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• RNA-Seq studies of Gene Expression in Cells and Networks in FI and ACC in Autism

  RNA-Seq studies of Gene Expression in Cells and Networks in FI (fronto-insular) and AC (anterior cingulate) cortex in Autism. We seek to understand the cellular bases of autism by using a new technology, RNA-Seq, to determine differences in gene expression in autopsy brains of subjects with well described autism versus age and sex matched neurotypical individuals. We have investigated two specific cortical areas involved in self-awareness and social reciprocity which are abnormal in autism and have found increased expression in a network of genes related to inflammation in autism group A, whereas the remaining cases, autism group B, have increased expression in a network of genes related to synapses. The current dbGaP study release includes RNA sequencing and phenotype data of n=27 subjects of African - American, Caucasian, or Hispanic origin.

  Study phs000609

• Intervention with Micronutrients and Long-Term Impact in Brazil-RECODISA

  Intervention with Micronutrients and Long-Term Impact in Brazil, a partnership between the Federal University of Ceará, Brazil and the University of Virginia, USA, enrolled infants in the age group of 2-36 months to investigate trends in gastrointestinal infections and their effects on growth and development and to identify genetic factors contributing to these diseases.A total of 1044 children from six urban communities in Brazil's semiarid region, were enrolled during active surveillance; those with diarrhea (three or more liquid stools in the last 24 hours at enrollment) were defined as a cases and matched with controls having no diarrhea during the past two weeks (at enrollment) to evaluate their growth and development. A subset of 664 children with their genetic and associated phenotypic data is included in this submission. More information on this project and its related projects can be found here: Studies of diarrheal susceptibility, growth, and development, in pediatric populations in Northeastern Brazil

  Study phs003174

• RNA Editing in breast cancer

  High-throughput sequencing screens suggest that RNA editing, which consists in the substitution of adenosine with inosine by the RNA-specific adenosine deaminase (ADAR) enzyme, occurs at several thousand positions across the human genome. Recent evidences have shown that RNA-editing could promote proliferation and carcinogenesis; however, the general principles of ADAR activity on the transcriptome and how ADAR is controlled in cancers remain to be established. The main aim of this project was to investigate the phenomenon of RNA editing in breast and other cancers. The frequency of A-to-I editing was evaluated in 58 breast cancers equally distributed among the different molecular subtypes and 10 normal breast tissues. The analysis was focused on defining: the relationship between the global amount of editing and ADAR expression; the ability to predict the level of editability of specific sites; the distribution of editing in normal and tumour samples and among different breast cancer subtypes; and the clinical, pathological and genomic factors affecting editing.

  Study EGAS00001000495

• Whole-Genome Sequencing in Multiplex Epilepsy Families

  Epilepsy is one of the most common neurologic disorders, affecting approximately 4% of individuals at some time in their lives. More than 30% of people with epilepsy continue to have seizures despite treatment, and improved approaches to treatment and prevention are sorely needed. In the search for new strategies to reduce the burden of disease, the discovery of specific genes that influence risk offers a novel opportunity to clarify pathogenic mechanisms, identify susceptible individuals prior to seizure onset, and treat and prevent seizures in people at risk. Despite clear evidence of the importance of genetics in susceptibility to epilepsy, only limited progress has been made in identifying the specific genes that influence risk. One of the greatest challenges for genetic research on this disorder is its extreme clinical and genetic heterogeneity. Although epilepsy is broadly defined by recurrent unprovoked seizures, it is so variable in its clinical manifestations, natural history, and treatment response that most epileptologists view it as a collection of different syndromes ("epilepsies") with distinct etiologies. The genetic effects on susceptibility are also likely to be extremely variable, ranging from rare variants with high penetrance (some of which produce Mendelian patterns of inheritance) to common variants with low penetrance. Recent findings strongly suggest that rare gene variants play a major role in the genetic architecture of the epilepsies. The purpose of this study was to discover new genetic risk factors for epilepsy. The primary approach was to use whole-genome sequencing to interrogate classes of genetic variants, including very rare variants, in multiplex families. Our main hypothesis was that, in at least some proportion of these families, a single variant would explain all instances of epilepsy. Variants identified within the families could then be tested for cosegregation within the family and also validated by seeing enrichment in sporadic epilepsy cases. Furthermore, understanding the impact of rare variation in epilepsy also has the potential to provide insight into the genetic architecture of other complex human diseases. Our analysis focused on families containing multiple individuals with non-acquired (idiopathic or unknown cause) epilepsy under the hypothesis that these would be enriched for genetic control. The families studied had been previously collected and phenotyped in detail, and contain an average of 3.8 individuals per family with a range of different types of epilepsy. We selected one or two affected individuals from each family for sequencing. This work has generated NGS data on 60 samples from 29 multiplex epilepsy families. We have established that, under a monogenic model of inheritance, sequencing pairs of distantly related relatives is an effective method for reducing the number of candidate variants. Critically, we have found that no single variant can explain a large proportion of these epilepsy families. This work emphasizes that identifying causal variants among the many genetic candidates found in this work will require very large sample sizes and gene-based analyses.

