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• Whole Genome Sequencing Data of High Grade Serous Ovarian Cancer

  Longitudinal whole genome sequencing data to study chemoresponse in ovarian cancer. These samples belong to an ongoing sample collection and the data already includes hundreds of samples from over 200 patients. Samples are from primary and metastatic tissues and ascites. All patients have been treated with platinum-taxane based chemotherapy and majority of them are diagnosed with high-grade serous ovarian cancer.

  Study EGAS00001006775

• Tools

  EGA Tools This page provides details of the applications available at the EGA. Submission Tool Description EgaCryptor Encrypt and create md5sum values. Crypt4gh Encrypt, decrypt or re-encrypt files. INBOX Upload your files once encrypted. FTP Upload your files once encrypted. Submitter Portal Submit and manage your submission metadata online (SEQUENCING AND PHENOTYPE ONLY) Submitter Portal API Submit and manage your submission metadata programmatically. Webin Submit and manage your submission metadata online (array data) Webin API Submit metadata using XML files. Aimed to array-based submissions. Star2xml Format conversion tool to transform tabular formats (e.g. spreadsheets) into EGA's XMLs. Used for large programmatic submissions. Data Access Tool Description DAC Portal Manage and control data access request. Download Tool Description PyEGA3 Download and decrypt datasets requested through your EGA web account. Live Outbox Download and decrypt datasets requested through your EGA web account. Fuse Client A quick and convenient way to browse through EGA files without the need for complete downloads. EGA QuickView A quick and convenient way to browse through EGA files without the need for complete downloads.

  Documentation tools

• Neuroblastoma relapse trio series from the AMC

  The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed RAS-MAPK pathway mutations. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

  Dataset EGAD00001001360

• Exome sequencing of blastic plasmacytoid dendritic cell neoplasms

  Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive haematological malignancy derived from precursors of plasmacytoid dendritic cells. Due to the rarity of BPDCNs our knowledge of their molecular pathogenesis was until recently confined to observations describing reccurent chromosomal deletions involving chromosomes 5q, 12p, 13q, 6q, 15q and 9. A recent publication went on to delineate the common deleted regions using aCGH and demonstrated that these centred around known tumour suppressor genes including CDKN2A/B (9p21.3), RB1 (12p13.2-14.3), CDKN1B (13q11-q12) and IKZF1 (7p12.2). These mutations are found recurrently in several different cancers and in most cases are thought to be involved in tumour progression rather than initiation. However, the well-defined nature and cellular ontogeny of these neoplasms suggests strongly that they share one or a few characteristic mutations as has been demonstrated for other uncommon but well-defined neoplasms such as Hairy Cell Leukemia (BRAF) and ovarian Granulosa Cell tumours (FOXL2).

  Dataset EGAD00001000406

• Whole genome sequencing in prime-edited human organoids

  We performed whole genome sequencing to detect possible off-target mutations induced by prime editing. Liver organoids, derived from a healthy control, were transfected with either control (GFP) plasmids or prime editing plasmids (GFP+PE2+pegRNA+nickRNA) to induce a 6-bp deletion in CTNNB1. One control and two prime-edited organoid lines were clonally expanded from single cells. High-throughput sequencing was performed on the complete genomic DNA isolated from these clonal lines, as well as the starting culture (bulk). After correction for germline mutations in the starting culture, new mutations in the control and prime-edited lines were compared. The same approach was followed in small intestinal organoids, derived from a patient with disease-causing 3-bp deletion in DGAT1. In these small intestinal organoids, prime editing was used to insert the 3 missing nucleotides. Two corrected clones were compared to one control clone.

  Dataset EGAD00001006352

• WES data for Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma

  Neuroblastoma (NB) is one of the most lethal childhood cancers due its propensity to treatment resistance. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicates these two contrasting scenarios and shows branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones, emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

  Dataset EGAD00001015413

• scDNA-seq for 'Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma'

  Neuroblastoma (NB) is one of the most lethal childhood cancers due its propensity to treatment resistance. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicates these two contrasting scenarios and shows branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones, emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

