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• Coloured Project - Lankheet et al

  The data is for non-commercial use only.

  Dac EGAC50000000240

• European Genome-phenome Archive 15th Anniversary Celebration

  2023 marks the 15th Anniversary of the EGA, jointly managed by the European Bioinformatics Institute (EMBL-EBI) and the Centre for Genomic Regulation (CRG). To mark the occasion, a simultaneous celebration was held in both institutions on the 13th of December 2023. The teams gathered online to play a quiz game and celebrate all the achievements and milestones with two wonderful anniversary cakes. In 2008, the European Genome-phenome Archive was created at the EBI-EMBL in Cambridge to guarantee that human genome and phenome data were available to the international scientific community while data privacy was preserved. The six-person staff at the beginning of the project is now far behind us, with a team that reaches the number of 35 members. Since 2013, the European Bioinformatics Institute and the Centre for Genomic Regulation share responsibility for The European Genome-phenome Archive (EGA). At that time, the EGA had data for about 0,5 petabytes. Currently, the Archive contains more than 12 petabytes. 2023 comes to an end with several good news. The EGA has been renewed as an ELIXIR Core Data Resource. This was announced during the GA4GH 11th Plenary held in San Francisco last September when ELIXIR-Beacon was also confirmed to be a GA4GH Driver Project. Thus, the Beacon API has maintained this title since 2018. What’s more, the first Federated EGA dataset is now live on our website. This year we also launched new services for EGA users in September. By the numbers, in 2023 the EGA counts 2.5 PB archived, 371 studies published, 208 new submitters and 19 active projects in which the team is participating, among others. We look forward to continuing to support your research in 2024!

  Blog 15-anniversary

• Sensitive detection of tumor mutations from blood and its application to immunotherapy prognosis

  Cell-free DNA (cfDNA) is attractive for many applications, including cancer detection, locating, and monitoring. A fundamental task underlying these applications is the SNV calling from cfDNA, which, however, faces a new challenge, namely, the generally very low tumor content in cfDNA. Thus all existing callers fail to achieve satisfactory performance. Here we present cfSNV, a method incorporating multi-layer error suppression and hierarchical mutation calling, to address this important challenge. Furthermore, by leveraging cfDNA’s comprehensive coverage of clonal landscape, for the first time cfSNV can profile mutations even in subclones. In both simulated and real patient data, cfSNV vastly outperforms existing tools, showing tens of times increase in sensitivity in detecting mutations with low allele frequency while maintaining high precision. cfSNV can enhance the clinical utilities of cfDNA by dramatically reducing the required sequencing depth and therefore reduce the cost by magnitudes, and further make the Whole-Exome-Sequencing of cfDNA a viable option. As an example, we demonstrate that cfDNA-WES allows a new biomarker to effectively select patients for immunotherapy.

  Study EGAS00001004373

• Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2

  Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of defined 3D hAT2 cultures as models for respiratory diseases.

  Study EGAS00001004508

• Genome-wide Association Study of Myasthenia Gravis

  The purpose of this project was to conduct a genome-wide associate study to search for the genetic factors that predispose to myasthenia gravis. The rationale for this study lies in the fact that, although the immunological and physiological processes affecting the neuromuscular junctions of myasthenia gravis patients are well understood, the spectrum of genetic factors that predispose to myasthenia gravis and influence its disease manifestations are not well known. Identification of the myasthenia gravis-related genes will shed light on the fundamental cellular events underlying myasthenia gravis, and will provide focus for research aimed at developing therapies that alter the natural course of the disease. A consortium of fourteen institutions in North America collected DNA samples from 1028 people diagnosed with autoimmune myasthenia gravis. Relevant clinical data have been collected for each patient, including age of onset, severity of disease, response to drug therapy, personal and family history of other autoimmune diseases. Genotyping of the case cohort was performed in the Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD. Genotyping of the case cohort was performed using the HumanOmniExpress-12v1_C SNP array manufactured by Illumina Inc. For the control cohort, we downloaded genotype data from dbGAP (accession phs000196.v2.p1) for 1,998 US neurologically normal individuals. The control cohort had been previously genotyped at the Center for Inherited Disease Research at Johns Hopkins University on HumanOmni1-Quad version 1.0B beadchips (Illumina) as part of the NeuroGenetics Research Consortium GWAS of Parkinson's disease. Analyses were confined to the 677,673 autosomal SNPs that were common to both chips. Of the 1028 samples which were genotyped, 21 samples were excluded due to mismatched genders, 9 were excluded due to low genotype call rate, 5 samples were excluded as duplicates, and 25 samples were excluded as ethnic outliers. The remaining 972 samples were used in analysis.

