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• DAC Composition and functional state of T and NK cells in Extramedullary Mulitiple myeloma

  Dac EGAC50000000599

• Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

  Study EGAS00001004219

• Sensitive and reproducible cell-free methylome quantification with synthetic spike-in controls

  Study EGAS00001005069

• Transcriptome sequencing in monozygotic twins discordant for Mayer-Rokitansky-Küster-Hauser syndrome

  Study EGAS00001006370

• Stromal cell diversity associated with immune evasion in human triple‐negative breast cancer

  Study EGAS00001005061

• From research to data sharing: exploring EGA user's experiences

  The Cell Plasticity and Regeneration Group at the Bellvitge Biomedical Research Institute-IDIBELL focuses on the process of recruitment of macrophages that takes place in the small intestine during injury and healing. They recently published a paper titled “Mucosal Macrophages Govern Intestinal Regeneration in Response to Injury" in Gastroenterology Journal. As part of the research, some experiments were conducted using human intestinal organoid lines. These cells were processed for RNA sequencing, and the sequencing data were deposited at the EGA to be made available to the scientific community. When dealing with human genomic information, repositories must ensure the availability of the datasets while ensuring data protection. In this context, the European Genome-phenome Archive stands as a service for secure archiving and sharing of genetic, phenotypic and clinical data resulting from biomedical research. Following the recent publication of their paper, we took the opportunity to talk to Ilias Moraitis, first author, and Jordi Guiu, group leader, to find out about their experience with data sharing. Could you explain the focus of your research? In the lab, we study intestinal regeneration and how immune cells participate in this process. We use several techniques: engineered mouse models, image tracing, as well as mouse and human cells intestinal organoids. What challenges do you face regarding data management? We didn’t have a lot of problems. Always the informatic part, the data analysis, can give problems. But everything was smooth and working. We think it’s very important to deposit the data in repositories. For the mouse data it is very straightforward, but for us it was the first time depositing human data, which is sensitive because it comes from patients, and this is legally regulated. That’s why we thought about the EGA, and it was our first time. Why do you think it is important to submit data to repositories such as EGA? Because we think data is important for the science. Nowadays, we are sequencing a lot everywhere worldwide and having these resources shared with the scientific community it’s not only good for science, but it is also saving money and reducing costs. And there is so much data in there that can be used for other projects and for other questions. And it saves time! How was the process of submitting the data to the EGA? The communication worked very well but it was slower than we would like. But I think this is something we learn on the way. People usually wait until the last minute to do this before publication but if you know it in advance, you can start the process earlier. If you had to repeat the process, would you do anything differently? It’s like everything, isn’t it? For the first time you don’t know, you aren’t sure, but for the second time you know the steps, you know what to do and it’s faster. Of course, we would to do it earlier. Also, there were some things related to the control access that we didn’t know how to manage, but it was something more internal to us. Who is going to receive the communications and when, is our ethical committee going to evaluate this? All these technicalities that we didn’t know before starting this process, so we had to think about all these things. Next time it will be faster on our side. Do you have any suggestions for us to improve the submission process? Maybe we’ll need to ask our bioinformatician who did it! He was in charge of this part. Besides that, we think if the process were faster, it would be better for everyone. Also, in science a lot of times you have to do a lot of things at the very last minute, because of the nature of the experiments, or the need to accomplish for submitting a paper. Being faster in the process would be a plus. On your side, we went through the process and were able to find some information, but there were aspects we weren't aware of and weren't sure how to handle. I'm not sure if other institutes have different protocols for managing data requests or how they handle these internally. We believe the main issue lies in how the forms are filled out. Do you have any recommendations for other submitters? The main advice is to do this with enough time. Submit the data when you have the sequences, and don’t wait until the last minute. And then it can be under embargo, so you don’t need to make it public at that moment. As soon as you sequence, upload it and then it will be there for whenever you need to publish. How do you think we could encourage other researchers to submit their data? There are different layers here. One is that it is mandatory. You have to do this. The other is that we belong to a research community, to the same community and sharing this is making our research community stronger and more efficient. And then, also because this gives you visibility. The data is there, other people can analyse your data, and this also will bring citations to your papers. It has many advantages.

