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• Circulating tumor cells Exome sequencing from breast cancer

  Single cell technologies allow interrogating the extent of tumor heterogeneity, providing novel insights into tumor evolution and treatment resistance mechanisms. Here, we investigated the level of genetic heterogeneity among circulating tumor cells (CTCs) at the single nucleotide variation and copy number aberration (CNA) levels and compared it to synchronous matched primary tumor/metastatic lesion from 3 metastatic breast cancer patients with triple-negative (TNBC), HER2-positive (HER2+) and estrogen-receptor-positive (ER+) tumors. Whole exome sequencing was performed on 3 synchronous bulk tumor tissue and 21 single/pooled CTC samples. When comparing bulk tissue with CTCs from the same patient, we found similar CNA profiles and the same patient-specific driver mutations for the HER2+ and TNBC tumors. Different CNA profiles and driver mutations were found for the ER+ tumor, with two distinct clones being identified in the CTCs, one harboring an activating ESR1 mutation, the other one bearing a TP53 mutation. These data suggest that tumor tissue and CTCs provide in a subset of patients complementary clinically relevant information to map tumor heterogeneity and monitor tumor evolution. Further validation is needed.

  Study EGAS00001005228

• Khoe-San genomes reveal unique variation and confirm deepest population divergence in Homo sapiens

  The southern African indigenous Khoe-San populations harbor the most divergent lineages of all living peoples. Exploring their genomes is key to understanding deep human history. We sequenced 25 full genomes from five Khoe-San populations, revealing many novel variants, that 25% of variants are unique to the Khoe-San, and that the Khoe-San group harbors the greatest level of diversity across the globe. In line with previous studies, we found several gene-regions with extreme values in genome-wide distributions, potentially caused by natural selection early in the modern human lineage and more recent in time. These gene-regions included immunity-, sperm-, brain-, diet- and muscle-related genes. When accounting for recent admixture, all Khoe-San groups display genetic diversity approaching the levels in other African groups and a reduction in effective population size starting around 100,000 years ago. Hence, all human groups show a reduction in effective population size commencing around the time of the Out-of-Africa migrations, which coincides with changes in the paleoclimate records, changes that potentially impacted all humans at the time.

  Study EGAS00001004459

• De novo assembly of 150 Danish genomes reveals rich structural complexity

  Most known genetic variation in human genomes has been called from comparison of short reads to the reference genome, an approach biased against finding complex variation. We sequenced 150 individuals from 50 parent-offspring trios with multiple insert-size libraries to very high coverage. We show that each genome could be independently de novo assembled into a small number of high-quality scaffolds (median N50 > 21 Mb), each of quality comparable to long read assemblies while being very cost-effective. We show that our variant call set from comparing de novo assemblies is far more complete in terms of complex variation than previous studies. Importantly, even the complex 4-5 Mb extended MHC region was assembled and resolved into haplotypes, revealing >700kb novel sequence in this important region of the genome, and major parts of the Y chromosome including some palindromes were assembled with high accuracy. Finally, we show that our variant call-set allows for the genotyping of many more complex variants when used as a reference-panel for imputation into SNP-chip data or into previously resequenced genomes.

  Study EGAS00001002108

• Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing

  Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations.

  Study EGAS00001003190

• Accurate detection of tumor-specific fusion genes reveals strongly immunogenic personal neo-antigens

  Fusion genes arising from cancer-associated somatic mutations are a potential rich source for highly immunogenic neo-antigens. However, their exploitation as targets for personalized cancer immunotherapy is currently limited by the lack of computational tools allowing transcriptome-wide identification of unique fusion genes in an accurate and sensitive manner. Here, we present EasyFuse, a computational pipeline, to detect individual and cancer-specific fusion genes in next-generation-sequencing transcriptome data obtained from human cancer samples. Using machine learning, EasyFuse predicts personal fusion genes with high precision and sensitivity and outperforms previously described approaches as qualified by an unprecedented ground-truth dataset of >1500 verification experiments in relevant patient samples. By testing immunogenicity with autologous blood lymphocytes from cancer patients we detected pre-established CD4+ and CD8+ T cell responses for 10 of 21 (48%), and for 1 of 30 (3%) of identified fusion genes, respectively. In conclusion, we demonstrate accurate detection of cancer-specific fusion genes. The high frequency of T cell responses detected in cancer patients support the relevance of private fusion genes as neo-antigens for personalized immunotherapies, especially for tumors with low point mutation burdens.

