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• Reference epigenome ADMSC04_smRNA-Seq data generated from KEP study

  A ADMSC04_smRNA-Seq single end data for adipose-derived mesenchymal stroaml cells

  Dataset EGAD00001003870

• Reference epigenome KNIH008 WGBS data generated from KEP study

  A KNIH008 Whole-Genome Bisulfite Sequencing(WGBS) paired end data for adipocytes

  Dataset EGAD00001002756

• IPF Core Biopsy Study RNA-Seq Fastqs

  RNA-Seq fastq files for 97 Idiopathic Pulmonary Fibrosis samples.

  Dataset EGAD00001007568

• GRIDSS somatic sv vcfs for EGAS00001004572

  Bulk GRIDSS somatic sv vcfs from tumour-normal analysis in EGAS00001004572

  Dataset EGAD00001006906

• Strelka somatic snv vcfs for EGAS00001004572

  Bulk Strelka somatic snv vcfs from tumour-normal analysis in EGAS00001004572

  Dataset EGAD00001006907

• Neuroblastoma sequencing data

  This dataset contains tumor and normal whole exome DNA sequence data for a patient with neuroblastoma

  Dataset EGAD00001008120

• How to upload Crypt4GH files

  Uploading files Users who hold an ega-box-XXX account can upload files using either INBOX or FTP. Users who have a Submitter role associated with their email will only be able to upload files using INBOX. Before uploading your files, please make sure that any files that will be uploaded to EGA do not use special characters in their naming convention, such as # ? ( ) [ ] / \ = + < > : ; " ' , * ^ | &. This can cause issues with the archiving process, leading to problems for end users. The EGA is a shared, public service with limited storage. To manage the available resources, we enforce a limit of 10TB per submission account at any one time. If you exceed this limit, a “permission denied” message will be displayed. This will prevent you from uploading more files, but connecting to your inbox.For submissions larger than 10TB, please perform uploads in 10TB batches: register all the metadata and then finalise the submission. Upload the next batch of files and repeat the same metadata registration and finalisation process until you have completed the file upload. Further information can be found in the SP documentation. INBOX FTP The INBOX is only compatible with files encrypted using the Crypt4gh tool Before uploading If you are not a registered EGA user, you will first need an EGA user account. Please note that it may take a few days for your account to be activated, as it needs to be vouched for by the EGA Helpdesk. Once your account is validated, you will be able to request a submitter role. [Optional] Meanwhile, you can create and add your public key to your EGA account profile. This option is not available for old submission accounts (e.g., ega-box-NNN). As soon as you have been granted a submitter role, you will be able to connect with your username and password to the EGA inbox using the SFTP protocol. If you have also registered a public key in your profile, you can also connect using this key. To upload files to your account, you can use the graphical user interface (GUI) or the command line. Graphical User Interface (GUI)We recommend using FileZilla, a free, open-source FTP client. However, you can use any other GUI that allows connecting over the SFTP protocol. For FileZilla as your GUI, follow these steps to upload files: Create a new connection in Site Manager (File > Site Manager) and select the following options (Figure 1): Protocol: SFTP - SSH File Transfer ProtocolHost: __EGA_INBOX_DOMAIN__Logon Type: Key fileUser: your EGA usernameKey file: Path/to/your/private_keyFigure 1: Process of establishing a new connection to __EGA_INBOX_DOMAIN__ using a key file as the logon method in FileZilla. The figure showcases the FileZilla version 3.52.2 operating on IOS v11.2.3. By following the depicted steps, users can create a secure and efficient connection to the inbox, ensuring seamless data transfers.Click Connect, and you will log in remotely to your home directory. You can think of this folder as a storage "in the EGA cloud" in which you will add your files for the EGA. The uploading area has three folders:To-encrypt: Files uploaded in this folder will be encrypted automatically on the fly.Encrypted: Files uploaded in this folder must already be encrypted with Crypt4gh. Upload your files here if your connection is unstable or you have problems completing the upload into-encrypt.Etc: This folder contains two files that allow the server to show you your username and group instead of some internal numbers. Please do not upload files here; otherwise, you will obtain a permission denied error. Find the files you want to upload by browsing your local storage (left side of your screen in FileZilla). Select all the files you want to upload, then right-click on them and select Upload (Figure 2). Figure 2: Step-by-step process of manually uploading files to __EGA_INBOX_DOMAIN__ using FileZilla, with FileZilla version 3.52.2 operating on IOS v11.2.3. The figure demonstrates how users can transfer data from their local storage to the "EGA cloud" by following the depicted steps Please note that regardless of which folder you upload your files in, both folders (to-encrypt, encrypted) will point to the same path (/) (Figure 3). Therefore, you will see your files in both folders. Figure 3: Both folders, to-encrypt and encrypted, point to the same path (/)" If your connection is unstable, please encrypt your files first using Crypt4gh. Then upload them to the ‘encrypted’ folder. The example above shows how to connect to __EGA_INBOX_DOMAIN__ using the private key. However, if you prefer to log in using your credentials, you can do so. Please go to the Frequently Asked Questions (FAQs)  for more information. SFTP command line To upload files securely to your private area of the EGA, you can use SFTP(Secure File Transfer Protocol) with your favorite FTP client. Here's what you need to