  Dataset EGAD00001015414

• The Primary Open-Angle Glaucoma Genes and Environment (GLAUGEN) Study

  Background Information: Primary open-angle glaucoma (POAG) is an age-related, intraocular pressure (IOP)-dependent progressive optic neuropathy that ultimately leads to irreversible blindness. Vision loss from POAG is a condition of public health significance. Current evidence suggests that POAG is a polygenetic disease modified by environmental influences. Despite the fact that a positive family history of disease is an important risk factor for POAG, conventional linkage and candidate gene approaches have revealed less than 5% of the genetic component of the disease. Furthermore, there is no consensus on environment risk factors for POAG. Elevated IOP is the only modifiable risk factor for POAG; yet, lowering IOP slows, but does not halt the disease process. Study Objectives: The overall goal of our research is to elucidate the pathogenesis of POAG so that cost-effective disease detection and primary prevention strategies can be implemented. The primary aim of the Glaucoma Gene Environment Initiative (GLAUGEN), funded by the Human Genome Research Institute (NHGRI), is to discover genetic loci associated with POAG. The secondary aim of GLAUGEN, funded by NHGRI and the National Eye Institute, is to discover gene environment interactions in POAG. Methods and study populations: For this study, we have assembled cases and controls from three studies: the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS) and the Genetic Etiologies of POAG (GEP) project based at Massachusetts Eye and Ear Infirmary (MEEI). This case-control group includes 1057 unrelated cases and 1272 controls. Members of the NHS and HPFS also have repeated environmental exposure data collected prior to a diagnosis of POAG. NHS - The Nurses Health Study started in 1976 under the direction of Dr. Frank E. Speizer. With funding from the NIH, registered nurses from 11 US states were invited to complete a detailed questionnaire regarding lifestyle and health biennially. Initially, 121,000 women responded to the baseline questionnaire. Currently, Dr. Susan Hankinson serves as the program director for the NHS. HPFS - The Health Professionals Follow-up Study began in 1986 under the direction of Drs. Walter Willett and Meir Stampfer. Under the auspices of the NIH, they enlisted 51,529 male health professionals from throughout the US to complete similarly designed biennial questionnaires. Beginning in 1990, questions regarding ocular health were added to biennial questionaires completed by health professionals participating in the NHS and HPFS. This allowed us to formulate (PI: S. Hankinson; NEI) and maintain (PI: L. Pasquale; NEI) a cohort at risk for POAG derived from the respective general cohorts who were under ophthalmic care. We then developed a definition of POAG that allowed us to identify cases from a population that was geographically dispersed. The centerpiece of this definition is the presence of reproducible visual field loss consistent with nerve fiber layer (NFL) dropout (the NFL contains the axons that comprise the optic nerve) on reliable tests. Reproducible visual field loss occurred in the context of anterior segment findings that did not suggest a secondary cause of elevated IOP and posterior segment findings that did not suggest a secondary cause of visual field loss. We selected controls from the cohort at risk for POAG on the basis of age, gender and time period when cases were identified. GEP - The Genetic Etiologies of POAG was initiated in 1996 with funding from the National Eye Institute under the direction of Dr. Janey Wiggs. The purpose of this work was to discover novel genetic loci associated with POAG. In the GEP, cases were derived predominantly from the Glaucoma Service at MEEI. The majority of cases had an examination by a glaucoma specialist and met the definition for POAG used in NHS and HPFS. Cases with only one reliable visual field consistent with NFL dropout were included if there was a cup-disc ratio of 0.7 or more. The majority of controls were patients who presented to the MEEI comprehensive ophthalmology service for routine eye examination or from spouses of MEEI patients with secondary forms of glaucoma. Other controls were identified from regional glaucoma screenings held throughout Massachusetts. Members of GEP have detailed ocular phenotype data but limited information on environmental exposures. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to primary open-angle glaucoma through large-scale genome-wide association studies of three well-characterized cohorts of cases and controls, some in matched pairs. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were performed at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000308

