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• Whole Genome Sequencing Analysis in a Family of Discordant Twins With Non-Syndromic Microtia and Hemifacial Microsomia: Identification of Novel Candidate Genes and Variants

  This research is a non-NIH effort to discover the pathogenesis of non-syndromic microtia and to detect potential candidate genes. Microtia (OMIM 600674, 612290, 251800) is a spectrum of congenital anomalies and facial abnormalities, 90% of the cases followed by hearing loss. Two types of the disease are described in terms of connection to the affected syndromes: anomalies (syndromic) and only clinical manifestation (non-syndromic) associated with other symptoms. Though the exact pathogenesis of microtia remains unknown, pathogenic genes of majority of the microtia syndromic types have been identified. However, the genetic mutation of the non-syndromic microtia has not been confirmed. In this study, whole genome sequencing (WGS) was utilized to screen mutations in monozygotic discordant twins of congenital microtia-atresia and their family members. One of the twins, along with her grandfather, was discordant for microtia-atresia. By bioinformatic analysis of the WGS data from monozygotic twins with microtia and their non-microtia relatives, we proposed that among 28 identified potential genes, 4 of them (CNOT1, ODAD4, TBX15, and GIPC3) could be more responsible for non-syndromic microtia development and phenotypic features. Interested investigators may request to access the DNA genomic sequencing data of the study participants via dbGaP authorized access. In addition to raw genomic sequencing data, datasets of germline mutations and candidate gene mutations may also be available for investigators to request.

  Study phs003216

• HuBMAP: A Spatially Resolved Molecular Atlas of Human Endothelium

  The human circulatory system plays a vital role in the proper functioning of every organ in the human body. Because vascular related diseases, such as atherosclerosis, do not occur homogeneously throughout the vascular tree, differences in the endothelium of various organs must exist. There is even evidence of heterogeneity of adjacent endothelial cells. We are studying normal endothelium throughout the body and across individuals of different ages to characterize these differences. The first step will be to procure normal tissue samples from a wide range of organs. From disaggregated samples of these tissues, we will perform single cell combinatorial indexing (sci-) to generate chromatin accessibility (sci-ATAC-seq) and transcriptome (sci-RNA-seq) data from millions of single cells across hundreds of samples.  Molecular heterogeneity might correlate with multiple facets of the anatomical distribution of endothelium, including vascular vs. lymphatic, arteries vs. veins, capillaries vs. larger vessels, differences between organs, organ zonation, cell-to-cell differences, etc. Based on heterogeneous markers defined from deep profiling of disaggregated cells, we will employ seqFISH to spatially relate the distinct endothelial subpopulations arising from the single nuclei data to histologic preparations. For example, this will allow us to identify subpopulations with particular markers as arterial, capillary, venous, or lymphatic. The end product will include multiparameter images in which the complete gene expression and chromatin accessibility profile can be interactively visualized for every cell.

  Study phs002267

• Assessing mitochondrial bioenergetics in coronary artery disease: A translational left ventricular tissue study in humans (The AMBITION study).

  Severe or recurrent myocardial ischemia can lead to long-term left ventricular (LV) dysfunction and heart failure in patients with coronary artery disease (CAD). In this study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients with evidence of preoperative inducible ischemia undergoing coronary artery bypass grafting (CABG). During surgery, paired transmural LV biopsies were acquired on the beating heart from a region of inducible ischemia (determined by stress perfusion cardiovascular magnetic resonance), and a remote LV segment. From 33 patients, 63 LV biopsies were acquired on the beating heart during CABG, comparing to analysis of LV samples from 11 donor hearts. The global myocardial ATP/ADP ratio was reduced in CAD patients as compared to donor LV tissue with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained during CABG from LV segments with or without inducible ischemia revealed no significant difference in the ATP/ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Finally, differential metabolite analysis suggested dysregulation of several intermediates in patients with impaired LVEF; this notably included the tricyclic acid cycle metabolite, succinate. Overall, our results suggest that viable human myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

  Study EGAS00001007351

• Epigenetic age deceleration reflects fitness improvements following a six-month endurance exercise intervention

  Epigenetic clocks are emerging as promising biomarkers of biological aging, yet their sensitivity to short-term interventions remains unclear. This pilot study investigates whether the GrimAge clock can capture the effects of a six-month cycling-based endurance exercise training intervention, with cardiorespiratory fitness (VO₂ max) and body composition as primary outcomes. We enrolled 42 adults aged 35-65, of whom 38 completed the study and 33 adhered to the protocol (>66% adherence). Participants demonstrated significant improvements in VO₂ max (+20%, P < 0.001) and body composition (P < 0.001). High-quality epigenetic data preprocessing yielded highly reproducible GrimAge estimates (< 2 months measurement error), which strongly correlated with chronological age (R² = 0.86, P < 0.001). On average, GrimAge decreased by 7.44 months relative to the expected trajectory (P = 0.012), reflecting improvements in VO₂ max (R² = 0.27, P = 0.002) but not body composition changes. Notably, GrimAge changes strongly correlated with fluctuations in leukocyte composition, particularly neutrophil fraction (R² = 0.74, P < 0.001). Adjusting for leukocyte composition improved consistency in GrimAge changes, aligning them with additional intervention outcomes and explaining up to 81% of variance. These findings demonstrate that GrimAge is responsive to short-term endurance training, serving as a meaningful biomarker of improved cardiorespiratory fitness, while also capturing immune system variability. This study supports the use of GrimAge in evaluating longevity interventions and highlights the importance of accounting for leukocyte composition in epigenetic aging research.