  Study EGAS00001004877

• MutWP4__CRUK_Grand_Challenge_Mutographs_of_Cancer__Pancreatic_Organoids

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003520

• Genomic_characterisation_of_MGUS__

  he hematological malignancy multiple myeloma (MM), also called Kahler’s disease or plasma cell (PC) myeloma, is characterized by a clonal expansion of PCs originating in the bone marrow (BM). The expansion of these cells leads to an overproduction of antibodies and results in typical symptoms such as anemia, renal failure and bone lesions. All cases of MM are preceded by the asymptomatic, non-malignant pre-stage monoclonal gammopathy of undetermined significance (MGUS). Of all MGUS patients, only 1% per year will progress to MM. Despite efforts to elucidate the molecular mechanisms underlying the MGUS-to-MM progression, its pathogenesis still remains largely unknown. Additionally, the genetic profiles of MGUS patients have only been limitedly investigated due to the only incidental finding of MGUS, the difficulties in BM sampling and isolating a sufficient number of aberrant PCs from the BM aspirates of MGUS patients. Consequently, reliable biomarkers to individually predict which MGUS patients will progress to MM and which will not, are lacking. Therefore, it is highly required to study the molecular pathogenesis of MGUS and the role of genetic events in relation to the malignant transformation to MM.

  Study EGAS00001004124

• Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

  Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient relationships of metastases that evade treatment, we performed genome- wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 142 metastatic regions from 10 organs harvested post-mortem from nine men who died from prostate cancer. We identified diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number change, we confirmed a common clone of origin across metastases and diagnostic biopsies; and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. Autosome-defined clusters were characterized by cluster-specific AR gene architectures that in two index cases were topologically more congruent than by chance (p-values 0.03, 3.07x10-8). Integration with anatomical site suggested patterns of spread and points of genomic divergence. Copy number boundaries identified treatment-selected clones with putatively distinct lethal trajectories.

  Study EGAS00001006598

• Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling (hipo_021)

  Parathyroid carcinoma (PC) is an orphan malignancy with a high risk of recurrence after surgery. Tumor-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (i) immune checkpoint inhibition with pembrolizumab based on high tumor mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (ii) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 and RET and, later in the course of disease, PARP inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

  Study EGAS00001006747

• HLA-DR is absent in primitive macrophages through epigenetic silencing of master regulator CIITA

  The earliest macrophages are generated during embryonic development from erythro-myeloid progenitors (EMPs) via primitive haematopoiesis. This process is poorly understood in humans and in the mouse is thought to be spatially restricted to the yolk sac. Human fetal placental macrophages, Hofbauer cells (HBC), arise during the primitive haematopoietic wave at ~18 days post conception. Here we identify a population of placental erythro-myeloid progenitors (PEMPs) in the early human placenta that give rise to HBC. PEMP are fetal CD34+CD43+ progenitors found exclusively at early gestational timepoints. Transcriptomic analyses reveal that PEMP have conserved features of primitive yolk sac EMPs, including the lack of HLF expression. Using in vitro single-cell culture experiments we show that PEMP generate HBC-like cells that completely lack HLA-DR expression  and demonstrate that this is a conserved feature of all macrophages generated by primitive haematopoiesis in humans. Finally, we demonstrate that the class II transactivator, CTIIA, the master regulator HLA-DR expression, is epigenetically silenced during primitive haematopoiesis, leading to HLA-DRneg macrophages. These findings demonstrate that HBC are derived locally from PEMP and establish the human placenta as an additional site of primitive haematopoiesis.