• Serrated Colorectal Cancer: An Emerging Disease Subtype

  This dataset represents two combined study populations. Serrated Colorectal Cancer: An Emerging Disease Subtype (called the Advanced Colorectal Cancer of Serrated Subtype Study or ACCESS Study) was a grant awarded to investigate a newly-recognized, biologically-distinct subtype of colorectal cancer (CRC) called “serrated CRC.” The objective of this project was to characterize factors related to the genetic predisposition, clinical presentation, and prognosis of serrated CRC. The study recruited incident invasive CRC cases diagnosed between April 2016 and December 2018, aged 20-74 years at diagnosis. Cases were identified through the Surveillance, Epidemiology and End Results (SEER) cancer registry serving 13 counties in western Washington State. Eligibility for all individuals was limited to those who were English-speaking and could consent. Participation included completing a baseline epidemiologic questionnaire shortly after diagnosis, optional donation of a saliva sample for genetic analysis, and optional consent to release of medical records and tissue specimens related to their diagnosis. Tumor specimens were tested for serrated CRC-defining molecular characteristics. Further, we have vital status on all participants and cause of death on those that have died since enrollment. Hormones and Colon Cancer: Epigenetic Subtypes, Risks, and Survival (called the Post-Menopausal Hormones Study or PMH Study) was a grant awarded to investigate the impact of post-menopausal hormone use on colon cancer risk, tumor molecular characteristics, and outcomes. Eligible cases were females, newly diagnosed with invasive colorectal adenocarcinoma between October 1998 and February 2002, aged 50 to 74 years. Cases were residents of 10 out of the 13 counties in western Washington State served by the Surveillance, Epidemiology and End Results (SEER) cancer registry. Eligibility for all individuals was limited to those who were English-speaking with available telephone numbers, in which they could be contacted. Unrelated population-based controls were randomly selected according to age distribution (in 5-year age intervals) of the eligible cases by using lists of licensed drivers from the Washington State Department of Licensing (for individuals aged 50 to 64 years) and rosters from the Health Care Financing Administration (now the Centers for Medicare and Medicaid, for individuals older than 64 years). Participation included completing a baseline epidemiologic questionnaire, optional donation of a saliva sample for genetic analysis, and (for cases only) optional consent to release of medical records and tissue specimens related to their diagnosis. Tumor specimens were tested for epigenetic and other molecular characteristics. The ACCESS study was supported by funding from the National Cancer Institute of the National Institutes of Health (NCI/NIH) (R01CA196337, PI: Newcomb, PA), as was the PMH Study (R01CA076366, PI: Newcomb, PA). Additional support for the PMH Study came from the Seattle site of the Colon Cancer Family Registry (SCCFR) (U01CA167551, PI: Jenkins, M, and U01/U24CA074794, PI: Newcomb, PA). Additional support for case ascertainment was provided by the Cancer Surveillance System of the Fred Hutchinson Cancer Center, which is funded by Contract Number HHSN261201300012I; NCI Control Number: N01 PC-2013-00012; Contract Number HHSN261201800004I; and NCI Control Number: N01 PC-2018-00004 from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute with additional support from the Fred Hutchinson Cancer Center and the State of Washington. This research was also supported by the Genomics and Bioinformatics, Comparative Medicine, Specialized Pathology, Collaborative Data Services, and Experimental Histopathology Shared Resources of the Fred Hutch/University of Washington Cancer Consortium (P30 CA015704).Tumor marker testing was performed using formalin-fixed paraffin-embedded diagnostic tumor tissue specimens, and DNA extracted from those specimens. Testing for microsatellite instability (MSI) was based on either a 10-gene panel (BAT25, BAT26, BAT40, MYCL, D5S346, D17S250, ACTC, D18S55, D10S197, BAT34C4) or a 4-marker immunohistochemistry panel of DNA mismatch repair proteins (MLH1, MSH2, MSH6, PMS2). CpG island methylator phenotype (CIMP) testing was based on a validated quantitative DNA methylation assay using a five-gene panel (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1) or eight-gene panel (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, MLH1, CRABP1, CDKN2A). Somatic p.V600E BRAF mutation status was tested for using a fluorescent allele-specific PCR assay. KRAS mutations in codons 12 and 13 were also assessed through forward and reverse sequencing of amplified tumor DNA. DNA was extracted from blood/saliva samples using conventional methods. The genotyping panel completed was the Build37 OncoArray500K-C, including 1%-6% blinded duplicates to monitor the quality of the genotyping. Quality control procedures were performed to 1) make sure that there were no patterns of missing data by batch, study, or plate, 2) check for gender discrepancies and kinship, 3) complete Principal Component Analysis, and 4) test for Hardy-Weinberg equilibrium (HWE). Samples were excluded based on call rate, heterozygosity, unexpected duplicates, gender discrepancy, and unexpectedly high identity-by-descent or unexpected genotypic concordance (>65%) with another individual. In addition, variants were excluded based on call rate (98%), lack of HWE in controls (P

  Study phs002171

• Maintenance of Brain Tumor Profile on Organotypic Brain Slice Culture (OBSC)

  We used uncultured tumor resection tissue from an NF2 mutation-driven grade II meningioma (MG-II) to investigate whether tumors engrafted onto organotypic brain slice cultures (OBSCs) maintained the genetic profile of the parent tumor. We prepared three groups of samples for whole exome sequencing (WES) from the same pool of dissociated MG-II tissue. Group HT is the original uncultured human tumor tissue (n = 3). Group CL is the parent tumor tissue expanded in standard in vitro cell culture until the minimum number of cells required for WES had grown. Because of initial cell loss and subsequent clonal expansion, this required six passages over the span of approximately one month (n = 3). Group BSHT is the uncultured tumor resection tissue engrafted onto OBSCs and subsequently dissected from the OBSCs at the conclusion of our standardized assay length (4 days; n = 4). WES analysis showed that tumor tissue engrafted onto OBSCs maintained a significant genetic resemblance to the parent tumor, while tumor tissue expanded in vitro displayed a distinctly different profile. Furthermore, the mutational profiles of all four BSHT biological replicates were markedly similar, indicating that each OBSC-engrafted tumor indeed contained a representative sample of the original patient tumor. A closer look at the hallmark NF2 mutations existing within all samples revealed that while all samples from the original tumor (HT1-3) and the OBSC-engrafted tumor (BSHT1-4) maintain the frame shift deletion at V24, this mutation was lost in all samples expanded in vitro (CL1-3) and replaced by mutations in other areas. Together, this data suggests that the rapid assay design and tumor-accommodating niche of our OBSC platform enables effective maintenance of the original patient tumor profile. The BBsplit algorithm from the BBtools suite was run on all samples to eliminate rat DNA contamination in the BSHT samples as well as to account for any biases that may result as a part of that process. Only the reads that were binned to the human reference were used for subsequent analysis. Reads were then mapped to the GRCh38 version of the human genome with BWA v0.7.17 and realigned together with ABRA2 v.23. Quality control was implemented using the GATK/Picard v4.1.7.0 toolkit. Somatic variants were called for each sample using the MuTect2 algorithm v4.1.7.0. Variants were merged into a single cohort variant call file and then converted to MAF via vcf2maf v1.6.21 tool. Variants were annotated using VEP v87. To identify mutations with potentially high biological impact, multiple filtering steps were applied to somatic mutation calling. First, we selected only the somatic variants that passed all filters from the MuTect2 FilterMutectCalls algorithm and second, only high/moderate impact (change coding) variants as defined by the VEP annotation were further analyzed. Over 1900 single nucleotide variants (SNVs) were detected across all samples. Figures that summarized the results were generated using maftools.