  Blog from-research-to-data-sharing

• Assessment of Neurological Deterioration in Subjects with Late Infantile Neuronal Ceroid Lipofuscinosis

  Late infantile ceroid lipofuscinosis (LINCL) is a rare, rapidly progressing lysosomal storage disease resulting from mutations in the CLN2 gene that lead to deficiency in the lysosomal protease tripeptidyl peptidase I (TPP-I). The symptoms are largely neurological with onset at 2-4 years age with progression to death at age 8-12 yrs. The rareness of the disease and the likelihood of non-uniform progression depending on genotype together limit the data available regarding the natural history of disease progression. Current neurological rating scales are used to give an overall quantitative description of the disease but the categories are generally broad and imprecise. With that background, the primary focus of this study is to use clinical rating scales and magnetic resonance imaging methods to define the natural history of LINCL and to provide objective and sensitive surrogates for neurological status and the impact of experimental treatments in children with LINCL. Together these parameters will be applicable to future clinical studies of novel therapies for LINCL and should be transferrable to other neurological lysosomal storage diseases. Subjects will be assessed at 2 visits separated by ≥1 yr. Brain morphometry, water self-diffusion coefficients and spectroscopic data will be obtained via magnetic resonance. Resulting MRI biomarkers will be compared with neurological assessment of disease severity using the Weill-Cornell LINCL rating scale.

  Study phs001575

• NHLBI TOPMed: Genome-Wide Association Study of Adiposity in Samoans

  The individuals sequenced here represent a small subset of the parent study (described below) and were carefully selected for the purpose of creating a Samoan-specific reference panel for imputation back into the parent study. The INFOSTIP algorithm of Gusev et. al. (2012) (PMID: 22135348) was used to optimally choose the individuals for sequencing. The research goal of the parent study (dbGaP ID phs000914) is to identify genetic variation that increases susceptibility to obesity and cardiometabolic phenotypes among adult Samoans using genome-wide association (GWAS) methods. DNA from peripheral blood and phenotypic information were collected from 3,119 adult Samoans, 23 to 70 years of age. The participants reside throughout the independent nation of Samoa, which is experiencing economic development and the nutrition transition. Genotyping was performed with the Affymetrix Genome-Wide Human SNP 6.0 Array using a panel of approximately 900,000 SNPs. Anthropometric, fasting blood biomarkers and detailed dietary, physical activity, health and socio-demographic variables were collected. We are replicating the GWAS findings in an independent sample of 2,500 Samoans from earlier studies. After replication of genomic regions and informative SNPs in those regions, we will determine sequences of the important genes, and determine the specific genetic variants in the sequenced genes that are associated with adiposity and related cardiometabolic conditions. We will also identify gene by environment interactions, focusing on dietary intake patterns and nutrients.

  Study phs000972

• ApoA-1 and Atherosclerosis in Psoriasis

  Apolipoprotein A-1 is a protein localized to high-density lipoprotein that functions to remove cholesterol from tissues for transport back to the liver. Psoriasis is a systemic inflammatory disease associated with poor high-density lipoprotein function and accelerated non-calcified burden by coronary computed tomographic angiography. In this study, 310 psoriasis patients from The Psoriasis, Atherosclerosis, and Cardiometabolic Disease Initiative (PACI) were studied at baseline to determine if levels of circulating apolipoprotein A-1 predict early onset coronary artery disease in inflammatory conditions. Of the 310 participants, 124 were followed for four years to determine if apolipoprotein A-1 predicts non-calcified coronary burden over time. The primary outcome of this study was non-calcified coronary burden by coronary computed tomography angiography. To assess non-calcified coronary burden, participants underwent coronary computed tomography angiography using the same scanner (320-detector row Aquilion ONE ViSION, Toshiba, Japan). For ApoA-1 quantification, fasting blood draw was performed the same day as the coronary computed tomography angiography. The 400MHz proton Vantera Clinical Analyzer was used to quantify Plasma apolipoprotein A-1. The study determined that low levels of apolipoprotein A-1 are associated with increased coronary artery burden and that this relationship persists over time. The data are available through dbGaP and the dataset includes all variables reported in the manuscript.