  Study phs000726

• Helse Bergen HF Data Access Committee for the MetBreCS trial dataset submitted to Federated EGA Norway

  This Data Access Committee is appointed by Helse Bergen HF to administer access requests for the MetBreCS trial dataset submitted to Federated EGA Norway.

  Dac EGAC50000000523

• Functional Analysis of Genetic Variants in African Americans with Breast Cancer

  The goal of this study is to identify and characterize novel genetic variants associated with a predisposition to breast cancer (BCa) in African Americans (AAs) using a family case-family control study design. Variants of unknown clinical significance (VUS) were characterized using bioinformatics tools. Future studies will further characterize select VUSs using in vitro genomic editing methods and functional assays to determine the functional consequences. The targeted sequencing data is made available for 85 actionable cancer genes. These genes have been previously classified with deleterious mutation(s) and whose phenotype results in a specific, defined medical recommendation(s).

  Study phs002977

• Rapid Acceleration of Diagnostics - Digital Health Technologies (RADx-DHT): NIH Digital Health Solutions for COVID-19: Clear2Go - A Digital Identity Wallet for Health Status

  Clear2Go is a solution/app that provides digital, non-refutable cryptographic proof of testing or vaccination that can be used to evaluate risk of allowing individuals to return to normal work, travel, and public life activities. It is a mobile service that maps a person's vetted identity and biometrics to the phone and then cryptographically binds it with their COVID-19 test and vaccination records. The person can then prove their status by utilizing the credentials with a QRCode or NFC tap.DOI: https://rapids.ll.mit.edu/10.57895/b2d6-8060

  Study phs002628

• mRNA-seq of paired Follicular Lymphoma (FL) patient samples before and after high-grade transformation to DLBCL (FL vs. tFL) from FFPE tissues

  The aim of this study was to analyze transcriptional changes in paired samples of follicular lymphoma (FL) and its histological transformation (tFL). Transformation of FL is an adverse event in the course of the disease and is associated with poor outcome. Several genetic aberrations have been linked to tFL pathogenesis, but gene expression changes and microenvironmental interactions have not been well characterized. We performed RNA profiling of FL and paired tFL samples transformed to DLBCL (n=11 pairs). For RNA profiling, we utilized libraries prepared using RNA isolated from archival FFPE tissues.

  Study EGAS50000000941

• miRNA-seq of paired Follicular Lymphoma (FL) patient samples before and after high-grade transformation to DLBCL (FL vs. tFL) from FFPE tissues

  The aim of this study was to analyze transcriptional changes in paired samples of follicular lymphoma (FL) and its histological transformation (tFL). Transformation of FL is an adverse event in the course of the disease and is associated with poor outcome. Several genetic aberrations have been linked to tFL pathogenesis, but gene expression changes and microenvironmental interactions have not been well characterized. We performed miRNA profiling of FL and paired tFL samples transformed to DLBCL (n=10 pairs). For miRNA profiling, we utilized libraries prepared using RNA isolated from archival FFPE tissues.

  Study EGAS50000000942

• Divergent WNT Signaling and Drug Sensitivity Profiles within Hepatoblastoma Tumors and Organoids

  Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic ‘fetal’ and WNT-high ‘embryonal’, displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes.

  Study EGAS50000000561

• Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

  Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas and characterize its features using multi-omics profiling. We aim to deepen the knowledge about the biology and clinical features of ALT-positive neuroblastomas by enriching ALT tumors in the study cohort independent of ATRX mutation status. Using a combination of genomic, transcriptomic and proteomic profiling, we provide evidence that this subgroup is clinically and molecularly distinct.