  Study EGAS00001006981

• Genomic_Advances_in_Sepsis__GAinS__genotyping

  This cohort comprises a subset of pateints enrolled in the Genomic Advances in Sepsis (GAinS) study, an established biobank of adult sepsis patients. Patients with sepsis due to community acquired pneumonia or faecal peritonitis were recruited from 35 hospitals across the UK from 2005-2018, with samples for functional genomics and detailed clinical information collected over the first five days of ICU admission. DNA was extracted from buffy coat or whole blood samples using the Qiagen DNA extraction protocol, the automated Maxwell Blood purification kit (Promega), or the QIAamp Blood Midi kit protocol (Qiagen). Genotyping data were generated using the Illumina HumanOmniExpress BeadChip (295 patients), the Infinium CoreExome BeadChip (655 patients), and the Infinium Global Screening Array BeadChip (307 patients). Genotyping QC and imputation into the Haplotype Reference Consortium was perfomed within each batch. The datasets were combined and following post-imputation filtering data were available on 1168 samples. 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/

  Study EGAS00001007786

• MECOM represses myeloid differentiation through CEBPA downregulation in AML

  Transcription factor MECOM, located at 3q26, is essential for hematopoietic stem cells (HSCs) in healthy individuals. Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in an aggressive subtype of leukemia (AML). Aberrantly expressed MECOM is essential for the survival and immature phenotype of these leukemia cells. Direct depletion of MECOM using an endogenous auxin-inducible degron rapidly upregulates expression of myeloid differentiation factor CEBPA. MECOM depletion is also accompanied by a severe loss of CD34 expression and gain of mature myeloid cell surface marker CD15. MECOM exerts its inhibitory effect on differentiation by binding to the +42kb CEBPA enhancer, which is essential for neutrophil development. This is partially dependent on the interaction between MECOM and its essential co-repressor CTBP2, a potential target in this type of AML. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, AML patients with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA. Our study provides insight into the mechanism by which MECOM maintains the stem cell state in AML. Furthermore, CEBPA levels are an important read-out for successful targeting of MECOM in 3q26-rearranged AML.

  Study EGAS00001008005

• MutWP4__CRUK_Grand_Challenge_Mutographs_of_Cancer__Mutagen_treated_organoids

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001004873

• MutWP4__CRUK_Grand_Challenge_Mutographs_of_Cancer__organoid_control_WGS

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001005449

• Profiling_the_Microbiome_of_Early_Life_Gut_Samples

  The human gut microbiome (GM), defined as the microorganisms that reside in the human gastrointestinal tract, has been identified as critical for normal intestinal development and physiology. However, to-date, the majority of studies characterizing the gut microbiome has relied on stool samples, thereby limiting insights into the regionality of the gut and how its microbiota differs along its length. As a result, this project seeks to profile the adjacent microbiota of various regions along the intestinal tract from pediatric intestinal tissue and their associated mucosal washes, enabling insights into tissue-specific microbiomes. Due to the expected low microbial biomass of these samples, donor stool (when available) will also be metagenomically profiled as positive controls, which will enable us to benchmark our low-biomass processing methods with existing protocols. By sampling pediatric patients of diverse ages and health statuses, this metagenomic data will also be valuable for understanding the gut microbiome of the developing human gut across time and space. 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 please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001008081

• Genome‐wide postnatal changes in immunity following fetal inflammatory response

  The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well‐established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR‐affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment‐wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR‐affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury.