  Study EGAS00001008221

• Oxidative phosphorylation is a key ontogenetic feature of monocyte immunometabolism promoting myeloid differentiation after birth

  Neonates primarily rely on innate immunity, yet their inflammatory responses to microbes, particularly those of monocytes, are usually restricted compared to adults. This is controversially interpreted as immaturity increasing the risk of sepsis or essential programming allowing immune adaptation after birth. Which changes the cellular immunometabolism undergoes after birth and its role in these concepts are poorly defined. Here, we applied transcriptomic, metabolic, and immunological approaches and found that monocytes exhibit an inverse ontogenetic balance of immunometabolism. Our data show that glycolysis in monocytes increases within the first year of life and fuels their inflammatory responsiveness. In contrast, oxidative phosphorylation (OXPHOS) is high in neonatal monocytes supporting myeloid differentiation but declines only gradually during the first five years of life. Treatment of neonatal monocytes with lipopolysaccharide induces an adult-like immunometabolic phenotype. Ketogenic diet restricts glycolysis in adult monocytes, but cannot reactivate OXPHOS and revive a neonatal-like immunometabolic phenotype, suggesting that neonatal metabolism is hardwired and cannot be restored by simple dietary changes. Transcriptional network and population-wide human variation analyses identified E2F1, MYB, STAT1 and FLI1 as important regulators of age-dependent cell functions and related energy demands in human monocytes. Collectively, our findings show that restricted glycolysis and increased OXPHOS are a physiological programming in neonatal monocytes. Premature switching to an adult-like metabolism could untimely enhance inflammatory responses and disrupt important myeloid differentiation, whereas microbial challenges accumulating during childhood seem to induce an essential gradual metabolic switch.

  Study EGAS00001007555

• Osteosarcoma 3D patient derived cultures to test genome-informed personalized treatment options; a feasibility study

  Background: Improving osteosarcoma treatment beyond conventional (neo)adjuvant chemotherapy and resection remains challenging. An urgent need for novel therapeutic options, particularly personalized and targeted approaches, has emerged due to high inter-patient molecular heterogeneity. A lack of representative in vitro and in vivo models impedes therapeutic development, therefore we aimed to create 3D in vitro long term culture models directly from patient material. Methods: Tumour cells from seven osteosarcoma patients were propagated in monolayer or collagen hydrogels, while whole-exome sequencing of corresponding primary tumour tissue was performed to identify potential drug targets. Established cultures were subsequently used to assess efficacy of the identified personalized treatment options. Results: Three out of seven hydrogel cultures harboured the same genetic alterations as the corresponding primary tumours. Among these, the L6565 patient line exhibited homozygous CDKN2A loss with retained Rb expression, rendering tumour cells sensitive to CDK4/CDK6 inhibition via palbociclib. This patient line was used to evaluate genome-informed therapy and to compare cell culture models of increasing complexity. Our findings demonstrate feasibility of establishing long-term patient-derived osteosarcoma cultures with a success rate of 14%. Tumour heterogeneity was reflected in advanced culture methods producing more variability in treatment response. Conclusion: These results highlight the potential of genome-informed therapies in osteosarcoma and the importance of refining culture techniques to enhance translational research and therapeutic outcomes.

  Study EGAS50000001583

• A New High-Throughput Sequencing-Based Technology to Study Heterochromatin Structure

  In this study we report epigenomic and transcriptomics datasets for normal control fibroblasts. The following cell lines were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research: AG08498, AG07095, originally collected as part of the NIA Aging Cell Repository study. We applied a high-throughput sequencing-based technique, named Sequential Analysis of MacroMolecules accessibilitY (SAMMY-seq), for the genome-wide mapping of chromatin regions separated by differential accessibility. The method is based on the sequential extraction of multiple chromatin fractions, corresponding to increasingly compacted and less accessible chromatin regions, which are mapped along the genome using high-throughput sequencing. Additionally we carried out ChIP-seq for the H3K9me3 and H3K27me3 histone modifications and RNA-seq for the characterization of transcriptome in control fibroblasts.

  Study phs002202

• Clinical Outcomes and ctDNA Correlates for CAPOX BETR: A phase II trial of Capecitabine, Oxaliplatin, Bevacizumab, Trastuzumab in Previously Untreated Advanced HER2+ Gastroesophageal Adenocarcinoma

  We performed circulating tumor DNA (ctDNA) analysis on plasma of patients with advanced HER2 positive gastroesophageal adenocarcinomas who were treated on a phase 2 clinical trial testing the addition of bevacizumab to capecitabine, oxaliplatin, and trastuzumab. ctDNA was analyzed using panel based next generation sequencing assay (Predicine CARE), low-pass whole genome sequencing (LP-WGS), and methylation based panel assay (Predicine ALERT). This allowed us to derive tumor mutational profiles, circulating tumor fractions in plasma, and changes in both over time. We show that tumor fraction and the presence of mutations in the MAPK pathway are prognostic in our patient cohort. LP-WGS data from baseline and cycle 2 of treatment is available through dbGaP. Additional data is submitted alongside the manuscript.