  Study EGAS00001004349

• Fetal Chorioamniotic Membranes Show Molecular Changes in Placenta Previa and Placenta Accreta Spectrum

  Placenta previa and the placenta accreta spectrum (PAS) are understudied pregnancy disorders with serious consequences for both mother and infant. To better understand the molecular and cellular etiologies of these diseases, we performed 3SEQ of formalin-fixed paraffin-embedded (FFPE) fetal chorioamniotic membrane samples from PAS, previa, and gestationally age-matched spontaneous pre-term birth samples to identify molecule signatures of these diseases. These samples were subsequently validated using a second validation cohort of previa, PAS, and control patients. FFPE archival samples provide opportunities for retrospective molecular investigation of many diseases.

  Study phs002075

• Probabilistic cell type assignment of single-cell transcriptomic data reveals spatiotemporal microenvironment dynamics in human cancers

  Single-cell RNA sequencing (scRNA-seq) has transformed biomedical research, enabling decomposition of complex tissues into disaggregated, functionally distinct cell types. For many applications, investigators wish to identify cell types with known marker genes. Typically, such cell type assignments are performed through unsupervised clustering followed by manual annotation based on these marker genes, or via "mapping" procedures to existing data. However, the manual interpretation required in the former case scales poorly to large datasets, which are also often prone to batch effects, while existing data for purified cell types must be available for the latter. Furthermore, unsupervised clustering can be error-prone, leading to under- and over- clustering of the cell types of interest. To overcome these issues we present CellAssign, a probabilistic model that leverages prior knowledge of cell type marker genes to annotate scRNA-seq data into pre-defined and de novo cell types. CellAssign automates the process of assigning cells in a highly scalable manner across large datasets while simultaneously controlling for batch and patient effects. We demonstrate the analytical advantages of CellAssign through extensive simulations and exemplify real-world utility to profile the spatial dynamics of high-grade serous ovarian cancer and the temporal dynamics of follicular lymphoma. Our analysis reveals subclonal malignant phenotypes and points towards an evolutionary interplay between immune and cancer cell populations with cancer cells escaping immune recognition.

  Study EGAS00001003452

• MediMer: A versatile do-it-yourself peptide-receptive MHC class I multimer platform for tumor neoantigen-specific T cell detection

  Peptide-loaded MHC class I (pMHC-I) multimers have revolutionized our capabilities to monitor disease-associated T cell responses with high sensitivity and specificity. To improve the discovery of T cell receptors (TCR) targeting neoantigens of individual tumor patients with recombinant MHC molecules, we developed a peptide-loadable MHC class I platform termed MediMer. MediMers are based on soluble disulfide-stabilized β2-microglobulin/heavy chain ectodomain single-chain dimers (dsSCD) that can be easily produced in large quantities in eukaryotic cells and tailored to individual patients’ HLA allotypes with only little hands-on time. Upon transient expression in CHO-S cells together with ER-targeted BirA biotin ligase, biotinylated dsSCD are purified from the cell supernatant and are ready to use. We show that CHO-produced dsSCD are free of endogenous peptide ligands. Empty dsSCD from more than 30 different HLA-A,B,C allotypes, that were produced and validated so far, can be loaded with synthetic peptides matching the known binding criteria of the respective allotypes, and stored at low temperature without loss of binding activity. We demonstrate the usability of peptide-loaded dsSCD multimers for the detection of human antigen-specific T cells with comparable sensitivities as multimers generated with peptide-tethered β2m-HLA heavy chain single-chain trimers (SCT) and wild-type peptide-MHC-I complexes prior formed in small-scale refolding reactions. Using allotype-specific, fluorophore-labeled competitor peptides, we present a novel dsSCD-based peptide binding assay capable of interrogating large libraries of in silico predicted neoepitope peptides by flow cytometry in a high-throughput and rapid format. We discovered rare T cell populations with specificity for tumor neoepitopes and epitopes from shared tumor-associated antigens in peripheral blood of a melanoma patient including a so far unreported HLA-C*08:02-restricted NY-ESO-1-specific CD8+ T cell population. Two representative TCR of this T cell population, which could be of potential value for a broader spectrum of patients, were identified by dsSCD-guided single-cell sequencing and were validated by cognate pMHC-I multimer staining and functional responses to autologous peptide-pulsed antigen presenting cells. By deploying the novel CHO producer cell-based dsSCD MHC-I MediMer platform, we hope to significantly improve success rates for the discovery of personalized neoepitope- specific TCR in the future by being able to also cover rare HLA allotypes.

