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• Long-read whole genome sequencing of gastric cancer

  Gastric cancer (GC) remains a significant health challenge globally, with a particularly high incidence in Asia, including Singapore. Understanding the genomic landscape of normal gastric and the different GC subtypes along with its precursor lesions such as intestinal metaplasia (IM) as well as GC metastatic sites is crucial for advancing diagnostics, prognostics, and therapeutics. Long-read sequencing technologies offer an opportunity to delve deeper into the genomic and epigenetic alterations underlying these conditions and to complement existing short-read omics data. By integrating these data with previously generated in-house multi-omics data (such as RNA sequencing and whole exome sequencing), we hope to better elucidate the molecular mechanism underlying GC initiation and progression.

  Study EGAS50000001607

• Decoding Human Heart Morphogenesis through Single-cell Multi-modal Analyses

  The heart, which is the first organ to develop, is highly dependent on its form to function. However, how diverse cardiac cell types spatially coordinate to create complex morphological structures critical for heart function remains to be elucidated. Here, we show that integration of single cell RNA-sequencing with high-resolution multiplexed error-robust fluorescent in situ hybridization (MERFISH) not only resolves the identity of cardiac cell types developing the human heart but also provides a spatial mapping of individual cells that enables illumination of their organization into cellular communities forming distinct cardiac structures. We discovered that many of these cardiac cell types further specified into subpopulations exclusive to specific communities, supporting their specialization according to cellular ecosystem and anatomic region. In particular, ventricular cardiomyocyte subpopulations displayed an unexpected complex laminar organization across the ventricular wall and formed, with other cell subpopulations, several cellular communities. Interrogating cell-cell interactions within these communities revealed signaling pathways orchestrating the spatial organization of cardiac cell subpopulations during ventricular wall morphogenesis. In vivo conditional genetic mouse models and in vitro human pluripotent stem cell studies confirmed an intricate multicellular PLXN-SEMA crosstalk among specific ventricular cardiomyocyte, fibroblast and endothelial cell subpopulations that directs the compaction of the ventricular wall layers. Thus, these detailed findings into the cellular social interactions and specialization of cardiac cell types constructing and remodeling the human heart offer new insights into structural heart diseases as well as engineering complex multi-cellular tissues for human heart repair. Reprinted from Farah et al. (In press), with permission from Nature.

  Study phs002031

• Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA)

  Asthma is a complex disease where the interplay between genetic factors and environmental exposures influences susceptibility and disease prognosis. Asthmatics of African descent tend to have more severe asthma and more severe clinical symptoms than individuals of European ancestry. Advances in genetic and genomic technologies have revolutionized gene discovery for several complex diseases, but going to the next step in gene discovery for asthma among populations of African descent requires considering unique characteristics of this ethnic group, including adequate sample sizes and population stratification due to (European and African) admixture. Thus far, coverage of common genetic markers both in public databases and commercially available SNP chips has been inadequate to detect and measure genetic associations among African admixed populations. The aim of this study was therefore to catalog genetic diversity in populations of African descent, especially those whose ancestry reflects the African Diaspora in the Americas.

  Study phs001123

• Mitochondrial peroxiredoxin 3 is a tractable cancer therapeutic target modulated by SLC7A11

  This study is aimed at elucidating the anti-tumor mechanism and therapeutic potential of the PRX3 inhibitor thiostrepton in mesothelioma by investigating its effects on mitochondrial redox homeostasis, oxidative stress–induced apoptosis, and tumor suppression in preclinical and clinical settings. Mesothelioma explants are treated with thiostrepton and subjected to RNA sequencing under baseline, untreated control, and thiostrepton-treated conditions to characterize treatment-induced transcriptional alterations and identify molecular pathways associated with therapeutic response and resistance.

  Study EGAS50000001827

• Standard epigenome mapping in human epithelial cells of the digestive and urogenital organs [ ChIP-Seq ]

  The aim of this study is to participate in International Human Epigenome Consortium (http://ihec-epigenomes.org/), through disclosure of quality reference epigenome profiles in normal and diseased cells obtained from multiple Japanese people.

  Study JGAS000165

• Standard epigenome mapping in human epithelial cells of the digestive and urogenital organs [RNA-Seq ]

  The aim of this study is to participate in International Human Epigenome Consortium (http://ihec-epigenomes.org/), through disclosure of quality reference epigenome profiles in normal and diseased cells obtained from multiple Japanese people.

  Study JGAS000080

• Standard epigenome mapping in human epithelial cells of the digestive and urogenital organs [BS-Seq ]

  The aim of this study is to participate in International Human Epigenome Consortium (http://ihec-epigenomes.org/), through disclosure of quality reference epigenome profiles in normal and diseased cells obtained from multiple Japanese people.