  Study phs003268

• Capturing sex-specific and infertility-linked effects of assisted reproductive technologies on the cord blood DNA methylome

  Background: Children conceived through assisted reproduction are at an increased risk for growth and genomic imprinting disorders, often linked to DNA methylation defects. It has been suggested that assisted reproductive technologies (ART) and the underlying parental infertility can induce epigenetic instability, specifically interfering with DNA methylation reprogramming events during germ cell and preimplantation development. To date, human studies exploring the association between ART and DNA methylation defects report inconsistent or inconclusive results, likely due to population heterogeneity and the use of technologies with limited coverage of the epigenome. In our study, we explore the epigenetic risk of ART by comprehensively profiling the DNA methylome of 73 human cord blood samples from singleton pregnancies (n=36 control group, n=37 ART/infertility group) from a human prospective longitudinal birth cohort, the Design, Develop, Discover (3D) Study using a high resolution sequencing based custom capture panel that interrogates over 2.4 million autosomal CpGs in the genome. Results: the main findings We identified striking sex-specific effects of ART on cord blood DNA methylation patterning both genome-wide and for imprinted genes. When compared to less invasive procedures such as in utero insemination, more invasive ARTs (IVF, ICSI, embryo culture) resulted in more marked and distinct effects on the cord blood DNA methylome, including targeting of loci involved in development. Background: Children conceived through assisted reproduction are at an increased risk for growth and genomic imprinting disorders, often linked to DNA methylation defects. It has been suggested that assisted reproductive technologies (ART) and the underlying parental infertility can induce epigenetic instability, specifically interfering with DNA methylation reprogramming events during germ cell and preimplantation development. To date, human studies exploring the association between ART and DNA methylation defects report inconsistent or inconclusive results, likely due to population heterogeneity and the use of technologies with limited coverage of the epigenome. In our study, we explore the epigenetic risk of ART by comprehensively profiling the DNA methylome of 73 human cord blood samples from singleton pregnancies (n=36 control group, n=37 ART/infertility group) from a human prospective longitudinal birth cohort, the Design, Develop, Discover (3D) Study, using a high resolution sequencing based custom capture panel that interrogates over 2.4 million autosomal CpGs in the genome. Results: We identified striking sex-specific effects of ART on cord blood DNA methylation patterning both genome-wide and for imprinted genes. When compared to less invasive procedures such as in utero insemination, more invasive ARTs (in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), embryo culture) resulted in more marked and distinct effects on the cord blood DNA methylome, including targeting of loci involved in development. Conclusions: Our study highlights the ability of a sensitive, targeted, sequencing based approach to uncover DNA methylation perturbations in cord blood associated with infertility and ART and influenced by offspring sex and ART technique invasiveness.

  Study EGAS00001006643

• Whole Exome Sequencing of Congenital Diaphragmatic Hernia Patients and Trios

  Congenital diaphragmatic hernia (CDH) is a common and severe birth defect characterized by structural defects of the diaphragm and by pulmonary hypoplasia. Congenital diaphragmatic hernia patient may present either as an isolated phenotype or together with other congenital anomalies in a complex phenotype. Despite the clinical significance of CDH, the underlying genetic and developmental pathways are incompletely understood. In order to establish a catalog of human genetic variation for this condition, we performed whole exome sequencing (WES) on 275 carefully phenotyped individuals with CDH in the Pediatric Surgical Research Laboratories at the Massachusetts General Hospital (Boston, MA, USA) and Boston Children's Hospital (Boston, MA, USA). The exome data generated are valuable for comparison of candidate genes derived from WES of other CDH cohorts or affected kindreds, and to provide ideal candidates for further functional studies with the ultimate goal of enhancing our understanding of the heterogeneous and, possibly, oligogenic molecular etiology of CDH. While familial clustering has been reported in rare kindreds, the majority of probands with CDH have no family history of CDH leading to the hypothesis that de novo variants are an important and relatively frequent etiological mechanism. In the second version of the study, we performed WES analysis on 87 trios, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify previously unknown candidate genes. This dbGaP submission includes WES data on: (a) 20 new probands, (b) 9 probands also reported in the previous version (dbGaP accession no. phs000783.v1.p1), (c) 174 unaffected parents, including the parents of 67 previously reported probands. Combined analysis with other available cohorts of congenital diaphragmatic hernia revealed a genome-wide enrichment of likely gene-disrupting de novo variants (i.e., nonsense, frameshift or splice site), and missense de novo variants predicted in silico to be damaging.