  Study EGAS50000000065

• Bulk and RIP-seq transcriptome datasets from skin fibroblasts in PTBP1- and PTBP2-related disorders

  PTBP1- and PTBP2-related disorders are rare human conditions that cause variable neurodevelopmental phenotypes, including intellectual disability and behavioral problems such as autism spectrum disorder, anxiety, aggressiveness, and attention disorders, with or without hyperactivity. PTBP1-related disorder is also associated with skeletal dysplasia. In this study, we generated bulk RNA sequencing and RNA immunoprecipitation sequencing (RIP-seq) data from skin fibroblasts obtained from patients and healthy controls.

  Study EGAS50000001210

• Rapid Acceleration of Diagnostics - Digital Health Technologies' (RADx-DHT) Collection of General Research Use Datasets

  This individual-level collection of datasets contains all the RADx Digital Health Technologies (RADx-DHT) studies in dbGaP for General Research Use (GRU). Access to studies in this collection is on the RAPIDS platform. To request access to this study collection, select phs003666 in the dbGaP when submitting a data access request.

  Study phs003666

• Slim Initiative in Genomic Medicine for the Americas (SIGMA): Mexico City Diabetes Study (MCDS)

  The ~52,000 sample Type 2 Diabetes Exome Sequencing project is a collaboration of six consortia with various funding mechanisms that have joined together to investigate genetic variants for type 2 diabetes (T2D) using the largest T2D case/control sample set compiled to date. This includes samples from: Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) Genetics of Type 2 Diabetes (GoT2D) Exome Sequencing Project (ESP) Slim Initiative in Genomic Medicine for the Americas: Type 2 Diabetes (SIGMA T2D) Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCAMP) Progress in Diabetes Genetics in Youth (ProDIGY) This data generated from the SIGMA Mexico City Diabetes Study was part of the Slim Initiative in Genomic Medicine for the Americas: Type 2 Diabetes (SIGMA T2D), which is an international research consortium funded by the Carlos Slim Foundation that seeks to identify the genetic risk factors for type 2 diabetes (T2D) in Mexico and Latin America and translate those findings into improved treatment and prevention of diabetes. The SIGMA T2D project has sequenced and genotyped more than 13,000 samples from Mexican and Mexican Americans. The individuals were obtained from over 20 cohorts across the 6 consortia that are listed in Table 1. The strategy was to perform deep exome sequencing of individuals, 24,991 with T2D and 24,953 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. The T2D-GENES, ProDIGY and SIGMA studies, sequencing was performed at the Broad Institute using the Agilent v2 capture reagent or Illumina Rapid Capture on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, two of the cohorts below are not in dbGaP, due to the samples not being consented for deposition. This includes the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study and Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) study. The Exome Sequencing Project (ESP) was deposited in dbGaP as part of their initial study and the phs numbers for that project can be found here: https://esp.gs.washington.edu/drupal/dbGaP_Releases Table 1. 52,000 sample T2D Case/Control Whole Exome Sequencing Studies Ancestry Consortia Study Countries of Origin # Cases # Controls African American T2D-GENES Project 1 Jackson Heart Study US 500 526 African American T2D-GENES Project 1 Wake Forest School of Medicine Study US 518 530 African American ESP Exome Sequencing Project (ESP) US 467 1374 African American T2D-GENES Follow up study BioMe Biobank Program (BioMe) US 1297 1256 East Asian T2D-GENES Project 1 Korea Association Research Project Korea 526 561 East Asian T2D-GENES Project 1& Follow up Study Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 1486 1568 East Asian T2D-GENES Follow up study Korea SNUH South Korea 450 475 East Asian T2D-GENES Follow up study Research Studies in Hong Kong (Hong Kong) Hong Kong 493 485 European T2D-GENES Project 1 Ashkenazi US, Israel 506 355 European T2D-GENES Project 1 Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European GoT2D Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European GoT2D Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European GoT2D UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European GoT2D Malmo-Botnia Study Finland, Sweden 478 443 European LuCamp Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) Denmark 997 997 European ESP Exome Sequencing Project (ESP) US 390 2843 European T2D-GENES Follow up study Genetics of Diabetes and Audit Research Tayside Study (GoDARTS) Scotland, UK 960 966 European T2D-GENES Follow up study Framingham Heart Study (FHS) US 396 596 Hispanic T2D-GENES Project 1 San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 218 Hispanic T2D-GENES Project 1 & SIGMAv2 Starr County, Texas US 1762 1738 Hispanic SIGMAv1 Mexico City Diabetes Study Mexico 281 549 Hispanic SIGMAv1 & v2 Multiethnic Cohort (MEC) US 1476 1443 Hispanic SIGMAv1 & v2 UNAM/INCMNSZ Diabetes Study (UIDS) Mexico 1998 1977 Hispanic SIGMAv1 & v2 Diabetes in Mexico Study (DMS) Mexico 1522 1546 Multi ethnic ProDIGY Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) US 3097 0 Multi ethnic ProDIGY SEARCH for Diabetes in Youth (SEARCH) US 553 0 South Asian T2D-GENES Project 1 London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 531 538 South Asian T2D-GENES Project 1 & Follow up study Singapore Indian Eye Study Singapore (Indian Asian) 1640 1478 South Asian T2D-GENES Follow up study Pakistan Genomic Resource (PGR) Pakistan 914 932