  Study phs003706

• Inferring causal genes at type 2 diabetes GWAS loci through chromosome interactions in islet cells

  Resolving causal genes for type 2 diabetes at loci implicated by genome-wide association studies (GWAS) requires integrating functional genomic data from relevant cell types. Chromatin features in endocrine cells of the pancreatic islet are particularly informative and recent studies leveraging chromosome conformation capture (3C) with Hi-C based methods have elucidated regulatory mechanisms in human islets. However, these genome-wide approaches are less sensitive and afford lower resolution than methods that target specific loci. Methods: To gauge the extent to which targeted 3C further resolves chromatin-mediated regulatory mechanisms at GWAS loci, we generated interaction profiles at 23 loci using next-generation (NG) capture-C in a human beta cell model (EndoC-βH1) and contrasted these maps with Hi-C maps in EndoC-βH1 cells and human islets and a promoter capture Hi-C map in human islets. Results: We found improvements in assay sensitivity of up to 33-fold and resolved ~3.6X more chromatin interactions. At a subset of 18 loci with 25 co-localised GWAS and eQTL signals, NG Capture-C interactions implicated effector transcripts at five additional genetic signals relative to promoter capture Hi-C through physical contact with gene promoters. Conclusions: High resolution chromatin interaction profiles at selectively targeted loci can complement genome- and promoter-wide maps.

  Dataset EGAD50000000517

• MATISSE bulk RNA-sequencing data

  Tumor availability: Bulk RNA sequencing was performed on tumor biopsies of 48 patients at baseline and 45 patients across time points (baseline n=48, week 1 n=38, week 2 n=34, week 4 n=37), including lymph node metastasis that were sequenced in addition to the primary tumor. Tumor RNA was extracted from formalin-fixed paraffin-embedded (FFPE) primary tumor and lymph node metastasis sections containing at least 10% viable tumor cells present in the sample, except for on-treatment samples with a complete pathological response in which we isolated samples with at least 10% immune-infiltration with no viable tumor cells. A pathologist (LS) scored the tumor percentage and indicated the most tumor-dense region on a hematoxylin and eosin (H&E) stain slide for subsequent RNA isolation. According to the manufacturer's protocol, five to 10 FFPE slides (10 µm) were used for RNA isolation using the AllPrep DNA/RNA FFPE isolation kit (Qiagen, 80234) and the QIAcube. Genetic Diagnostics and Sequencing Services (CeGaT) performed RNA sequencing in Germany. Data processing: Demultiplexing of the sequencing reads was performed with Illumina bcl2fastq (v2.20). Adapters of the reads (Pico v2 SMART adapter, first three nucleotides of the second sequencing read) were trimmed with Skewer (v0.2.2), without quality trimming. RNA-sequencing data was aligned to GRCh38 (Ensembl v109) using STAR (v2.7.9) in 2-pass mode with default settings. Gene counts were generated with the HTSeq (v2.0.2). FastQC (v0.12.1) and MultiQC (v1.14) were used for assessing data quality, on FASTQ files and intermediate processing steps.

  Dataset EGAD50000001470

• Nala TAS-LRS PGx Study

  Sequencing was performed on the PromethION Flow Cell R10 (M version) using the P2 Solo Sequencer (MinION release 24.02.16). The library was divided into three portions and loaded in a tapered manner across three time points. At the first time point, the initial portion of the library was loaded, and sequencing began in whole-genome mode (without adaptive sampling), to monitor QC (N50 within the expected range). After one hour, adaptive sampling was activated. A custom BED file was used to define the target regions (N=326). Each region was extended by 20 kb upstream and downstream, and overlapping regions were merged into non-redundant intervals using bedtools43, covering a total of 1.3% of the human genome. At the second time point (20–24 hours after sequencing began, or when fewer than 2000 pores remained active), the flow cell was washed following ONT’s Flow Cell Wash Kit protocol, and the second portion of the library was loaded. At the third time point (40–48 hours), the second portion of the library was retrieved, and merged with the third portion. The flow cell was washed and reloaded with the mixed library. POD5 files were basecalled using Dorado v0.8.1 in super-accuracy (SUP) mode with the dna_r10.4.1_e8.2_400bps_SUP@v5.0.0. Reads from the initial 1 h Whole Genome Sequencing (WGS) and subsequent 72 h adaptive sampling were filtered for Q-scores >10. Passing reads were demultiplexed using Dorado’s demux function, then combined per sample and mapped to the GRCh38 reference genome using Minimap2 v2.22. Files were converted to CRAM using samtools.

  Dataset EGAD50000001609

• A single-cell multi-omic atlas of nodal B-cell non-Hodgkin lymphomas

  Nodal B-cell non-Hodgkin lymphomas (B-NHL) are a clinically diverse set of cancers thought to originate from distinct stages of B-cell maturation. To characterize intratumor heterogeneity across B-NHL entities, we performed CITE-Seq (cellular indexing of transcriptomes and epitopes) on 51 lymph node samples including mantle cell lymphoma (MCL, n = 8), follicular lymphoma (FL, n = 12), germinal center (GCB, n = 5) or activated B-cell (non-GCB/ABC, n = 7) diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL, n = 11) tumors, in addition to non-malignant reactive lymph nodes (rLN, n = 8). We also performed 5 prime scRNA-seq with immune receptor profiling for 11 of these samples (2 rLN, 2 MCL, 3 FL, 2 DLBCL, and 2 MZL).

  Study EGAS50000000342

• Multiregional sequencing of IDH-WT glioblastoma reveals high genetic heterogeneity and a dynamic evolutionary history

  Glioblastoma is the most common and aggressive primary brain malignancy in adults. In addi-tion to extensive inter-patient heterogeneity, glioblastoma shows intra-tumor extensive cellular and molecular heterogeneity, both spatially and temporally. This heterogeneity is one of the main reasons for the poor prognosis and overall survival. Moreover, it raises the important question of whether the molecular characterization of a single bioptic sample, as performed in standard di-agnostics, actually represents the entire lesion. In this study, we sequenced the whole-exome of nine spatially different cancer regions of three primary glioblastomas. We characterized their mutational profiles and copy number alterations, with implications for our understanding of tu-mor biology in relation to clonal architecture and evolutionary dynamics, as well as therapeuti-cally relevant alterations.