  Study phs000783

• National Institute on Aging (NIA) Late-Onset Alzheimer's Disease Genetics Initiative: The Multiplex Family Study

  Multiplex Family StudyThe purpose of the NIA Genetics Initiative: Multiplex Family Study is to identify families with multiple members diagnosed with late-onset Alzheimer's Disease. Families will be characterized clinically and blood samples will be collected to establish cell lines. If a blood sample is not available, autopsy samples will be collected for DNA extraction and storage. Our goal is to recruit 1,000 families over the course of the study. Clinical and demographic data from these families will be collected at the local site and coded data, without identifiers, will be sent and included in a national database of families with Alzheimer's Disease. This database, along with the biological samples, will be housed at the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University. The Center or provider and the Cell Repository must sign a Material Transfer Agreement for shipment of biological samples and phenotypic data to NCRAD. The biological samples and data from these families will be available to qualified researchers, who must sign a Material Transfer Agreement before receiving DNA and data. An oversight committee known as the Cell Bank Advisory Committee (CBAC) will review and monitor the process of family identification and enrollment, data collection, the establishment of cell lines and access to samples. LOAD CIDR ProjectThe first 362 families of the Multiplex Family Study (including 2,105 family members) were included in a 6K SNP genome-wide scan at the NIH-supported, Center for Inherited Disease Research (CIDR). An additional 297 unrelated, healthy controls were also genotyped at CIDR. The average age of onset of AD in the genotyped sample is 74 years and 62% of the sample is women. While primarily Caucasian, 3% are African-American, and 3% are of Hispanic ancestry. 72% of the families had at least 2 affected siblings, whereas 21% had 3 or more sampled affected individuals and 7% had 4 or more genotyped, affected family members.

  Study phs000160

• 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

• Effect of the Placental Transcriptome on Stunting in a Longitudinal African Cohort

  Mammals with placentas and flowering plants evolved genomic imprinting in nutritive tissues, the placenta and endosperm, respectively. In these tissues, the genomes inherited from the mother and father are in conflict over resource allocation to offspring. In imprinted genes, transcription is repressed on the paternal or the maternal allele, resulting in allele specific expression (ASE). We investigated the variation in ASE of imprinted genes in term human placentas in order to detect loss of imprinting (LOI), which leads to partial expression of the repressed allele. We collected the placental tissue from birth to women in our multigenerational, prospective cohort study in Mali, West Africa. We followed the women from their own infancies, early childhood to adulthood (age 18+ years). Contingent on prior informed consent, we collected placental tissue and umbilical cord tissue. We conducted RNA-Seq of the fetal compartment of the placentas and targeted DNA-Seq of the umbilical cord tissue, which is fetal, and of saliva samples from parents. Our sequencing effort produced two datasets. The first dataset is the whole transcriptome RNA-Seq dataset of 111 biopsies (59 placentas) and genotyping of 96 genes. Birth length, weight, and placental weight for the children associated with this dataset are listed in the phenotype file (DOI: 10.1093/molbev/msz226). The second dataset includes targeted RNA-Seq of 262 samples (251 placentas) and targeted DNA-Seq for 766 genes. The genes were selected because they met any one of the following criteria: (1) imprinted and reported in some studies, (2) highly expressed in placenta, or (3) relevant to diseases of interest in this cohort (https://doi.org/10.1093/g3journal/jkab176). This study provides the first systematic analysis of variation in LOI across genes and individuals in a human population, and should shed light on the hypothesis that the modulation of imprinting is an epigenetic mechanism and plays a role in the regulation of offspring growth.

  Study phs001782

• Polycystic Ovary Syndrome (PCOS) Genetics

  PCOS is a complex genetic disease reflecting the interplay of susceptibility genes and environmental factors. The cardinal reproductive feature of the syndrome, hyperandrogenemia, appears to play a direct role in the pathogenesis of the associated metabolic abnormalities. Male as well as female first-degree relatives have reproductive and metabolic phenotypes including increased prevalence rates of type 2 diabetes (T2D), metabolic syndrome (MBS) and other risk factors for cardiovascular disease (CVD). Northwestern University (NU) investigators lead a team that has extensive experience in phenotyping PCOS and in the genetic analysis of complex diseases including genome-wide association study (GWAS). Together with an expert group of collaborators from the Hershey Medical Center, and The University of Chicago, we have conducted a GWAS to identify PCOS susceptibility alleles using a large cohort of extensively and consistently phenotyped PCOS cases. Population controls for this study come from the NUgene project described below. NUgene project: In 2002, Northwestern committed to the development of a DNA repository to serve as a platform for the identification and validation of genotype-phenotype associations that will impact healthcare. The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants' DNA samples are coupled with data from a questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators.