  Study phs001375

• Somatic Mutation in Normal Bladder Study

  Adult human somatic tissues are landscapes of mutant clones, but little is known about how these landscapes are shaped by known cancer risk factors. The goal of this study was to determine how the main bladder cancer risk factors (sex and smoking) change the mutational landscape of the normal urothelium. We collected normal urothelium from 45 donors at autopsy by brushing ~2cm² of the surface epithelium in the upper part (dome) and lower part (trigone) of the bladder (79 samples total). To identify mutations with high sensitivity we employed ultradeep (~5000x) DNA error-correcting duplex-sequencing on a panel of 15 protein coding genes and the TERT promoter, previously described to be under positive selection in normal urothelium or relevant to bladder cancer. We identified thousands of clonal driver mutations, which demonstrate pervasive positive selection in the normal urothelium. Males showed a significantly higher number of driver truncating mutations in RBM10, CDKN1A and ARID1A, despite similar rates of non-coding mutations, indicating stronger positive selection and clonal expansion in the male urothelium. We also discovered clonal expansions driven by activating TERT promoter mutations in the normal bladder, which were strongly associated with age and smoking. These results demonstrate that sex and smoking shape the clonal landscape of the normal bladder and indicate that the high mutational content of normal tissues might be leveraged to study the effect of mutations in vivo (i.e. natural saturation mutagenesis). We will deposit in dbGaP de-identified relevant clinical information from the 45 donors and the fastq files derived from duplex sequencing of the 79 samples in the study. We will also deposit fastq files derived from duplex sequencing of 3 control cord blood samples.

  Study phs004105

• ATAC-seq samples from 9 cHL cell lines

  The dataset contains 21 ATAC-seq samples from 9 cHL cell lines. Files within the dataset are raw fastq files for each cell line.