  Study EGAS00001005128

• Relaxed selection during a recent human expansion

  To better understand and quantify the effect of a recent expansion process on the amount and pattern of mutation load, we screened the ascending genealogies of 3916 individuals from the CARTaGENE cohort (Awadalla et al. 2013) that were linked to the BALSAC genealogical database (http://balsac.uqac.ca/). Using stringent criteria on the quality of genealogical information, we selected (front) individuals whose ancestors were as close as possible to the front of the colonization of Quebec, and (core) individuals whose ancestors were as far as possible from the front. We then sequenced these 102 individuals at very high coverage (mean 89.5X, range 67X-128X) for 106.5 Mb of exomic and UTR regions and contrasted their genomic diversity to detect if sites with various degrees of conservation and deleteriousness had been differentially impacted by selection.

  Study EGAS00001001957

• Samples linked to the study "Performance comparison of three DNA extraction kits on human whole-exome data from formalin-fixed paraffin-embedded normal and tumor samples"

  We generated 42 human whole-exome sequencing data sets from fresh-frozen (FF) and FFPE samples. These samples include normal and tumor tissues from two different organs (liver and colon), that we extracted with three different FFPE extraction kits (QIAamp DNA FFPE Tissue kit and GeneRead DNA FFPE kit from Qiagen, Maxwell\textsuperscript{TM} RSC DNA FFPE Kit from Promega). Variant calling analysis shows a very high rate of concordance between matched FF / FFPE pairs and equivalent performance for the three kits we analyzed. We find a significant variation in the difference of total number of variants called between FF and FFPE samples for the three different FFPE DNA extraction kits. Coverage analysis shows that FFPE samples have less good indicators than FF samples, yet the coverage quality remains above accepted thresholds. We detect limited but significant variations in coverage indicator values between the three FFPE extraction kits. Globally, the GeneRead and QIAamp kits have better variant calling and coverage indicators than the Maxwell kit on the samples used in this study, although this kit performs better on some indicators and has advantages in terms of practical usage. Taken together, our results confirm the potential of FFPE samples analysis for clinical genomic studies, but also indicate that the choice of a FFPE DNA extraction kit should be done with careful testing and analysis beforehand in order to maximize the accuracy of the results.

  Dataset EGAD00001004066

• Open Targets 020 Epigenomes of Cell Lines (2018-10-23)

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-10-23.

  Dataset EGAD00001004415

• FOXM1 is a biomarker of resistance to PI3Kα inhibition in ER+ breast cancer that is detectable using metabolic imaging (RNA-seq data)

  PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires novel predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER+ breast cancer. Since the transcription factor drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II), changes in FOXM1 expression can be detected using magnetic resonance imaging of LDH-catalyzed hyperpolarized 13C label exchange between pyruvate and lactate but not by PET measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[18F]fluorodeoxyglucose.

  Study EGAS00001004452

• Population Architecture Using Genomics and Epidemiology (PAGE): Epidemiologic Architecture for Genes Linked to Environment (EAGLE) - BioVU Cancer Project

  As part of Population Architecture using Genomics and Epidemiology PAGE study (Phase I), the Epidemiologic Architecture using Genomics and Epidemiology (EAGLE I) project accessed both epidemiologic- and clinic-based collections. The epidemiologic-based collection of EAGLE I included the National Health and Nutritional Examination Surveys (NHANES), ascertained between 1991-1994 (NHANES III), 1999-2002, and 2007-2008. NHANES is a population-based cross-sectional survey now conducted every year in the United States to assess the health status of Americans at the time of ascertainment and to assess trends over the years of survey. Genetic NHANES consists of 19,613 DNA samples linked to thousands of variables including demographics, health and lifestyle variables, physical examination variables, laboratory variables, and exposures. NHANES is diverse with almost one-half of the samples (46.4%) coming from self-reported Mexican Americans and non-Hispanic blacks. In contrast to NHANES, BioVU is a clinic-based collection of >150,000 DNA samples from Vanderbilt University Medical Center linked to de-identified electronic medical records (EMRs). Approximately 12% of BioVU's overall DNA sample collection is from African American, Hispanic, and Asian patients. The overall goals of PAGE I and EAGLE I were broad and several-fold: Replicate genome-wide association study (GWAS)- identified variants in European Americans; Identify population-specific and trans-population genotype-phenotype associations; Identify genetic and environmental modifiers of these associations. NHANES is an excellent resource for the study of quantitative traits associated with common human diseases. However, given that the age range of NHANES spans childhood to late adulthood and not all diseases are surveyed, NHANES is less useful for the study of adult-onset diseases such as major cancers. Therefore, under American Recovery and Reinvestment Act (ARRA) funding, EAGLE as part of PAGE I defined eight major cancers sites for genetic analysis in BioVU, Vanderbilt's biorepository linked to de-identified EMRs. The eight major cancers defined for this study included melanoma, breast, ovarian, prostate, colorectal, lung, endometrial, and Non-Hodgkin's lymphoma (NHL). Cancer cases were defined using a combination of ICD-9 codes and tumor registry entries. Controls include BioVU participants without cancer and encompassing the age and gender distributions of cancer cases. Targeted genotyping of GWAS-identified variants for these diseases (124 SNPs) and ancestry informative markers (128 AIMs) was performed by the Center for Human Genetics Research Vanderbilt DNA Resources Core. After quality control, a total of 116 cancer-associated SNPs and 122 AIMs were available for downstream analyses.