  Study JGAS000082

• Standard epigenome mapping in human epithelial cells of the digestive and urogenital organs [ ChIP-Seq ]

  The aim of this study is to participate in International Human Epigenome Consortium (http://ihec-epigenomes.org/), through disclosure of quality reference epigenome profiles in normal and diseased cells obtained from multiple Japanese people.

  Study JGAS000079

• Standard epigenome mapping in human epithelial cells of the digestive and urogenital organs [BS-Seq ]

  The aim of this study is to participate in International Human Epigenome Consortium (http://ihec-epigenomes.org/), through disclosure of quality reference epigenome profiles in normal and diseased cells obtained from multiple Japanese people.

  Study JGAS000078

• Standard epigenome mapping in human epithelial cells of the digestive and urogenital organs [RNA-Seq ]

  The aim of this study is to participate in International Human Epigenome Consortium (http://ihec-epigenomes.org/), through disclosure of quality reference epigenome profiles in normal and diseased cells obtained from multiple Japanese people.

  Study JGAS000081

• Regulatory T cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors

  Immune checkpoint inhibitors (ICI), which target immune regulatory pathways to unleash antitumor responses, have revolutionized cancer immunotherapy. Despite the remarkable success of ICI immunotherapy, a significant proportion of patients whose tumors respond to these treatments develop immune-related adverse events (irAEs) resembling autoimmune diseases. Although the clinical spectrum of irAEs is well characterized, their successful management remains empiric. This is in part because the pathogenic mechanisms involved in the break-down of peripheral tolerance and induction of irAEs remain elusive. Herein, we focused on regulatory T cells (Tregs) in individuals with irAEs because these cells are vital for maintenance of peripheral tolerance, appear expanded in the peripheral blood of individuals with cancer and abundantly express checkpoint molecules, hence representing direct targets of ICI immunotherapy. Our data demonstrate an intense transcriptomic reprogramming of CD4+CD25+CD127– Tregs in the blood of individuals with advanced metastatic melanoma who develop irAEs following ICI immunotherapy, with a characteristic inflammatory, apoptotic and metabolic signature. This inflammatory signature was shared by Tregs from individuals with different types of cancer developing irAEs and individuals with autoimmune diseases. Our findings propose an inflammatory Treg reprogramming as a feature of immunotherapy-induced irAEs, that may facilitate translational approaches aiming to induce robust antitumor immunity without disturbing peripheral tolerance.

  Study EGAS00001004694

• Multimodal single-cell and bulk glioma analyses

  Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We show that local DNA methylation disorder associates with cell-to-cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption, and is altered in environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identifies an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.

  Study EGAS00001005300

• Integrative analysis of small cell lung cancer

  Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype. We conducted integrated analysis of genome sequencing, transcriptome, and copy number analysis and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million basepairs. Evidence for inactivation of TP53 and RB1 was found in all sequenced cases. Furthermore, we identified recurrent mutations in CREBBP, EP300, and MLL, observed mutations in PTEN, in SLIT2, and EPHA7, as well as focal amplifications of the FGFR1 locus. As a major feature of SCLC we found mutation in histone modifying genes, observed genome alterations that are therapeutically tractable, and provide a framework for identifying biologically relevant genes in the context of a high mutation rate. Peifer et al., 2012, Nature Genetics.

  Study EGAS00001000299

• Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

  Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds will relapse with fatal disease within five years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure, and disease relapse 1–5. Despite the central role of LSC in poor patient outcomes, little is known about the genetic determinants driving their stemness properties. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC) 6, we investigated accessible chromatin unique across normal hematopoietic and cancer cell states and identified transposable elements (TEs) as genetic determinants of both primitive populations in comparison with their downstream mature progeny. A clinically-relevant TE chromatin accessibility-based LSCTE121 signature was developed that enabled patient classification based on survival outcomes. Through functional assays, primitive cell specific-TE subfamilies were found to serve as docking sites for stem cell-associated regulators of genome topology or lineage-specific transcription factors, including LYL1 in LSCs. Finally, using chromatin editing tools, we establish that chromatin accessibility at LTR12C elements in LSCs are necessary to maintain stemness properties. Our work identifies TEs as genetic drivers of primitive versus mature cell states, where distinct TE subfamilies account for stemness properties in normal versus leukemic hematopoietic stem cells.