  Study phs003231

• Symptom Clusters in Oncology Patients Receiving Chemotherapy

  The parent longitudinal study evaluated the symptom experience of oncology outpatients receiving chemotherapy. Patients completed questionnaires in their homes a total of six times (assessments 1 through 6). The questionnaires were timed to evaluate symptoms associated with the receipt of two cycles of chemotherapy that were administered approximately a month apart. Assessments 1 and 4 evaluated symptoms prior to the receipt of chemotherapy. Assessments 2 and 5 evaluated symptoms in the week following the administration of chemotherapy. Assessments 3 and 6 evaluated symptoms two weeks following the administration of chemotherapy. For this analysis, morning and evening fatigue data from the enrollment assessment (i.e., prior to the second or third cycle of chemotherapy) and the assessment that was done approximately 1 week after administration of chemotherapy were evaluated. Patients completed the Lee Fatigue Scale to obtain information on morning and evening fatigue severity. For the morning fatigue assessment, patients were asked to describe how they “felt over the past week when they woke up in the morning”. For the evening fatigue assessment, they were asked to describe how they felt over the past week “before they went to bed at night”. Medical records were reviewed for disease and treatment information. Epigenome assays (microarray) were completed for 1170 patients. Whole transcriptome sequencing (bulk RNA-Seq) was completed for 651 patients.

  Study phs003863

• Single-Cell RNA-Seq Profiling of Peripheral Immune Responses to Severe Infection in Uganda

  We conducted a prospective observational study (RESERVE-U-2-TOR) of adults admitted to Tororo General Hospital in eastern Uganda with severe, undifferentiated infection (i.e., suspected sepsis). Peripheral blood mononuclear cells (PBMCs) were isolated from freshly collected heparinized whole-blood samples (4 - 5 mL) using a standard density-gradient protocol (STEMCELL Technologies). PBMCs were aliquoted, cryopreserved in CryoStor CS10 (STEMCELL Technologies), stored overnight at -80°C, and transferred to liquid nitrogen for longer-term storage. Upon thawing, viability was assessed using the Nexcelom Cellaca Cell Counter, and cells were diluted to optimal concentrations for loading onto the Chromium Controller (10X Genomics). Each sample targeted the capture of ~10,000 GEMs (gel bead-in-emulsions). Single-cell RNA libraries were prepared using the Chromium Single Cell 3' Reagent Kit v3.1 following the manufacturer's standard protocol. Libraries were quality-assessed using an Agilent TapeStation and quantified using both Qubit 2.0 Fluorometer (Invitrogen) and qPCR (Applied Biosystems). Sequencing was performed on the NovaSeq X Plus platform (Illumina) using a 28×91 read configuration per 10X guidelines, targeting ~50,000 reads per cell. Data from this study available through dbGaP include raw single-cell RNA-seq data generated from PBMC samples collected from a subset of RESERVE-U-2-TOR participants at study enrollment (N=8).

  Study phs004100

• Identification of RNA biomarkers in Parkinson's disease iPSC-derived neuronal cells

  Parkinson?s disease (PD) is an age-related, chronic and progressive neurodegenerative disorder characterized by a loss of multifocal neurons and subsequent motor symptoms. These overt motor symptoms are often preceded by prodromal non-motor symptoms. Though a number of genetic and environmental factors have been identified to play a role in PD, more exact methods for both diagnosing and assessing prognosis are yet to be discovered. Probing the transcriptomes of control and PD cells can give some interesting insight into changes caused by the disease (in both coding and non-coding gene expression), highlighting potential RNA biomarkers that may be used for PD diagnosis and as new drug targets. The study consists of two main sources of data: matched neural stem cell (NSC) and fully differentiated dopaminergic neurons derived from iPS cells. Both sets of data are made up of three samples from a control cell line, and five samples carrying a mutation in one of several genes known to be linked to heritable PD: PARK2, PARK22 or PARK9. All transcriptome libraries were synthesized and sequenced using no-amplification non-tagging cap analysis of gene expression (nAnT-iCAGE) on the Illumina HiSeq 2500 platform. Resulting data was mapped to the human genome annotation (hg38) and processed CAGE tags were clustered ready for differential expression analyses. The 16 samples here described were sequenced across two lanes.