  Study phs000559

• National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) Consortium Glaucoma Genome-Wide Association Study

  This is a case-control study of primary open angle glaucoma (POAG). POAG is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. For this study we have formed a collaborative consortium contributing 2170 POAG cases and 2347 controls with a unified definition of POAG (the NEIGHBOR consortium: NEI Glaucoma Human genetic collaBORation). The case definition has also been harmonized with an additional 976 cases and 1140 controls from the NHGRI supported GENEVA (gene-environment) study of glaucoma (GLAUGEN) (NIH/NHGRI U01HG004728, Pasquale PI). 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. Cases and controls were also drawn from two clinical trial populations: Advanced Glaucoma Intervention Study (AGIS, NEI U10EY006827, D. Gaasterland PI) and Collaborative Initial Glaucoma Treatment Study (CIGTS, NEI U10 EY009149, P. Lichter PI). The NEIGHBOR consortium has two Co-Principal Investigators: J. Wiggs (Harvard, MEEI), and M. Hauser (Duke). The consortium includes eleven different centers where data collection and analysis take place. The eleven sites and investigators are: Harvard Medical School (Massachusetts Eye and Ear Infirmary) (J. Wiggs, L. Pasquale); Duke University Medical Center (M. Hauser, E. Hauser, R. Allingham, S. Schmidt); University of Michigan (J. Richards, S. Moroi, P. Lichter); University of Miami (M. Pericak-Vance, R. Lee, D. Budenz); Vanderbilt University (J. Haines); University of California San Diego (K. Zhang, R. Weinreb; T. Gaasterland); University of Pittsburgh (J. Schuman, G. Wollstein); University of West Virginia (A. Realini, J. Charlton, S. Zareparsi); Johns Hopkins University (D. Friedman, D. Zack); Stanford University (D. Vollrath, K. Singh), Eye Doctors of Washington (D. Gaasterland). Hemin Chin serves as the NEI Staff Collaborator. This national collaborative study is supported by multiple NIH grants: NEI R01 EY015543 (Allingham); NEI U10 EY006827 (D. Gaasterland); NHLBI R01 HL073389 (E. Hauser); NEI R01 EY13315 (M. Hauser); NEI U10 EY009149 (Lichter); NEI R01 EY015473 (Pasquale); NEI U10 EY012118 (Pericak-Vance); NEI R03 EY015682 (Realini); NEI R01 EY011671 (Richards); NEI R01 EY09580 (Richards); NEI R01 EY013178 (Schuman); NEI R01 EY015872 (Wiggs); NEI R01 EY009847 (Wiggs); NEI R01 EY010886 (Wiggs); NEI R01 EY144428 (Zhang); NEI R01 EY144448 (Zhang); NEI R01 EY18660 (Zhang). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Eye Institute (X01HG005259).

  Study phs000238

• NHLBI TOPMed - NHGRI CCDG: The Johns Hopkins University School of Medicine Atrial Fibrillation Genetics Study

  Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is the primary cause of many hospital admissions, and is associated with significant secondary morbidity by increasing the risk of stroke, heart failure, and all-cause mortality. The incidence of AF is on the rise, and it is projected that by the year 2050 more than 10 million patients will be affected by AF in the United States alone. Anti-arrhythmic medications have limited success in maintaining sinus rhythm, are associated with side effects, and appear ineffective at reducing mortality compared to a strategy of rate control and anticoagulation. Given the significant morbidity associated with this common arrhythmia, surgical and catheter ablation techniques have been developed to treat AF. However, despite the incorporation of various strategies for ablation, long-term recurrence rates of AF remain higher than 25 percent after ablation. Current techniques for catheter ablation of AF include pulmonary vein isolation and complex fractionated atrial electrogram (CFAE) ablation. However, the contribution of each strategy to long-term procedural success and the relative importance of each strategy for different patients remain unknown. Recent advances in cardiac imaging have allowed detailed analysis of left atrial myocardial anatomy. Parallel advances in molecular genetics have identified several candidate genes involved in familial and non-familial AF. However, the pathophysiology of AF generation and maintenance, and the potential contribution of such genetic or anatomic substrates for patient selection, and for target identification during catheter ablation have not yet been examined. Advances in molecular genetics and imaging, coupled with techniques for endocardial and epicardial mapping in the electrophysiology laboratory present an opportunity to significantly improve our understanding of (1) The relation of paroxysmal versus persistent AF with (a) structural left atrial changes (left/right atrial scar, wall thinning, pulmonary vein anomalies, and coronary sinus dilation) and with (b) candidate genetic variants. (2) The relation of candidate genetic variants with (a) structural left atrial changes and with (b) electrophysiologic properties (atrial effective refractory period (AERP) inhomogeneity, voltage abnormalities, trigger burden and location, C FAE extent and location), (3) The relation of structural left atrial changes with (a) CFAE location as targets for catheter ablation and with (b) reversible conduction block/myocardial injury after pulmonary vein isolation, and (4) Individualized endocardial targets for AF ablation based on candidate genes and anatomic substrates. The proposed study will improve our understanding of the underlying pathophysiology of AF, and may improve current techniques for treatment of this important arrhythmia.