  Study EGAS50000001141

• Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis

  Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds will relapse with fatal disease within five years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure, and disease relapse 1–5. Despite the central role of LSC in poor patient outcomes, little is known about the genetic determinants driving their stemness properties. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC) 6, we investigated accessible chromatin unique across normal hematopoietic and cancer cell states and identified transposable elements (TEs) as genetic determinants of both primitive populations in comparison with their downstream mature progeny. A clinically-relevant TE chromatin accessibility-based LSCTE121 signature was developed that enabled patient classification based on survival outcomes. Through functional assays, primitive cell specific-TE subfamilies were found to serve as docking sites for stem cell-associated regulators of genome topology or lineage-specific transcription factors, including LYL1 in LSCs. Finally, using chromatin editing tools, we establish that chromatin accessibility at LTR12C elements in LSCs are necessary to maintain stemness properties. Our work identifies TEs as genetic drivers of primitive versus mature cell states, where distinct TE subfamilies account for stemness properties in normal versus leukemic hematopoietic stem cells.

  Study EGAS50000001147

• Mapping genetic variants underlying gene regulation in intestinal cell types to identify novel IBD 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/

  Dataset EGAD00001016069

• NHLBI Recipient Epidemiology Donor Evaluation Study (REDS)-III - Red Blood Cell Omics (RBC-Omics) Study

  The Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) is an initiative launched by the National Heart, Lung, and Blood Institute (NHLBI) with the goal to improve transfusion medicine practice, ensure safety and reduce risks. Extensive variation exists in donor iron metabolism, hemoglobin production, and hemolysis. Despite this variation, current blood banking guidelines regulating blood donation frequency, donation volume, and storage time and conditions remain uniform for all donors. The RBC-Omics study proposed to investigate if this approach is appropriate. Specifically, the RBC-Omics study: Established a multi-ethnic cohort of blood donors with well-characterized demographic, behavioral, and donation history. Developed a database linking donations from these blood donors to outcomes in transfusion recipients. Identify genetic factors impacting hemoglobin, donation history, ferritin, and iron metabolism. Identify markers and clinical factors associated with the iron-related disorders pica and restless leg syndrome (RLS). Define the genetic and metabolic basis for donor-specific differences in spontaneous, osmotic and oxidative hemolysis at the end of storage. RBC-Omics study has 13,403 blood donors over the age of 18 that were recruited from December 2013 to December 2015 at four REDS-III blood centers: the American Red Cross (Farmington, CT), the Institute for Transfusion Medicine (ITxM, Pittsburgh, PA), Blood Center of Wisconsin (Milwaukee, WI), and the Blood Centers of the Pacific (San Francisco, CA). All blood donors are healthy volunteers who passed donation screening and were not anemic. The samples were genotyped with a customized Affymetrix Axiom array called the TM-Array. The TM-array was specifically designed to cover genetic variations related to transfusion medicine. Also copy number polymorphisms in the alpha globin, beta globin and Rh gene clusters were added. The genetic variations among different ethnicity groups were considered as well.

  Study phs001955

• The landscape of somatic mutation in normal colorectal epithelial cells

  The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic events and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ~1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

  Dataset EGAD00001004193

• Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver

  Highly metabolic liver is exposed to many sources of spontaneous mutagenesis resulting in increased genome instability that, potentially, causes age-related functional liver failure. Here we comparatively characterize the somatic mutational landscape in single human liver cells from individuals of various ages. Mutation frequency is very high in normal human hepatocytes, increasing dramatically with age as compared to other tissues and cell types, e.g., B-cells, neurons, and clonal surrogates of various adult stem cells. Moreover, differentiated hepatocytes tend to accumulate more mutations compared to age-matched proliferating liver stem cells (LSCs). Mutation spectra also differ dramatically between different cell types. Elevated oxidative hallmarks are observed in mouse liver and ex vivo cultured LSCs, but not during liver aging. Overall, human liver is prone to high age-dependent genome instability, compared to other tissues, and reveals functional difference between LSCs and hepatocytes.

  Study phs001956

• Diabetes Multi-Omic Investigation of Drug Response (DIAMOND)

  The Diabetes Multi-omic Investigation of Drug Response (DIAMOND) cohort is a population-based cohort of individuals with type-2 diabetes (T2D) who receive their care through a large health system serving southeast Michigan and metropolitan Detroit. The cohort represents the diversity of the population from which it was created. Because of their health plan membership, participants have a rich dataset of longitudinal clinical health information related to their care. The intent of the DIAMOND study is to use genomic profiling, drug exposure information, and electronic health record (EHR) derived outcome data to identify genetic predictors of treatment response. Genome-wide genotyping was performed using the AxiomTM Precision Medicine Research Array (ThermoFisher Scientific Inc.).

