause of neonatal mortality and post-natal morbidity. PTB affects one in nine all live births in the U.S. Notably, the highest rate of PTB occurs among African Americans (one in six). PTB is a complex trait, likely determined by multiple environmental and genetic factors and their interactions. We demonstrated strong familial aggregation of preterm and low birthweight in the US Blacks and Whites (Wang et al, NEJM, 1995) and conducted the largest candidate gene study of preterm birth at that time (Hao et al, HMG, 2004). We showed that a subset of mothers with certain metabolic gene variants are particularly vulnerable to the adverse effects of cigarette smoking on low birthweight and preterm births (Wang et al, JAMA, 2002). We also published a number of papers that examined the effect of maternal pre-pregnancy BMI, micronutrient status, stress and environmental toxins on the risk of preterm birth and related conditions. This project, supported by a grant from the NICHD (2R01HD41702, PI, Xiaobin Wang), aimed to conduct a genome-wide association study (GWAS) and apply advanced statistical methods to identify susceptibility loci of PTB in a predominantly urban low-income African American sample, a subset of the Boston Birth Cohort. PUBLIC HEALTH REVELANCE: We anticipate that this study will lead to the identification of novel genetic loci of PTB and gene-environment interactions. Such findings not only will provide important insights into mechanisms leading to PTB, but also may help identify women at high-risk of PTB, which in turn, may lead to the development of early and targeted interventions that can prevent PTB or mitigate the severity and consequences of PTB.

  Study phs000332

• Hispanic Community Health Study /Study of Latinos (HCHS/SOL)

  The Hispanic Community Health Study / Study of Latinos (HCHS/SOL) is a multi-center epidemiologic study in Hispanic/Latino populations to determine the role of acculturation in the prevalence and development of disease, and to identify risk factors playing a protective or harmful role in Hispanics/Latinos. The study is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and six other institutes, centers, and offices of the National Institutes of Health (NIH). The goals of the HCHS/SOL include studying the prevalence and development of disease in Hispanics/Latinos, including the role of acculturation, and identifying disease risk factors that play protective or harmful roles in Hispanics/Latinos. A total of 16,415 persons of Cuban, Dominican, Mexican, Puerto Rican, Central American, and South American backgrounds were recruited through four Field Centers affiliated with San Diego State University, Northwestern University in Chicago, Albert Einstein College of Medicine in the Bronx area of New York, and the University of Miami. Seven additional academic centers serve as scientific and logistical support centers. Study participants aged 18-74 years took part in an extensive clinic exam and assessments to ascertain socio-demographic, cultural, environmental and biomedical characteristics. Annual follow-up interviews are conducted to determine a range of health outcomes. The HCHS SOL Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000810 HCHS SOL Cohort. phs000555 PAGE CALiCo SOL phs000880 HCHS/SOL Omics in Latinos (Ola)

  Study phs000810

• RNAseq: Acquired non-permissive bone marrow microenvironment impairs hematopoietic stem cell proliferation and maintenance and B-cell development post-HSCT

  Defects in B-cell reconstitution upon hematopoietic stem-cell (HSC) transplantation (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective and complete B-cell deficiency in the context of full donor-chimerism in a patient with X-linked lymphoproliferative disease and aimed to identify the contribution of the BM-microenvironment in disrupted B-cell reconstitution post-HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the index patient BM, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient-HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy-HSCs which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients’ MSCs and a progressive loss of CXCL12 expression. Indeed, survival of patients HSCs improved supplementing in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent non-permissive state for normal B-cell development.

  Study EGAS50000001437

• ATAC-seq: Acquired non-permissive bone marrow microenvironment impairs hematopoietic stem cell proliferation and maintenance and B-cell development post-HSCT

  Defects in B-cell reconstitution upon hematopoietic stem-cell (HSC) transplantation (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective and complete B-cell deficiency in the context of full donor-chimerism in a patient with X-linked lymphoproliferative disease and aimed to identify the contribution of the BM-microenvironment in disrupted B-cell reconstitution post-HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the index patient BM, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient-HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy-HSCs which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients’ MSCs and a progressive loss of CXCL12 expression. Indeed, survival of patients HSCs improved supplementing in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent non-permissive state for normal B-cell development.

  Study EGAS50000001438

• Whole genome and transcriptome analysis of a sporadic and recurring parathyroid carcinoma

  Parathyroid carcinoma is an extremely rare endocrine malignancy with an estimated incidence of less than 1 per million population. Excessive secretion of parathyroid hormone, extremely high serum calcium level and the deleterious effects of hypercalcemia are the clinical manifestations of the disease. Up to 60% of patients develop multiple disease recurrences and although long-term survival is possible with palliative surgery, permanent remission is rarely achieved. Molecular drivers of sporadic parathyroid carcinoma have remained largely unknown. Previous studies, mostly based on familial cases of the disease, suggested a potential role for the tumor suppressor MEN1 and proto-oncogene RET in benign parathyroid tumorigenesis while the tumor suppressor HRPT2 and proto-oncogene CCND1 may also act as drivers in parathyroid cancer. Here, we report the complete genomic analysis of a sporadic and recurring parathyroid carcinoma. Mutational landscapes of the primary and recurrent tumor specimens were analyzed using high throughput sequencing technologies. Such molecular profiling allowed for identification of somatic mutations never previously identified in this malignancy. These included single nucleotide point mutations in well characterized cancer genes such as mTOR, MLL2, CDKN2C and PIK3CA. Comparison of acquired mutations in patient-matched primary and recurrent tumors revealed loss of PIK3CA activating mutation during the evolution of the tumor from the primary to the recurrence. Structural variations leading to gene fusions and regions of copy loss and gain were identified at a single-base resolution. Loss of short arm of chromosome 1 along with somatic mis-sense and truncating mutations in CDKN2C and THRAP3, respectively, provide new evidence for the potential role of these genes as tumor suppressors in parathyroid cancer. The key somatic mutations indentified in this study can serve as novel diagnostic markers as well as therapeutic targets.

  Study EGAS00001000484

• An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia (CML)

  Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

  Study EGAS00001001751