  Study phs000368

• A Genome-Wide Association Study of Sporadic ALS in an Irish Population (SIALS) and Sequencing and Analysis of an Irish Human Genome

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons. Epidemiological studies indicate that 2-5% of cases are familial, usually with an autosomal dominant pattern of inheritance. For a portion of these, causative genes have been identified. The remaining 95% of ALS cases are described as sporadic, and believed to result from a combination of genetic and environmental factors. This study utilized samples from Irish patients with sporadic ALS and Irish control individuals. The aim of the study was to identify susceptibility alleles for ALS in the Irish population. Genome-wide, single-nucleotide polymorphism (SNP) genotyping was undertaken using Illumina 550K version 3 chips. Genotyping data are available on 221 SALS patients and 211 controls. Future work will aim to examine ALS genetic risk at individual sequence level. As an initial step, as of September 2010 we have made available the human genome sequence from a single anonymous male control individual from the SIALS collection. Recent studies generating complete human sequences from Asian, African and European subgroupings have revealed population specific variation and illuminated disease susceptibility loci. The Irish population is of interest because of its location at the periphery of Europe and also the impact its emigrants have had on the genetics of populations in a number of other countries. We have identified sequence variants that may be specific to this population and have identified potentially novel disease associated variants. We describe a novel method for improving SNP calling accuracy at low genome coverage using haplotype information. Overall we demonstrate utility in generating whole genome sequences to test general principles and reveal specific instances of human biology. With increasing access to low cost sequencing we would predict that similar studies will emerge.

  Study phs000127

• NEI CIDR Methylation Profiling of Primary Open Angle Glaucoma in GLAUGEN Samples

  This is a case-control study of Primary Open Angle Glaucoma (POAG). POAG is a progressive optic neuropathy that eventually leads to blindness. More than 30 million people worldwide have Primary Open Angle Glaucoma (POAG), of which greater than 3 million are blind. Gene expression changes in the retina have been observed for POAG. Several recent studies, including the GLAUGEN (Glaucoma Gene Environment) initiative have used GWAS to identify correlative regions of the genome. Despite this, the genetic basis of Glaucoma is not well understood. Epigenetic variation may account for low heritability and environmental effects on human disease. Despite the significant advances being made in understanding the role of epigenetics in gene regulation in other fields, little is known about the relationship between DNA methylation patterns, retinal gene expression, and retinal disease. The goal of this study is to identify differentially methylated regions in the peripheral blood of patients with POAG. The case identification is as per the GLAUGEN description: Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. POAG and control samples come from Massachusetts Eye and Ear Infirmary (MEEI). These samples were collected and genotyped as part of the GLAUGEN study. From the MEEI, 50 patients were selected from POAG pedigrees, to include all the probands genotyped by CIDR and are currently undergoing exome sequencing, and to include additional genotyped probands who belong to pedigrees of sufficient size and structure that parent of origin effects could be evaluated. Additional individual-level phenotype and genotype data may be obtained through the authorized access portal of phs000308 (Geneva - Glaugen GWAS Study).

  Study phs000461

• Optimizing Primary Stroke Prevention in Children with Sickle Cell Anemia (STOP II)

  The STOP II trial evaluated whether prophylactic transfusion in patients with sickle cell disease and high risk of stroke can be safely halted after 30 months of treatment during which patients became low risk for stroke.Stroke causes substantial morbidity in children with sickle cell disease. To prevent first strokes, the Stroke Prevention Trial in Sickle Cell Anemia (STOP) used prophylactic transfusions in children who were identified by transcranial Doppler (TCD) ultrasonography as being at high risk for stroke. This strategy reduced the incidence of stroke among such children from 10% per year to less than 1% per year, leading to recommendations for TCD screening and prophylactic transfusion for children with abnormal velocities on ultrasonography. Despite the reduced risk of stroke, long-term use of transfusions can cause adverse side effects, such as iron overload or alloimmunization. However, cessation of transfusions is associated with recurrence of stroke, and at the time of the STOP II trial, there were no clinical or laboratory indicators to guide the duration of prophylaxis. Therefore the STOP II trial was initiated to determine whether transfusions could be limited by monitoring patients with TCD examinations after transfusions were halted and resuming transfusions if the examination indicated a high risk of stroke.The trial was halted for safety concerns after 79 of a planned 100 children were randomized. Discontinuation of transfusion for the prevention of stroke in children with sickle cell disease resulted in a high rate of reversion to abnormal blood-flow velocities on Doppler studies and stroke incidence.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002386

• National Institute of Neurological Disorders and Stroke (NINDS), Family Study of Essential Tremor (FASET), Identification of Susceptibility Genes for Essential Tremor