  Study phs001598

• Germline and Somatic Genetic Landscape of Pediatric Rhabdomyosarcoma

  Dynamic approaches that integrate population-based research and molecular biology are needed to explain the mechanisms underlying pediatric rhabdomyosarcoma (RMS) and to determine novel prevention strategies. RMS, the most common soft-tissue sarcoma in children and adolescents, has one of the poorest 5-year survival rates among all pediatric cancers (less than 65%). One of the strongest risk factors for RMS is having a cancer predisposition syndrome. The syndromes that are most commonly seen among those with RMS are Li-Fraumeni, neurofibromatosis type 1, Costello, Noonan, and DICER1. Based on smaller clinic-based studies, only about 7% of RMS cases are thought to be associated with the genes responsible for these syndromes. However, there have been no population-based assessments to support this estimate. Even in the most recent large-scale evaluations of germline mutations in predisposition genes among children with cancer, very few RMS cases were included (43 cases). Furthermore, no distinctions were made between the major histologic subtypes of RMS: embryonal (eRMS) and alveolar (aRMS), which display differences in terms of age distribution, incidence, and cytogenetics. For instance, nearly 80% of alveolar cases are driven by a chromosomal translocation between either PAX3 or PAX7 and FOXO1, whereas these fusions are not seen in embryonal cases. In fact, RMS research is shifting from categorization based on histology to fusion status (eRMS is overwhelmingly fusion-negative). Another limitation in previous studies has been the inability to evaluate the frequency of de novo germline mutations (DNMs) in cancer predisposition genes due to the absence of any well-characterized cohorts of RMS case-parent trios. Therefore, a major gap in our understanding of the role of cancer predisposition in pediatric RMS that limit translational impact is there have been no population-based assessments to determine the true impact of these mutations on pediatric RMS, which limits clinical sequencing guidelines and surveillance protocols in these children.Overall Project Strategy: The objective of this project is to advance our understanding of the relationship between cancer predisposition genes and pediatric RMS. Our central hypotheses are: 1) mutations in cancer predisposition genes are more common than expected in children with RMS; and 2) children with fusion-negative tumors have a higher burden of germline mutations than those with fusion-positive tumors. The framework for this study relies on >600 well annotated samples collected from newly diagnosed RMS patients and stored in the Children’s Oncology Group (COG) Biopathology Center.

  Study phs002304

• Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease

  The purpose of this project is to identify the genetic factors contributing to dental caries in children and adults. The datasets come from the Center for Oral Health Research in Appalachia (COHRA), which has the long-term goal of determining the sources of oral health disparities in a high risk, Northern Appalachian population so that effective preventive interventions can be designed and targeted. The Specific Aims of this project are to perform genome-wide association scans of dental caries of the (1) primary dentition in children, and (2) permanent dentition in adults, to identify novel risk variants and to replicate previously nominated risk variants. This project brings together samples from three cohorts: COHRA1 is a cross-sectional cohort comprising members of 862 northern Appalachian families; approximately 80% of the cohort has been previously genotyped by the Center for Inherited Disease Research with support from NIDCR using the Illumina Quad W array (see dbGaP Study Accession: phs000095.v3.p1). Dental SCORE is a cross-sectional cohort comprising approximately 550 unrelated individuals who underwent the same data collection protocol as COHRA1. COHRA2 is an ongoing longitudinal cohort that recruited approximately 1100 northern Appalachian women during pregnancy, and followed them and their children through their children's early childhood; the current project period will continue data collect though age 6 of the child. Phenotypes for this project were derived from intra-oral examinations performed by trained and calibrated research hygienists. In brief, each tooth was recorded as present or absent, and each surface of each present tooth was scored for evidence of decay. From these data, dental caries indices were generated. This project contains two phases of genotyping: (1) collection of exome SNP Chip data for the previously genotyped COHRA1 samples, and (2) collection of whole-genome SNP Chip data for the remaining COHRA1 samples and all Dental SCORE and COHRA2 samples. These data will support efforts to test hypotheses regarding the causal relationships of risk factors contributing to the unusually high rates of caries formation in the Appalachian population. Ultimately, these data may inform the development of an integrated model of caries risk, in which the effects of genetics, oral ecology, diet, and other environmental/psychosocial factors and behaviors are modeled in concert to explain the disparities, including the high rate of caries onset before age 6. The gene-mapping Aims of this project, which seek to identify the genetic factors that contribute to caries risk, are a requisite step in realizing this integrated model.

  Study phs001591

• Heart Failure Network: Functional Impact of GLP-1 for Heart Failure Treatment (HFN FIGHT-BioLINCC)

  Objectives To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure. Background Heart failure was the leading cause of hospitalization in the United States with more than 4 million admissions per year from 2003–2009. Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). As heart failure progresses, these abnormalities become more pronounced and are observed in both patients with and without type 2 diabetes. At this time of this study, there was no heart failure therapy that targeted these metabolic abnormalities; however, in earlier clinical studies, glucagon-like peptide 1 (GLP-1) agonists showed cardioprotective effects in patients with advanced heart failure, irrespective of type 2 diabetes status. Glucagon-like peptide 1 is an endogenous incretin hormone that improves insulin sensitivity with minimal risk of hypoglycemia. This study was created to determine if use of GLP-1 agonists improved clinical stability in recently hospitalized patients with acute heart failure and reduced LVEF. Participants There were 300 participants. Design Participants were identified by hospital admission records and were enrolled during either the last 24 hours of his or her hospitalization for heart failure or the 2-week interval after the hospitalization. Baseline evaluations were conducted, which included echocardiographic measures, the 6-minute walk test, the Kansas City Cardiomyopathy Questionnaire (KCCQ), and blood tests. After the baseline evaluation, patients were randomized in a 1:1 ratio to receive either the GLP-1 agonist liraglutide or placebo as a daily subcutaneous injection. The protocol involved titration of study drug dosage as tolerated every 14 days from 0.6 mg/d to 1.2 mg/d to 1.8 mg/d during the first 30 days of the trial (as tolerated). Follow-up testing was performed at 30-, 90-, and 180-day study visits. The primary end point was a global rank score in which all participants, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level from baseline to 180 days. Conclusions The GLP-1 agonist liraglutide did not improve post-hospitalization clinical stability in patients with advanced heart failure and reduced LVEF. There was no significant between-group difference in the global rank scores and furthermore, there were no significant differences detected in any of the secondary endpoints.