  Study JGAS000142

• Identification of RNA biomarkers in Parkinson's disease iPSC-derived neuronal cells

  Parkinson���s disease (PD) is an age-related, chronic and progressive neurodegenerative disorder characterized by a loss of multifocal neurons and subsequent motor symptoms. These overt motor symptoms are often preceded by prodromal non-motor symptoms. Though a number of genetic and environmental factors have been identified to play a role in PD, more exact methods for both diagnosing and assessing prognosis are yet to be discovered. Probing the transcriptomes of control and PD cells can give some interesting insight into changes caused by the disease (in both coding and non-coding gene expression), highlighting potential RNA biomarkers that may be used for PD diagnosis and as new drug targets. The study consists of two main sources of data: matched neural stem cell (NSC) and fully differentiated dopaminergic neurons derived from iPS cells. Both sets of data are made up of three samples from a control cell line, and five samples carrying a mutation in one of several genes known to be linked to heritable PD: PARK2, PARK22 or PARK9. All transcriptome libraries were synthesized and sequenced using no-amplification non-tagging cap analysis of gene expression (nAnT-iCAGE) on the Illumina HiSeq 2500 platform. Resulting data was mapped to the human genome annotation (hg38) and processed CAGE tags were clustered ready for differential expression analyses. The 16 samples here described were sequenced across two lanes.

  Study JGAS000318

• Epigenetic profiling of human CD4+ memory T cells reveals their proliferative history and argues in favor of a progressive differentiation model driven by epigenetically controlled master regulators.

  A key element of adaptive immunity is the development of long-lived memory cells, which protect against recurring infection by providing a highly enriched pool of antigen-specific cells ready to react to the pathogen. Different classes of memory T cells occur upon primary activation of naive T cells, however, their detailed differentiation pathway is not entirely clear. As part of the IHEC consortium, we generated genome-wide epigenetic maps of a number of CD4+ T cell memory (Tmem) stages including rare subsets such as terminally differentiated (TEMRA) and bone marrow-resident Tmem. We found that CD4+ T cells show progressive global DNA demethylation with differentiation into memory stages, which reflects their proliferative history and likely indicates their decline in differentiation and proliferation potential. Furthermore, transcriptomic profiling combined with co-regulation network analyses arranged different Tmem subsets into a successive differentiation pathway. In addition, we identified a number of epigenetically controlled candidate master regulators for Tmem formation, of which we functionally validated a new methylation-sensitive promoter for the known 'naive-keeper' transcription factor Foxp1. Our study highlights the power of epigenomic datasets in the elucidation of the cellular history but also of the functional potential of T cell populations including the identification of epigenetically controlled master regulators.

  Study EGAS00001001624

• Spatial concordance of DNA methylation classification in diffuse glioma

  Background: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. Methods: We used neuronavigation to acquire 133 image-guided and spatially-separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast enhanced T1 weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a three-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. Results: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. Conclusion: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.

  Study EGAS00001005434

• BinDel: software tool for detecting clinically significant microdeletions in low-coverage WGS-based NIPT samples

  Clinically pathogenic chromosomal microdeletions causing genetic disorders such as DiGeorge syndrome are rare genetic aberrations that can cause clinically relevant fetal and childhood developmental deficiencies. Clinical severity of such deficiencies depend on the exact genomic location and genes affected by the fetal chromosomal aberration. Here we present the BinDel, a novel region-aware microdeletion detection software package developed to infer clinically relevant microdeletion risk in low-coverage whole-genome sequencing NIPT data. To test BinDel, we quantified the impact of sequencing coverage, fetal DNA fraction, and region length on microdeletion risk detection accuracy. We also estimated BinDel accuracy on known microdeletion samples and clinically validated aneuploidy samples. BinDel identified each positive control sample as high risk. We also determined that it is critical to take into account that the sample with a detected high microdeletion risk does not have a full chromosome aneuploidy, as the latter can cause erroneous high microdeletion risk findings. We observed that lower sequencing coverage resulted in reduced microdeletion detection accuracy, and higher fetal fractions considerably increased the microdeletion detection accuracy, with coverage becoming increasingly relevant as fetal DNA fraction decreased. In conclusion, we developed an R package-based software tool BinDel for inferring fetal microdeletion risks, which accurately identified all positive control samples with microdeletion or -duplication aberrations as high-risk samples.