  Study EGAS00001003635

• SINGLE-CELL RNA SEQUENCING Single-cell RNA sequencing was performed on 13 ‘mild-moderate’ and 10 ‘critical’ COVID19 PBMC samples

  Summary Epidemiological and clinical reports have indicated that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we performed cytokine and multiplex immune profiling in mild-moderate and critically ill COVID-19 patients. Hypercytokinemia in COVID-19 differed from the IFN-γ-driven cytokine storm in macrophage activation syndrome, and was more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling showed that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Expression of antigen presenting machinery was also reduced in critical disease. Furthermore, we found that neutrophils contributed to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together these findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

  Study EGAS00001005039

• H3Africa - Kidney Disease Research Network

  Chronic kidney disease (CKD) affects an estimated 14% of adults in sub-Saharan Africa but very little research has been done on the etiology, progression and prevention of CKD on the continent. As part of the Human Heredity and Health in Africa (H3A) Consortium, the H3Africa Kidney Disease Research Network was established to study prevalent forms of kidney disease in sub-Saharan Africa and increase the capacity for genetics and genomics research. The study is performing comprehensive phenotypic characterization with analysis of environmental and genetic factors from seven clinical centers in two African countries (Ghana and Nigeria) over a five-year period. Approximately 4,000 participants with specified kidney disease diagnoses and 4000 control participants will be enrolled in the four African countries. In addition, approximately 50 families with hereditary glomerular disease will be enrolled. The study includes both pediatric and adult participants ages <1 to 74yrs across a broad spectrum of kidney diseases secondary to hypertension, diabetes, human immunodeficiency virus, sickle cell disease, biopsy-proven glomerular disease and CKD of unknown origin. Clinical and demographic data with biospecimens are collected for assessment of clinical, biochemical and genetic markers of kidney disease.

  Study EGAS00001006558

• Resuscitation Outcomes Consortium (ROC) Controlled Study of the Clinical Effectiveness of Automated Real-Time Feedback on CPR Process Conducted at a Subset of ROC Sites (CPR) (ROC-CPR-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: A substudy of the ROC PRIMED trial, the ROC CPR trial sought to investigate whether real-time audio and visual feedback during cardiopulmonary resuscitation (CPR) outside a hospital increases the proportion of participants who achieved prehospital return of spontaneous circulation.Background: Cardiopulmonary resuscitation is an essential link in the chain of survival for treating cardiac arrest. However, performance of CPR is highly variable both outside hospital and in hospital. Interruptions in chest compression, inadequate depth of chest compression, and high rates of ventilation adversely affect blood flow during chest compressions and can hinder resuscitation. Suboptimal CPR, particularly time spent without chest compressions (low chest compression fraction), can reduce survival of cardiac arrest patients.Current technology incorporated into a monitor-defibrillator can assess core components of CPR through the use of an accelerometer and impedance changes across the defibrillation electrodes. This technology can also provide real-time audiovisual feedback so that the rescuer is prompted to perform according to guideline specifications. Use of such feedback increases the likelihood of performing CPR in accordance with guidelines during training and simulation. Participants: There were 1586 participants: 771 treated without feedback and 815 with feedback.Design: CPR feedback was provided through proprietary Q-CPR software operating in the Philips MRx monitor-defibrillator. The feedback feature of the defibrillator includes audible voice prompts and visual messages on the monitor screen that are triggered when measured chest compressions or ventilation deviate from guidelines or are interrupted.The study was conducted in 21 emergency medical service (EMS) agencies at three ROC regions in the U.S. and Canada. Randomized treatment clusters, which ranged from individual emergency medical vehicles to groups of emergency agencies, were assigned to feedback-on or feedback-off treatments. Each cluster remained in its assigned mode for two to seven months, after which it switched to the opposite treatment arm. At the end of those two treatment periods, each cluster was again randomly assigned to feedback-on or feedback-off. This cycle continued for the duration of the study. Each cluster switched treatment arms at least once, and up to four times, during the study. Conclusions: Real-time visual and audible feedback during CPR altered performance to more closely conform with CPR guidelines. Clusters assigned to feedback were associated with increased proportion of time in which chest compressions were provided, increased compression depth, and decreased proportion of compressions with incomplete release. However, frequency of prehospital return of spontaneous circulation did not differ according to feedback status, nor did the presence of a pulse at hospital arrival, survival to discharge, or awake at hospital discharge (Hostler, et al., 2011, PMID: 21296838).