  Study phs003542

• Framingham Heart Study-Cohort (FHS-Cohort) - Imaging

  The Framingham Heart Study (FHS) is a population-based, observational cohort study initiated in 1948 to prospectively investigate the determinants of cardiovascular disease to guide public health prevention. The FHS began by recruiting an Original Cohort of 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, who had not yet developed overt symptoms of cardiovascular disease or suffered a heart attack or stroke. The Original cohort Exam 1 took place between 1948 and 1953. Since that time the cohort has had a total of 32 biennial exams (ending in 2014) and event follow-up through 2022. In 1971, the FHS added the Offspring cohort, comprising 5124 children whose parents were enrolled in the Original cohort and the spouses of the children. This cohort on average has been examined every three to four years. However, there was an eight year gap between Exam 1 and Exam 2 and a seven year gap between Exam 7 and Exam 8. The latest exam (10) was completed in 2022. In 2002, the transgenerational FHS design was facilitated with the recruitment of 4095 children of the Offspring cohort (Third Generation), and 103 spouses of the Offspring who were not previously enrolled in the study (New Offspring Spouses, NOS). These cohorts have completed 3 exams through 2019. To reflect the changing demographic characteristics of the greater Framingham community, the FHS additionally recruited and enrolled 2 cohorts comprising racial and ethnic minority groups, termed Omni-1 and Omni-2, (n = 506 and 410, respectively) in 1995 and 2002, respectively. These cohorts included individuals of African American, Hispanic, Asian, Indian, Native American, and Pacific Islander descent. The OMNI-1 cohort have completed 5 exams through 2022. The OMNI-2 cohort have completed 3 exams through 2019. Data available for request include Echocardiogram images, available from the following exams in each cohort. Original Cohort: exams 18-32; Offspring cohort: exams 3-10; Third Generation, NOS and OMNI-2 cohorts: exams 1-3; OMNI-1 cohort: exams 1-5.CT image data at one or two timepoints were added for 4427 participants in the offspring, third generation, and OMNI1 and OMNI2 cohorts.Summary level phenotypes for the Framingham Cohort study participants can be viewed at the top-level study page phs000007 Framingham Cohort. Individual level phenotype data and molecular data for all Framingham top-level study and substudies are available by requesting Authorized Access to the Framingham Cohort study phs000007.

  Study phs003593

• TNBC ctDNA Targeted Panel

  Circulating tumour DNA (ctDNA) detection in liquid biopsy is an emerging alternative to tissue biopsy, but its utility in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) remains to be well understood. In this study, we determined the presence of early stage TNBC ctDNA detectable actionable mutations with a clinically validated hotspot treatment indication panel. Sequencing of plasma DNA from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in NAT protocols may be identifiable by combining tissue response and sensitive ctDNA detection.

  Study EGAS00001006937

• Targeted gene fusion sequencing (Fus-seq) in mesothelioma

  This is a small pilot data set to test the feasibility of cDNA exomes across 1200 cancer cell line panel. cDNA exomes or Fus-seq is further explained in this studies Abstract.

  Dataset EGAD00001000361

• Signatures of mismatch repair deficiency in cancer genomes

  DNA replication errors occurring in mismatch repair (MMR) deficient cells persist as mismatch mutations and predispose to a range of tumors. Here, we sequenced the first whole-genomes from MMR-deficient endometrial tumors.

  Dataset EGAD00001000641

• Siberia.Pakendorf

  The tar archive contains a) the txt file with the genotypes, b) illumina annotation file with info on SNPs, c) sample info file unfiltered illumina data, autosomes only data from Pugach et al MBE 2016 The Complex Admixture History and Recent Southern Origins of Siberian Populations

  Dataset EGAD00010002304

• WGS of human colorectal cancer organoid exposed to genotoxic pks+ E. coli

  Organoid cultures were exposed to different E.Coli strains and a dye control. In total 25 organoid cultures were whole-genome sequenced using the Novaseq6000 platforms. The data is deposited as .bam format.

  Dataset EGAD50000000304

• A neoadjuvant, phase II trial demonstrates efficacy and tolerability of Talimogene laherparepvec in cutaneous basal cell carcinoma (NeoBCC trial)

  This dataset is related to the NeoBCC trial and includes 12 human tissue samples

  Dataset EGAD50000000371

• NHLBI TOPMed: Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid (CLIC)

  Within-subject clinical responses to either inhaled corticosteroids or Montelukast were compared in 126 children with mild to moderate asthma.

  Study phs001729

• DupiAERD

  Dataset contains bulk RNA sequencing reads from 44 NERD patients under dupilumab therapy before and after aspirin provocation at baseline and after 24 weeks of treatment. Dataset is a multiplexed .bam file containing all sequencing reads with tagged identifiers.