  Study EGAS00001006663

• Genome wide variation in the Angolan Namib desert reveals unique Pre-Bantu ancestry

  The populations of the Angolan Namib Desert have been largely neglected in previous surveys of the genomic landscape of southern Africa. Although at present, the Namib is culturally dominated by Southwest Bantu-speaking cattle-herders, the region exhibits an extraordinary ethnographic diversity which includes an array of semi-nomadic peoples whose subsistence strategies fall outside the traditional division between foraging and food production and can thus be referred to as “peripatetic”. Among these small-scale populations are the last speakers of the Kwadi branch of the Khoe-Kwadi language family associated with the introduction of pastoralism into southern Africa (Kwepe), as well as a range of groups whose origins remain enigmatic (Kwisi, Twa and Tjimba). Using genome-wide data from 208 individuals belonging to nine ethnically diverse groups from the Angolan Namib and adjacent areas (Kwepe, Kwisi, Twa, Tjimba, !Xun, Kuvale, Himba, Nyaneka, Ovimbundu) in combination with published data from other regions of Africa, we reconstruct in detail the histories of contact emerging from pre-historic migrations to southern Africa and show that peripatetic groups from southwestern Angola stand out for exhibiting elevated levels of an unique, regionally-specific and highly divergent Pre-Bantu ancestry. These findings highlight the importance of the Namib for understanding the deep genetic structure of Africa.

  Study EGAS00001007011

• African American Multiple Myeloma GWAS

  The case set is from a case-control study designed to identify common genetic risk factors for multiple myeloma in African Americans, the population with the highest risk for this cancer. We conducted two GWAS and combined each of these with convenience controls consisting of unaffected African American participants in cohorts with existing GWAS data. We then conducted a meta-analysis of the two sets. Cases were persons of African ancestry with smoldering or active multiple myeloma identified at participating oncology clinics or through SEER registries, as part of the African American Multiple Myeloma Study (AAMMS) diagnosed from Jan 1, 1988 through July 31, 2016. The majority of the samples were collected from incident and prevalent cases diagnosed since Jan 1, 2008 (80.9%), with a minority obtained from biobanks from cases diagnosed prior to 2008 (19.1%). Additional samples were obtained from the Multiethnic Cohort (USC and University of Hawaii) (n=40), the University of California at San Francisco Multiple Myeloma Study (n=27), and from the Multiple Myeloma Research Consortium for secondary analysis (samples originally provided to MMRC by 8 additional sites (n=84)). We have identified the phenotype (smoldering myeloma, plasma cell multiple myeloma, or myeloma not otherwise specified (myeloma NOS) when myeloma phenotype was not known), sex and age at diagnosis in this data set. The initial GWAS set consisted of 1308 (1,305 passed QC) cases with DNA samples, with a GWAS performed on the Illumina Human Core. Controls consisted of 7,078 unaffected African American subjects who were participants in the African American Prostate and Breast Consortium, with existing GWAS data from the Illumina1M Duo BeadChip. The second GWAS set consisted of 529 African American multiple myeloma patients with samples (406 from University of Arkansas, results not contained in this dataset because NCI funds were not used for the collection and genotyping) with GWAS data resulting from the Illumina Mega-BeadChip v1.1. Controls were 2,390 unaffected African American participants in the Multiethnic Cohort with existing GWAS data from the same array. After QC and removal of duplicates within sets, sex mismatches, and removal of plasmacytoma cases (ICD-0 code 9731), this deposited data set contains the typed GWAS data for the Illumina Human Core (set 1) (n=1298), and for the MegaBead Chip v1.1 (set 2) (n=123), with the University of Arkansas samples removed, for a total of 1,421 case genotypes. Note that 13 samples that overlap set 1 and set 2 were included.

  Study phs001632

• The Genomics and Randomized Trials Network (GARNET) Vitamin Intervention Stroke Prevention (VISP) Trial

  The VISP trial (PI Jim Toole, M.D., Wake Forest University School of Medicine) was a multi-center, double-blind, randomized, controlled clinical trial that enrolled patients aged 35 or older with homocysteine (Hcy) levels above the 25th percentile at screening and a non-disabling cerebral infarction (NDCI) within 120 days of randomization (Toole, 2002, PMID: 12417369). The trial was designed to determine if daily intake of a multivitamin tablet with high dose folic acid, vitamin B6 and vitamin B12 reduced recurrent cerebral infarction (primary endpoint), and nonfatal myocardial infarction (MI) or mortality (secondary endpoints). Subjects were randomly assigned to receive daily doses of the high-dose formulation (n=1,827), containing 25mg pyridoxine (B6), 0.4mg cobalamin (B12), and 2.5mg folic acid; or the low-dose formulation (n=1,853), containing 200mcg pyridoxine, 6mcg cobalamin and 20mcg folic acid. Enrollment in VISP began in August 1997, and was completed in December 2001, with 3,680 participants enrolled. Within the trial, 2,164 participants from 46 clinic sites provided DNA and agreed for it to be shared for use in a genetic subset study of VISP. This study is part of Genomics and Randomized Trials Network (GARNET), funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of treatment response in randomized clinical trials. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington. The data of the VISP trial have been released to dbGaP users in several segments: Version 1 (phs000343.v1.p1), consisted of n=4 phenotype datasets, and all raw, cleaned and imputed genotype data. Version 2 (phs000343.v2.p1) included n=14 additional phenotype datasets (plus pedigree, consent, and sample-mapping data), and increased the available data to a total of n=970 phenotype variables. Version 3 (phs000343.v3.p1) included all n=36 phenotype datasets (plus pedigree, consent, and sample-mapping data), and increased the available data to a total of n=1918 phenotype variables.Version 4 (phs000343.v4.p1), the current release, includes all previous phenotypic datasets, includes one new phenotypic dataset for the untargeted metabolomics data of 50 individuals, includes DNA methylation profiles for n=180 individuals, and sequencing data for n=179 individuals.