  Study phs000690

• Cystic Fibrosis Nasal Epithelium Gene Expression by RNAseq

  Cystic fibrosis (CF) is a monogenic disorder leading to multi-organ system dysfunction, with the primary cause of morbidity and mortality being lung disease. Mutations in CFTR result in defective ion channel transport leading to hyperviscous mucus, airway infection, inflammation and lung function decline. While the Phe508del mutation is the most common CFTR mutation in North American people with CF, it is well known that there is a broad range of lung disease severity even amongst Phe508del homozygotes, including twins/siblings. Heritability analyses showing the relative contribution of non-CFTR modifier genes in such differences in phenotype, have led to our genomic and transcriptomic studies of gene modifiers in CF. Complementary to two international CF GWAS studies, this study was performed to a) determine differential expression of genes relative to a quantitative lung disease severity phenotype score (KNoRMA; as used in CF GWAS studies) and b) to assess expression quantitative trait loci. To better understand genetic modification of CF lung disease severity, we analyzed gene expression (transcriptomic) profiles by mRNA sequencing from nasal mucosal biopsy specimens of 134 people with CF. Each study participants was characterized for CF lung disease severity phenotype by averaging three years of lung function data (forced expiratory volume in 1 second; FEV1), normalized to a CF-specific reference population matching for age, sex, and height. Participants completed nasal lavage and nasal curettage mucosal sampling, with directed sampling to the inferior nasal turbinate, a well validated surrogate for cellular characteristics and CFTR function of the lower CF airways. Participants were further invited to complete a second set of these sampling procedures for validation analysis. Specimen and concurrent clinical data collection occurred across four North American study sites and nasal mucosal specimens were subjected to RNASeq analysis. These data were to be made available in the dbGaP. Our association analyses of gene expression relative to quantitative CF lung disease phenotype, taken together with previously identified GWAS signals, identified biological pathways correlated with CF lung disease pathogenesis. Our further association analyses of gene expression relative to single nucleotide polymorphism variation at significant CF GWAS loci further identified potential mechanisms of genetic variants associated with CF lung disease. This resource is intended to aid researchers in characterizing airway mucosal gene expression from the CF airways for the purpose of gene expression profiling in CF and in muco-obstructive airways disease.

  Study phs002254

• Genetics and transcriptomes of pediatric B cell precursor leukemia with gain of chromosome 21

  Down syndrome (DS, constitutive trisomy 21) children have a 27-fold increased risk of developing B-ALL (DS-ALL), face a worse outcome due to treatment-related morbidities, and an increased rate of relapses compared to other children. This highlights the need to better understand the mechanisms of DS-associated leukemogenesis to develop more adapted treatment. In this study, we characterized the genetic and transcriptomic landscapes of DS-ALL and found a high incidence of somatic mutations leading to RAS/MAPK pathway activation in DS-ALL, as seen in other pediatric B-ALL presenting somatic gains of the chromosome 21 (B-ALL+21).

  Study EGAS00001003760

• The genomic complexity of sporadic and inherited retinoblastoma with a matched orthotopic xenograft

  Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.

  Study phs000352

• Proteomic measurements in BioBank Japan

  The BioBank Japan (BBJ) is a biobank established in the Institute of Medical Science, the University of Tokyo to collect clinical information and biological materials (DNA and serum samples). It collected about 200 thousand participants of 47 diseases started in 2003 (BBJ 1st cohort), and 67 thousand participants of 38 diseases started in 2013 (BBJ 2nd cohort), both in collaboration with 12 medical centers through the MEXT and AMED's "The BioBank Japan Project." This project is aiming at further utilization of the materials, and clinical and genomic information managed by BBJ to contribute to precision medicine by storing, managing, and providing the materials and data, as well as identifying biomarkers associated with disease risk, prognosis, and drug sensitivity.

  Study JGAS000785

• The mutational landscape of primary central nervous system lymphoma (Hipo H050, A050, XD013)

  ]Primary lymphomas of the central nervous system (PCNSL) are diffuse large B-cell lymphomas (DLBCLs) which are confined to the central nervous system (CNS). Despite extensive research, the molecular alterations leading to PCNSL have not been fully elucidated. In order to provide a comprehensive description of the mutational landscape in PCNSL, we here performed integrative whole genome and transcriptome sequencing analysis of 51 lymphomas presenting in the CNS, including 42 EBV-negative PCNSL, 6 secondary CNS lymphomas (SCNSL) and 3 EBV+ CNSL.

  Study EGAS00001005339

• Clonal Evolution in Patients with Chronic Lymphocytic Leukemia

  We analyzed clonal evolution in serial samples from five CLL patients who became resistant to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, using whole-exome and deep targeted sequencing. We observe a BTK-C481S mutation in one of five patients, and multiple PLCG2 mutations in a second patient. The other patients had an expansion of clones harboring del(8p) carrying additional driver mutations (EP300, MLL2, EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. We calculated the growth kinetics of ibrutinib-resistant subclones and estimated the size of the resistant clones at treatment initiation, which we validated by droplet-microfluidic technology. Haplo-insufficiency of TRAIL-R, a consequence of del(8p), led to TRAIL insensitivity which may contribute to development of ibrutinib resistance. These findings demonstrate that ibrutinib therapy has the potential to lead to clonal selection and expansion of rare cell populations already present at the time of treatment initiation. They also provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance, previously attributed solely to mutations in BTK and related pathway molecules.

  Study phs001091