  The Familial Study of Essential Tremor (FASET) was designed to identify susceptibility genes for Essential Tremor. ET is among the most common neurological diseases with a prevalence (age > 40 years) estimated to be 4.0% and prevalence in advanced age (> 90 years) exceeding 20%. ET, often referred to as "familial tremor", is generally regarded as a highly genetic disorder with families, with affected members over multiple generations, and twin studies show high concordance among monozygotic twins. Probands (affected with ET) and relatives were enrolled in a family study of ET at Columbia University, New York between 2011 - 2014. The study was approved by the Institutional Review Board at Columbia University and written informed consent was obtained from all enrollees. The criteria for enrollment were: 1) the proband had early-onset ET with age at onset < 50 years, 2) the proband had a diagnosis of definite or probable ET, 3) in addition to the proband, there were at least two affected relatives in the family, 4) additional affected and unaffected family members were willing to participate in the study, and 5) the families contained more than two affected individuals in different generations. Blood samples were also collected for genetic research. For the genetic analyses, we excluded enrollees that we or others had diagnosed with Parkinson's disease (PD) or dystonia. The final sample includes 52 families (52 probands [affected with ET]) and 155 relatives). The number of affected individuals enrolled per family ranged from 3 - 7 (mean = 4.1). Genetic samples from FASET were analyzed with whole genome SNP genotyping (for linkage analyses) and whole exome sequencing. It is hoped that this resource will better help researchers to understand the genetic causes of ET and underlying disease pathogenesis.

  Study phs000966

• Investigating Genetics of Human Natural Short Sleepers (IGHNSS)

  Sleep is essential for life. A good night's sleep is pleasurable and sleep deprivation is stressful. Prolonged sleep loss impairs temperature control, metabolism, immunity, and ultimately leads to death. Extensive observational and epidemiological evidence indicates that optimal sleep duration of 8 hours is associated with the maintenance of good health. In our society, however, most people only get 6.5 - 7 hours. Suboptimal sleep duration has a strong association with mortality and morbidity. Lack of sleep has been linked to cardiovascular diseases, obesity, hypertension, type 2 diabetes, and other health/cognition conditions. It is clear that the biological need for sleep varies dramatically among humans. Sleep and circadian disorders can include Familial Advanced Sleep Phase (FASP), Delayed Sleep Phase (DSP), Advanced Sleep Phase (ASP), Natural Short Sleepers (NSS) or Long Sleeping. In example, Natural Short Sleepers (NSS) have a lifelong tendency to sleep only 4 - 6 hours per night and to awaken refreshed and energetic. Natural Long Sleepers biologically require 9 - 10 hours/night to feel well rested. The 'Sleep and Circadian Disorders Study' (SACDS) at the University of California San Francisco, set out to investigate the mechanisms involved in regulating sleep duration, patterns and sleep quality regulation by identifying and characterization of individuals and families with unusual sleep and circadian rhythm behavior patterns. SACDS participants were screened with a "General Sleep Questionnaire" that inquired about multiple aspects of sleep, including habitual work-day versus non-work day sleep-wake schedules, permits calculation of subjective habitual initial sleep onset, final sleep offset, and number of awakenings. There was an additional screening process including demographic data, sleep, mood, behavioral and general medical questionnaires, plus the study consent. After the extensive screening of 117 participants, blood samples were collected from 38 individuals and of those 10 samples were chosen for whole exome sequencing analysis.

  Study phs001270

• Childhood Cancer Data Initiative (CCDI): Genomic Analysis in Pediatric Malignancies

  Pediatric solid tumors are highly heterogeneous, encompassing a large number of histotypes. The genomic landscape of these diseases is characterized by few single-nucleotide variants (SNVs) compared to adult cancers. In contrast, many exhibit a high prevalence of structural or epigenetic changes that alter gene expression, underlining the need for comprehensive genomic approaches such as whole-genome sequencing (WGS). Several studies have specifically addressed the clinical utility of genomic analysis in the pediatric and AYA cancer setting. Review of these studies point to key challenges that must be addressed in order to advance the routine use of genomics in this population. We have established a large collection of solid tumor tissue samples through our biobanking efforts. Where possible, we obtain longitudinal samples from the same patient. These primary patient samples and their corresponding germline have been analyzed using whole genome and whole transcriptome sequencing methods and have been linked to clinical metadata using both manual curation and robust methods for automatic extraction from the electronic health record (EHR). Importantly, research-grade genomic analysis is performed in parallel to our CLIA-grade sequencing (“UCSF500”) efforts for some of the patients in this study cohort and have been submitted as part of the American Association for Cancer Research's project GENIE and/or the National Childhood Cancer Registry. For our sequenced tumor samples, we have retrospective clinical data and ongoing efforts to prospectively record key events throughout the patient's cancer journey. In our solid tumor program, we have developed many patient-derived xenograft models and a number of PDX-derived cell lines. These unique models have been evaluated using genomic and functional approaches including (in some cases) treatment with conventional chemotherapy or investigational agents. Lastly, these samples were collected from a population that is among the most diverse in the nation and includes significant numbers of Asian, Latino, Indigenous and African-American patients, groups that are traditionally underrepresented in many banking efforts.