  Study phs000343

• Virginia PrIMeD Study

  The goal of this study was to determine whether screening children (2-16 yrs) in pediatric waiting rooms for genetic risk of type 1 diabetes (T1D) could be applied to diverse (by geography, genetic ancestry) communities, and for those at "high genetic risk," if barriers prevent subsequent screening for presence of islet autoantibodies. A total of 3,818 children were recruited from eight general pediatric and specialty clinics across Virginia. Clinical Research Coordinators were stationed at each clinic and obtained informed consent/assent, a brief medical history, and a saliva sample for DNA extraction and determination of their genetic risk using a T1D Genetic Risk Score (T1D GRS). Children were present in the clinic for a "healthy" visit, although children with and without a history of T1D were recruited into the study. Age, sex, self-reported ancestry/race, T1D history, and other medical history information was obtained. DNA was extracted from the saliva samples and genotyping with a T1D-focused array using 74 SNPs (including 26 SNPs in the HLA region) provided data to generate a T1D GRS for each individual. Of the 3,818 children recruited, there was a slight excess of males (1,959, 51.3%), a majority of white and Hispanic/Latino ancestry (82.8%), and 91 (2.4%) with prevalent T1D. A total of 542 (14.2%) had "high T1D genetic risk" (T1D GRS > 5). Although the T1D GRS included non-HLA genetic variants, 80% of those with "high genetic risk" would have been classified using only those SNPs in the HLA region alone. Of children with "high genetic risk" and without pre-existing T1D (n=494), 7.0% (34/494) consented for islet autoantibody screening. Among children with pre-existing T1D (n=91), 52% (n=48) also had a "high genetic risk." The HLA-focused T1D GRS was not significantly associated with age at onset of T1D. Of those at high genetic risk that consented for autoantibody testing (n=34) and completed the blood collection (n=28), two (2/28, 7.1%) tested positive for multiple autoantibodies and were at significant risk of developing T1D. Follow up of 55% of parents/guardians identified 2 (of 2,096, 0.095%) participants who developed T1D, one at "high genetic risk" and one with a first-degree relative with T1D. A major factor in obtaining islet autoantibody testing was concern over SARS-Cov-2 exposure and an independent non-scheduled blood collection.Individual-level data at each SNP (genotyped and imputed) for T1D genetic risk and affiliated data are provided in dbGaP.

  Study phs003609

• NHLBI TOPMed: San Antonio Family Heart Study (SAFHS)