  Dataset EGAD50000000565

• Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH

  We report single-cell RNA sequencing data from myeloid cells of the human visceral adipose tissue in non-alcoholic fatty liver disease patients

  Dataset EGAD50000000615

• Whole Genome - HAP-1 clones

  Whole genome sequencing on HAP-1 clones wild-type or knockout for MBD4 and/or TDG. Libraries were prepared using the Kapa HyperPrep kit (Roche, 07962363001). Paired-end libraries (2 x 100 bp) were sequenced on a NovaSeq 6000 instrument (Illumina).

  Dataset EGAD50000000765

• Moroccan Genome Project: Sequencing Data from 109 Whole Genomes of Moroccan Individuals

  This study is the first phase of the Moroccan Genome Project, which included the complete sequencing of 109 genomes from the Kingdom of Morocco. The sequencing was performing using the Illumina NovaSeq6000 platform, with a mean coverage of 30X.

  Dac EGAC50000000353

• CRC organoid RNA-seq data access committee

  This DAC is responsible for granting access to RNA-seq data (paired-end FASTQ files) from 10 patient-derived colorectal cancer organoid patients. The data was ad hoc generated as part of the development of NovumRNA, a non-canonical tumor-specific antigen prediction pipeline.

  Dac EGAC50000000406

• Exome-sequencing on early oral squamous cell carcinoma with clear margins

  Whole exome sequencing (WES) on early oral squamous cell carcinoma (OSCC) with clear margins, and on resection margins, 86 patients with a median follow-up of 58 months (range 30.4-83 months). Raw data (fastq format).

  Dataset EGAD50000001209

• Acute Lymphoblastic Leukemia WES dataset

  This dataset includes illumina paired-end reads (fastq) of whole-exome sequencing (WES) data from three acute lymphoblastic leukemia patients. Tumor samples were obtained from patients, each with matched patient’s peripheral blood mononuclear cells (PBMCs). PBMCs are provided as a germline reference.

  Dataset EGAD50000001355

• single cell RNA seq

  A selection of samples was analyzed using single-cell RNA sequencing to explore cellular heterogeneity. 4 inflammatory diseases were chosen for this purpose: Still’s disease, recurrent pericarditis, familial Mediterranean fever (FMF), and chronic non-bacterial osteomyelitis (CNO).

  Dataset EGAD50000002022

• T cell receptor repertoire in cell-free DNA as a proxy for tumor infiltrates in patients treated with pembrolizumab

  Bulk TCR sequences from tumor, peripheral blood mononuclear cell (PBMC), and cell-free DNA (cfDNA) samples from 81 patients with solid tumors treated with pembrolizumab.

  Dataset EGAD50000001857

• Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas

  55 Supratentorial Ependymomas patient samples were sequenced scRNA-sequencing using Smart-Seq2 and 10x protocol (51 samples) and 10x Genomics protocol (4 samples) on a NextSeq 550 sequencer (Illumina).

  Dataset EGAD50000002186

• Pacbio_methylation_cases

  The PacBio cases dataset for differential methylation analysis included 10 case samples with known KMT2A loss-of-function variants, 2 VUS samples. All samples were sequenced using PacBio Revio® HiFi reads at a matched coverage of 15X, and methylation was called using pb-cpg-tools on aligned BAM files.

  Dataset EGAD00010002807

• RNA-seq for 8 samples

  This dataset contains RNA-seq data from 8 acute leukemia cases (diagnosis or relapse) belonging to a newly identified subtype, termed FOXF1/FENDRR ALL. All the 8 samples are in bam file type.

  Dataset EGAD50000001789

• ATAC-seq for 2 samples

  This dataset contains ATACseq data from ta primary sample and a patient derived model (PDX) of the novel FOXF1/FENDRR ALL subtype. All the 2 samples are in bam file type.

  Dataset EGAD50000001791

• Long-read whole-genome sequencing dataset of aplastic anemia

  This dataset contains long-read whole-genome sequencing data generated from patients with aplastic anemia and RCC. Genomic DNA was prepared for long-read sequencing and sequenced using single-molecule real-time technology on a PacBio platform.

  Dataset EGAD50000002257

• Cancer RNA-seq consisting of FASTQ single-end reads from colon cancer sample

  Cancer RNA-seq consisting of FASTQ single-end reads from 1 colon-cancer individual RNA-seq was performed on illumina This dataset contains reads from a single region.

  Dataset EGAD00001007949

• ctDNA mutation analysis using the SiMSen-seq approach

  Mutation analysis in plasma samples with low ctDNA levels using a molecular barcoding technology, i.e. the single target approach SiMSen-seq (Simple, multiplexed, PCR-based barcoding of DNA for sensitive mutation detection using sequencing).

  Dataset EGAD00001006104

• DESIGN-VUMC low coverage WGS

  Low-coverage whole genome sequencing data of 37 HPV-negative HNSCC specimens from patients treated at the VU Medical Centre, Amsterdam. HNSCC biopsy samples obtained prior to treatment (chemo-radiotherapy) were used for WGS to a depth of approx. 0.5X.

  Dataset EGAD00001005719

• DESIGN-NKI low coverage WGS

  Low-coverage whole genome sequencing data of 37 HPV-negative HNSCC specimens from patients treated at The Netherlands Cancer Institute. HNSCC biopsy samples obtained prior to treatment (chemo-radiotherapy) were used for WGS to a depth of approx. 0.5X.

  Dataset EGAD00001005718

• HV31 - Oxford Nanopore PromethION long-read sequencing

  Oxford Nanopore long-read sequencing data for individual HV31 generated using DNA from CD14+ monocytes, to a sequencing depth of ~63×. Sequencing was performed at the Wellcome Centre for Human Genetics using the Oxford Nanopore PromethION platform.

  Dataset EGAD00001007043