  Dataset EGAD50000001273

• Examination of Engineered LINE-1 Integration Events in HeLa Cells

  Long Interspsesed Element-1 (LINE1 or L1) encodes two proteins (ORF1p and ORF2p) required for its mobilization (i.e. retrotransposition) in the human genome. Human ORF2p, a 150kDa protein, has endonuclease (EN) and reverse transcriptase (RT) activities. L1 EN is classified as apurinic/apyrimidin-like endonuclease (APE) and is responsible for initiating target-site primer reverse transcription (TPRT) during the L1 retrotransposition cycle. During canonical TPRT, the L1 EN activity makes a single-strand endonucleolytic nick at a double-strand DNA target sequence in genomic DNA. The endonucleolytic nick is typically made at an L1 EN degnerate consensus cleavage sequence (5'-TTTT/A-3') exposing a free 3' hydroxy group that can be used as a primer by the ORF2p L1 RT activity to reverse transcribe the associated L1 RNA. Here, we characterized over 21,000 de novo engineered L1 retrotransposition events in HeLa cells to determine if L1 exhibits overt integration preferences in the human genome. Bru-seq of HeLa cells to determine actively transcribed regions of the genome was also performed. This Bru-seq data was used to determine if engineered L1 integration events preferentially integrate into transcribed regions of the genome, and to determine which strand during transcription may present itself as preferential during L1 retrotransposition.

  Study phs001669

• SAIF Alignment File

  This is the bam file generated after alignment using BWA program for the SAIF genome

  Dataset EGAD00001000249

• Nivolumab and Ipilimumab and Radiation Therapy in Microsatellite Stable (MSS) and Microsatellite Instable (MSI) High Colorectal and Pancreatic Cancer

  This is a single-arm, non-randomized, phase 2 trial (NCT03104439) combining radiation, ipilimumab and nivolumab in patients with metastatic MSS Colorectal Cancer (CRC; n=40) and Pancreatic Ductal Adenocarcinoma Cancer (PDAC; n=25). Patients were previously treated population, and the primary endpoint was disease control rate. Pre- and post-treatment samples were subjected to RNA sequencing and whole exome sequencing. The primary data is shared via GEO and dbGaP at National Center for Biotechnology Information (NCBI), National Institutes of Health (NIH).

  Study phs002545

• Transcriptional Profiling of PD-1+ and PD-1- Teff and Treg Cells in Glioblastoma and Health

  PD-1 is an important immune checkpoint inhibitor that shows great promise in the clinic, particularly for melanoma and lung cancers. Since PD-1 is also expressed on infiltrating CD4+ Treg and Teffector cells in glioblastoma, we sought to better understand the role of PD-1 on these infiltrating CD4+ Treg and Teffector cells. To this end, we performed functional and transcriptional profiling using CD4+ Treg and Teffector cells isolated from healthy donors and glioblastoma patients (from both tumors and blood).

  Study phs001079

• Genomic Studies in Charcot-Marie-Tooth Disease

  The various forms of Charcot-Marie-Tooth disease (CMT) comprise a genetically heterogeneous set of peripheral neuropathies. Currently, >90 different CMT genes have been identified; yet, for the axonal CMT2 subtype these genes explain only 30-40% of the genetic effect. In particular, the application of exome sequencing has led to an unprecedented pace in identifying about half of those genes in the past five years. We have been at the forefront of this development with 22+ published new gene identifications in the past seven years. This success was only possible through broad national and international collaborations, data sharing, and the development of advanced analysis tools and methods. We also learned that despite an accumulation of exome sequencing data, over 50% of axonal CMT patients remain undiagnosed, suggesting even more genes are involved; additionally, our preliminary data also support the existence of non-coding variations as Mendelian allele contributors. In this study, we will continue our highly impactful work in CMT family recruitment, exome sequencing and traditional gene identification. In addition, we will expand the genetic studies to whole genome sequencing with a focus on families already explored unsuccessfully in whole exome studies. We further plan to perform the first large rare variant burden analysis in the rare disorder CMT2. This is only possible through the exceptional clinical resources we have built over the past decade. Finally, with many CMT genes available, we will perform statistical network analyses on a CMT-ome to identify gene modules and pathways that will be the starting point of polypharmacology, and provide insight into pathophysiology of peripheral nerve degeneration. All data will be available in real-time to an existing network of CMT investigators worldwide, and deposited in dbGaP annually.

  Study phs003389