  The San Antonio Family Heart Study (SAFHS) is a complex pedigree-based mixed longitudinal study designed to identify low frequency or rare variants influencing susceptibility to cardiovascular disease, using whole genome sequence (WGS) information from 2,590 individuals in large Mexican American pedigrees from San Antonio, Texas. The major objectives of this study are to identify low frequency or rare variants in and around known common variant signals for CVD, as well as to find novel low frequency or rare variants influencing susceptibility to CVD. WGS of the SAFHS cohort has been obtained through three efforts. Approximately 540 WGS were performed commercially at 50X by Complete Genomics, Inc (CGI) as part of the large T2D-GENES Project. The phenotype and genotype data for this group is available at dbGaP under accession number phs000462. An additional ~900 WGS at 30X were obtained through Illumina as part of the R01HL113322 "Whole Genome Sequencing to Identify Causal Genetic Variants Influencing CVD Risk" project. Finally, ~1,150 WGS at 30X WGS were obtained through Illumina funded by a supplement as part of the NHLBI's TOPMed program. Extensive phenotype data are provided for sequenced individuals primarily obtained from the P01HL45522 "Genetics of Atherosclerosis in Mexican Americans" for adults and R01HD049051 for children in these same families. Phenotype information was collected between 1991 and 2016. For this dataset, the SAFHS appellation represents an amalgamation of the original SAFHS participants and an expansion that reexamined families previously recruited for the San Antonio Family Diabetes Study (R01DK042273) and the San Antonio Family Gall Bladder Study (R01DK053889). Due to this substantial examination history, participants may have information from up to five visits. The clinical variables reported are coordinated with TOPMed and include major adverse cardiac events (MACE), T2D status and age at diagnosis, glycemic traits (fasting glucose and insulin), blood pressure, blood lipids (total cholesterol, HDL cholesterol, calculated LDL cholesterol and triglycerides). Additional phenotype data include the medication status at each visit, classified in four categories as any current use of diabetes, hypertension or lipid-lowering medications, and, for females, current use of female hormones. Anthropometric measurements include age, sex, height, weight, hip circumference, waist circumference and derived ratios. PBMC derived gene expression assays for a subset of ~1,060 individuals obtained using the Illumina Sentrix-6 chip is also available from the baseline examination. The WGS data have been jointly called and are available in the current TOPMed accession (phs001215).

  Study phs001215

• Immunogenomics of Malignant Brain Tumors

  We performed systematic and comprehensive multi-sector immunogenomic analyses on 93 samples from a cohort of 30 patients with primary or recurrent gliomas or metastatic brain tumors, representing the largest cohort of these brain cancers studied spatially to date. For each patient, we characterized multiple spatially distinct regions using whole-exome (WES), custom capture validation, RNA, and TCR-sequencing. Our findings underscore the significant differences in clonal architecture between gliomas and metastatic brain tumors which translates into distinct neoantigen landscapes and, in turn, tumor infiltrating T cell clonotypic diversity. These data therefore provide high resolution insights into the immunogenomic landscapes within malignant brain tumors which may inform tumor-specific therapeutic approaches.

  Study phs002612

• Cancer Genetic Markers of Susceptibility (CGEMS) Breast Cancer Genome-wide Association Study (GWAS) - Primary Scan: Nurses' Health Study - Additional Cases: Nurses' Health Study 2

  The initial stage of the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer genome-wide association study (GWAS) included genotyping 528,173 SNPs (Illumina HumanHap550) in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls from the Nurses' Health Study (NHS). Subsequently, incident invasive breast cancer cases from the Nurses' Health Study 2 (NHS2) cohort were genotyped using the Illumina HumanHap 610 quad. The NHS2 cases are younger than the cases in the first stage of the CGEMS breast cancer GWAS, which only included postmenopausal women. The NHS2 cases are a mix of pre- and postmenopausal women

  Study phs000147

• Phase I Clinical Trial Describing the Pharmacogenomics of Aspirin

  The study protocol for both cohorts has been previously described (Journal of Thrombosis and Thrombolysis 2012:1-12). HV1 cohort: Briefly 50 healthy volunteers were exposed to two weeks of 325mg/day aspirin after which whole blood RNA was collected in PAXgene tubes and profiled by microarray before and after aspirin exposure. The pre-aspirin samples were profiled on the U133A 2.0 array and the post-aspirin samples were profiled on the U1333plus 2.0 array. HV2 cohort: Briefly 53 healthy volunteers were exposed to four weeks of 325mg/day aspirin after which whole blood RNA was collected in PAXgene tubes and profiled by U133plus 2.0 array before and after aspirin exposure.

  Study phs000548

• Germline

  This study is part of the 'First 1,000 Days of Life and Beyond' study at the Inova Translational Medicine Institute. Whole-genome sequencing data from 1,291 parent-offspring trios was used to study the properties of clustered de novo mutations. The maternal clusters were found to be enriched in regions with accelerated maternal mutation rate and show distinct mutational signatures. For additional details, please refer to: "Germline de novo mutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence". Jakob M. Goldmann, Vladimir B. Seplyarskiy, Wendy S.W. Wong, Thierry Vilboux, Pieter B. Neerincx, Dale L. Bodian, Benjamin D. Solomon, Joris A. Veltman, John F. Deeken, Christian Gilissen, John E. Niederhuber. Nature Genetics.

  Study phs001522