  Study phs003818

• Ghana Breast Health Study

  The Ghana Breast Health Study (GBHS) was a multi-disciplinary, population-based case-control study conducted in Accra and Kumasi, Ghana that was designed to investigate breast cancer etiology in the West Africa region. The study enrolled 1,126 invasive breast cancer cases and 2,106 frequency matched population-based controls using census-based sampling. GHBS participants were between the ages of 18 to 74 years of age. Breast cancer cases were recruited at the time they presented with lesions suspicious of breast cancer at three hospitals: Korle Bu Teaching Hospital (Accra), Komfo Anoyke Teaching Hospital (Kumasi) and Peace and Love Hospital (Kumasi). These hospitals are the primary providers of treatment for breast cancer in Ghana, allowing for cases in our study to represent most breast cancers diagnosed in these areas during the study period. The following publications describe the GBHS in detail: 1) Brinton LA et al. Design considerations for identifying breast cancer risk factors in a population-based study in Africa. Int J Cancer 2017;140:2667-2677 (PMID:28295287). 2) Nyante SJ et al. Recruiting population controls for case-control studies in sub-Saharan Africa: The Ghana Breast Health Study. PloS one 2019;14:e0215347 (PMID:30990841)Among subjects with an available source of germline DNA genotyping was performed using the Infinium Global Screening Array-24 per the manufacturer’s guidelines using the Infinium automated protocol. We excluded probable duplicates and close relatives, and samples with a call rate < 95% or samples with extreme heterozygosity. Female sex was verified by Identifiler using X chromosome heterozygosity and the X chromosome inbreeding coefficient F statistics. The GLU genetics’ ld.tagzilla module was used to confirm African ancestry. To resolve more detailed population substructure, principal components analysis was conducted among all unrelated subjects using the EIGENSOFT v7.2.1. Imputation was performed using the Michigan imputation server Minimac3 with 1K genomes phase3 as reference panel.

  Study phs002387

• 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

• Acquired Copy Number Alterations in Adult Acute Myeloid Leukemia Genomes

  We performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo AML using the Affymetrix Genome-Wide Human SNP array 6.0 containing 1.85 million features. Acquired copy number alterations (CNA) were confirmed using an independent, higher resolution, custom array comparative genomic hybridization platform. A total of 201 somatic CNA were found in the 86 AML genomes (mean 2.34 CNA/genome), with FAB M6 and M7 AML genomes containing the most changes (10-29 CNA/genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, while 40% of patients with an abnormal karyotype had additional CNA detected by SNP array, and several regions contained CNA in multiple AML genomes. The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size. Array data are available online at http://www.ncbi.nlm.nih.gov/geo/ as GEO accession #GSE10358. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes and 6/8 UPD regions occurred in samples with a normal karyotype. Collectively, 40% of AML genomes contained alterations not found with cytogenetics, and 96% of these regions contained known or novel AML associated genes. 43/86 AML genomes had no CNA or UPD at this level of resolution. The number of CNA per genome was not associated with overall survival, independent of cytogenetic classification. In this study of 86 adult AML genomes, subcytogenetic CNAs or UPD did not add prognostic information to standard cytogenetics. However, arrays identified many somatically mutated oncogenes and tumor suppressor genes, and also genes not previously implicated in AML that may be relevant for pathogenesis. AML CNA segments from 86 adult AML patients are available through dbVar at ftp://ftp.ncbi.nlm.nih.gov/pub/dbVar/data/Homo_sapiens/nstd11_Walter_et_al_2009.

  Study phs000201

• Center for Common Disease Genomics [CCDG] - Cardiovascular: PEGASUS-TIMI 54

  This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1 . Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules. Source: ccdg.rutgers.eduFor this study, The Broad Institute of MIT and Harvard generated genetic data for 7,481 individuals from the PEGASUS-TIMI 54 clinical trial run by Brigham and Women's Hospital TIMI study group using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all samples serving as controls.  