  Study phs003350

• The Placenta Harbors a Unique Microbiome

  This study is to investigate placental microbiome through 16S rDNA-based and whole genome shotgun metagenomic sequencing. Identified taxa and their gene carriage patterns were compared to other human body sites niches. The placental microbiome profiles were most akin to the human oral microbiome.

  Study phs000735

• Transcriptomic Profile of Whole Blood Cells from Elderly Subjects fed Probiotic Bacteria Lactobacillus rhamnosus GG ATCC 53103 (LGG) in a Phase I Open Label Study

  Open label study to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) in elderly subjects. Fifteen healthy elderly volunteers, ages 65-80 were enrolled in a study in which they received LGG capsules containing 1 x 1010 CFU, twice daily for 28 days and were followed through day 56. The study subjects completed a daily diary, a telephone call on study days 3, 7 and 14 and study visits at the Massachusetts General Hospital Clinical Research Center at baseline, day 28 and day 56. During each visit, the subject diary, interim history, potential adverse effects and concomitant medications were reviewed and vital signs and a physical examination were performed. Routine blood tests were obtained to monitor for safety during visits and nasopharyngeal and stool samples were collected for microbiome analysis. Volunteers interested in participating in the effect of LGG probiotic on the Human whole Blood Transcriptome substudy also had blood drawn for DNA and RNA extraction, after signing the substudy consent form. The main objective of the study was to assess the safety and tolerability of 2 x 1010 CFU LGG administered orally to elderly subjects for 28 days. Secondary objectives were to evaluate the richness and microbial diversity in nasopharyngeal and stool specimens using pyrosequencing, and to compare cytokine production in response to bacterial stimulation by following the kinetics of mRNA expression of pro and anti-inflammatory genes and different signaling pathways, in relation to changes in stool Bifidobacterium and Lactobacillus spp. The study was reviewed and approved by the Partners Human Research Committee (IRB # 2010P001695) and was registered at ClinicalTrials.gov (NCT01274598). The main results regarding the clinical signs and safety of intervention is published in PLoS One. 2014 Dec 1;9(12):e113456. doi: 10.1371/journal.pone.0113456. eCollection 2014. PMID: 25438151. RNA sequencing for transcriptome analysis was only done in 11 of the 15 subjects as RNA integrity and quantity had to be optimal for the three times where blood was collected in order for a subject to be included in the study. The information regarding the microbiome data associated with this study is presented in a separate paper, which can be found at dbGaP study accession, phs000896, and PMID: 25873374.

  Study phs000928

• The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR)

  The Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) Registry and Repository, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), was established in 2000 to provide a resource for the scientific community to explore genetic and non-genetic factors affecting rheumatoid arthritis (RA) occurrence and outcomes in African Americans. The long term objective is a database and a repository of 1,100 RA and 550 matched healthy African-American subjects. This CLEAR Registry and Repository has two arms: a longitudinal arm for subjects with early RA (enrollment from 2000 to 2005) and a cross-sectional arm for subjects with any disease duration (enrollment from 2006 to 2012). CLEAR has two components: a database and a repository. The database contains extensive demographic, socioeconomic, clinical and radiographic (radiographs of hands and feet) information and bone mineral density data from DEXA scans. The repository contains genomic DNA, plasma and serum on most of the participants. Participants in CLEAR II had RNA isolated from peripheral blood cells.

  Study phs001360

• ICR Centre for Paediatric Experimental Medicine

  This is the DAC for granting access to consented patient data generated in association with the Centre for Paediatric Experimental Medicine at ICR. Data access can be granted by bioinformatician Claire Lynn: claire.lynn@icr.ac.uk

  Dac EGAC50000000362

• CIDR/NICHD Genetic Basis of Recessive Pediatric Brain Diseases - Group 2

  The purpose of this study is to identify new genetic causes of recessive forms of pediatric neurodevelopmental disorders (NDDs) including Cerebellar hypoplasia (CBH), Lissencephaly (LIS), Microcephaly (MIC), Corpus callosum hypoplasia (CCH), Pontocerebellar hypoplasia (PCH), Pontine tegemental cap dysplasia (PTCD), and Aicardi syndrome among many others. Using whole exome sequencing on one or two affected members per family, we are able to identify many pathogenic genes for these families. Using Human SNP Linkage Scans, which takes advantage of the Illumina HumanCore Array, and parametric linkage analysis software (Genehunter, Allegro, and others), we seek to identify pathogenic loci utilizing 60-70 families per year. Through the combination of parametric linkage analysis with exome sequencing and bioinformatics approaches, we will refine our search for superior sensitivity and accuracy when investigating candidate genes and identifying causative mutations for disease.

  Study phs001267