  Study phs002430

• GATA2 Deficiency and the MonoMAC Syndrome

  The aim of this study was to identify the germline mutation(s) in an extended family with individuals having MonoMAC Syndrome/GATA2 deficiency but lacking a canonical GATA2 mutation. GATA2 deficiency patients develop bone marrow failure, severe immunodeficiency and may progress to myeloid malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). The definitive treatment for GATA2 deficiency is a bone marrow transplant. Approximately 90% of GATA2 deficiency patients have a known de novo or inherited germline mutation in the GATA2 gene, but ~10% have no identified mutation. The study was initiated with the first patient and her second cousin, both of whom were treated for MonoMAC Syndrome and received bone marrow transplants at the NIH. Pedigree analysis and clinical evaluation identified the individuals in several generations of these patients' near and distant relatives who are/were presenting or carrying the disease manifestations of GATA2 deficiency. Whole Genome Sequencing (WGS) was employed on these patients' two related nuclear families to identify variants that segregated with the disease trait and carrier status of their families. Genotyping was confirmed with direct DNA sequencing of these and other family members within the extended family across generations. A single base adenine-to-thymidine change was identified in a highly conserved enhancer element ~117,000 bp upstream of the GATA2 gene. It creates a new Composite Element, a DNA motif known to be critical in the regulation of hematopoiesis. This variant is unique to this family and is not present in dbSNP or other variant databases. It segregates with the disease trait and obligate carriers throughout a large pedigree. In vitro studies show that this variant drives allele-specific overexpression of the GATA2 gene in cultured cells and luciferase assays. The WGS sequence from the nuclear families will be shared on dbGaP.

  Study phs003269

• Center for Craniofacial and Dental Genetics (CCDG): Genetics of Orofacial Clefts, Sub-types, and Subclinical Phenotypes - CIDR

  The purpose of this project is to identify the genetic factors contributing to nonsyndromic orofacial clefts (OFCs), common subtypes, and related subclinical phenotypes. The most common subtypes of OFCs are cleft lip alone (CL), cleft lip with cleft palate (CLP), and cleft palate alone (CP). CL and CLP can be unilateral (left or right) or bilateral. Related subclinical phenotypes include occult lip muscle defects, characteristics of craniofacial morphology, and subtle speech abnormalities, which are distributed within families of affected individuals, and may reflect the underlying genetic susceptibility revealing clues about OFC etiology. The multi-ethnic dataset comprises participants recruited from Pennsylvania, Puerto Rico, Colombia, Philippines, Nigeria, and Ghana, and includes individuals with OFCs (cases), their unaffected relatives, and unrelated healthy controls. The specific aims of this project are to perform genome-wide association (GWAS) scans of (1) OFCs, (2) cleft subtypes (CL, CLP, CP, and laterality subtypes), and (3) cleft-associated subclinical phenotypes to identify variants associated with manifestations across the cleft-risk spectrum. Phenotyping for participants involved characterization of the overt clefts in cases, including affected structures (lip, alveolus, hard and soft palates), visible microforms, completeness, and laterality. Individuals with syndromic forms of OFCs were excluded from participation. Subclinical features were collected for all participants, including unaffected relatives and controls. Orbicularis oris (upper lip muscle) defects were assessed by high-resolution ultrasonography and scored by three independent raters. Lip print patterns were assessed by digital photography and scored for paramedical whorls by three independent raters. Velopharyngeal insufficiency was assessed with perceptual screening by a speech-language pathology expert. This dataset has potential to improve knowledge of the genetic contributors to OFCs, subtypes, and associated subclinical phenotypes by facilitating genetic association discovery, meta-analysis, and replication efforts. Findings may ultimately be useful for predicting OFC risk and recurrence, and may enhance our understanding of OFC biology.

  Study phs002815

• Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma

  We performed massively parallel whole exome sequencing of 55 primary tumor samples from patients with diffuse large B cell lymphoma (DLBCL) and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, as well as in genes for which a functional role in DLBCL has not been previously suspected. Significantly mutated genes include MYD88, CARD11, EZH2, CREBBP, as well as MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO and TNFRSF14. Analysis of somatic mutations in patients with DLBCL also revealed that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, likely caused by activation-induced cytidine deaminase (AID)-mediated somatic hypermutation, and those non-synonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. We further identified genes with mutations that are likely to be functionally relevant despite being mutated at a low rate. These genes include KRAS, BRAF and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients.In order to facilitate additional in vitro and in vivo analyses of the discrete molecular clusters and associated targeted therapies in preclinical models, we also performed our subtyping analysis on 28 Diffuse Large B-Cell Lymphoma (DLBCL) cell lines. We performed whole exome sequencing (WES) on these cell lines to capture structural variants (SVs), from which we obtained full genetic characterization and segregation of these cell lines into our previously defined molecular clusters by DLBclass assignment. These analyses are available in an interactive DLBclass portal available to the public. Our data provide an unbiased view of the landscape of mutations in DLBCL. These data may point towards new targets for the treatment of DLBCL.

  Study phs000450