  Study phs002243

• Genome-wide Association Study for Non-syndromic Clefts in the African Population: CIDR

  The focus of this project is to identify genetic variants that are associated with orofacial clefts in African populations in sub-Saharan Africa. Most genetic studies of CLP (including the vast majority of GWAS) have been conducted in populations of European origin with only a few focused on Asian or African populations. We choose to study the genetics of these complex traits in African populations because, African populations have the greatest genetic variation amongst the various populations in the world by virtue of being the primary ancestral population to modern humans (Cavalli-Sforza and Feldman, 2003; Ramsay et al., 2011). Therefore, the potential for finding novel loci for CLP is quite high. To date 6 genome wide association studies (GWAS) for cleft lip with or without cleft palate (CL/P) have been conducted and 18 risk loci identified (Birnbaum et al., 2009; Grant et al., 2009 ; Beaty et al., 2010; Mangold et al., 2010; Ludwig et al., 2012; Sun et al., 2015). All these studies have either been conducted in European populations, Asian populations or both. There is currently no published GWAS for clefts in African populations. African populations represent a novel and richly productive populations for genetic and environmental exposure studies for CL/P. Investigating the presence of genetic variants in diverse population groups can identify novel variants and candidate genes that are population specific. Environmental factors may also increase the risks in certain population groups due to genetic susceptibility and/or specific exposures. Understanding the role these susceptibility genes play in the effects of environmental risk factors can inform strategies designed towards reducing the outcome of these complex traits, e.g. through the modification of the environmental influences. The study population comprises a large number of individuals (3205 individuals) from Africa (Ghana, Ethiopia and Nigeria). There are cases, case triads (nuclear families), as well as controls with no history of OFC nor other developmental defects.

  Study phs001090

• Elucidating Transcription Regulation by Epigenetics in Neuroblastoma

  PURPOSE Whole-genome profiles of the epigenetic modification 5-hydroxymethylcytosine (5-hmC) are robust diagnostic biomarkers in adult patients with cancer. We investigated if 5-hmC profiles would serve as novel prognostic markers in neuroblastoma, a clinically heterogeneous pediatric cancer. Because this DNA modification facilitates active gene expression, we hypothesized that 5-hmC profiles would identify transcriptomic networks driving the clinical behavior of neuroblastoma. PATIENTS AND METHODS Nano-hmC-Seal sequencing was performed on DNA from Discovery (n = 51), Validation (n = 38), and Children's Oncology Group (n = 20) cohorts of neuroblastoma tumors. RNA was isolated from 48 tumors for RNA sequencing. Genes with differential 5-hmC or expression between clusters were identified using DESeq2. A 5-hmC model predicting outcome in high-risk patients was established using linear discriminant analysis. RESULTS Comparison of low- versus high-risk tumors in the Discovery cohort revealed 577 genes with differential 5-hmC. Hierarchical clustering of tumors from the Discovery and Validation cohorts using these genes identified two main clusters highly associated with established prognostic markers, clinical risk group, and outcome. Genes with increased 5-hmC and expression in the favorable cluster were enriched for pathways of neuronal differentiation and KRAS activation, whereas genes involved in inflammation and the PRC2 complex were identified in the unfavorable cluster. The linear discriminant analysis model trained on high-risk Discovery cohort tumors was prognostic of outcome when applied to high-risk tumors from the Validation and Children's Oncology Group cohorts (hazard ratio, 3.8). CONCLUSION 5-hmC profiles may be optimal DNA-based biomarkers in neuroblastoma. Analysis of transcriptional networks regulated by these epigenomic modifications may lead to a deeper understanding of drivers of neuroblastoma phenotype. "Reprinted from Applebaum et. JCO Precision Oncology, 2019, with permission from creative commons license."

  Study phs001831