know to get started: Connect to the target host __EGA_INBOX_DOMAIN__. This is the new hostname for the EGA SFTP service. Log in with your EGA username and key files (or password). Upload files to your private EGA inbox to ensure that only you can access the files. By following these steps, you can securely upload your files to the EGA for safe storage and sharing. Using the SFTP command line client in Linux/Unix Open a terminal and type sftp username@hostnameEnter your EGA passwordTo see a list of available SFTP commands, type helpsftp> put – Upload filesftp> get – Download filesftp> cd path – Change remote directory to ‘path’sftp> pwd – Display remote working directorysftp> lcd path – Change the local directory to ‘path’sftp> lpwd – Display local working directorysftp> ls – Display the contents of the remote working directorysftp> lls – Display the contents of the local working directoryType the "put" command to upload files. For example: put *.bamUse the bye command to close the connection (SFTP session). After uploading- Once you have uploaded files to the inbox, please bear in mind that the checksum needs to be calculated, which can take up to two days. You will only be able to link your files to a run/analysis once the encrypted checksum has been calculated.- When linking your files to the 'Run' or 'Analysis', ensure that the file name matches the file path '/name' in the INBOX folder.- Please delete the files from your SFTP INBOX after all the runs/analyses have been registered and files are ingested (SP > Files > Files ingested). This will clear your inbox space an allow you to upload more files. This will also prevent the files from reappearing in your Submitter Portal inbox. Frequently Asked Questions Specific to the inbox What username should I use to log in to my inbox? The authentication process for logging in to the EGA website, as well as accessing your inbox and outbox, requires the use of your username.  If you have forgotten your registered username, please contact our Helpdesk team for assistance. How are checksums calculated in your inbox? If you encrypt the file beforehand and upload it to the "encrypted" folder, the unencrypted checksum will not be calculated until the file is ingested (i.e., until it is used in a run/analysis). If the file is uploaded to the "to-encrypt" folder, then both checksums are calculated.Please bear in mind that after files have been uploaded to the inbox, the checksum must be calculated, which can take from a few hours to two days.  Specific to using keys to authenticate Can I access one EGA account from different devices? Yes, you can access your account from different devices by linking several public keys to your EGA account. Each device can generate a unique public-private key pair, and the corresponding public keys can be linked to the same account. This way, you can use different public keys on different devices and still have access to the same account and data. I have several keys and I don't remember which one is which When generating SSH keys, it's a good practice to add a comment using the -C flag. This will allow you to add a descriptive tag to your key, making it easier to identify later on. Here's an example command that generates an SSH key with a comment: ssh-keygen -t ed25519 -C work-pass In this example, we're generating an ed25519 SSH key with the comment work-pass. Once you have multiple keys with different comments, you can use the comments to easily identify each key. To view the comments for your existing SSH keys, you can use the following command: ssh-keygen -l -f /path/to/key This will display the key fingerprint and the associated comment. By checking the comments, you should be able to identify which key is which. What if I can't find my SSH keys for uploading files with a key file, and how can I use new keys? If you can't find your SSH keys, don't worry - you can make new ones. To do this, open your terminal or command prompt and type a command to make a new SSH key. You can pick a name for the key, and choose a password to keep it safe. After making the key, you can add the new key to your account or server where you want to upload files using the key file. This usually involves copying and pasting the key's "public" (e.g. file.pub) part to the right place. If you lose track of the key again, just make a new one and add it again. Keep in mind that SSH keys belong to you and your computer, so if you switch computers or accounts, you'll need to make new keys. I don't want to type the passphrase every time I use the key. What can I do? You can use an ssh-agent to avoid typing the passphrase every time you use the key. An ssh-agent is a program that stores your private keys in memory and provides them to ssh when needed. You can add your key to the ssh-agent using the command ssh-add followed by the path to your key file.Here's an example of the steps to follow: Open a terminal window.Start the ssh-agent by typing the command eval $(ssh-agent).Add your key to the ssh-agent by typing the command ssh-add [key filepath]. For instance, if your key file is located in the home directory with the name mykey, the command will look like this: ssh-add ~/mykey After adding your, key to the ssh-agent, you should be able to use ssh without having to enter your passphrase every time. Can I use my password for authentication (without my private key)? If you prefer to use your username and password for authentication instead of your private key, you can still do so. When using a Graphical User Interface (GUI) such as FileZilla, you can select Ask for password as your Logon Type (Figure 3). This option will prompt you to enter your password when you click Connect, instead of using your private key. Figure 3: This option will prompt you to enter your password when you click "Connect", instead of using your private key. Figure 3: Process of establishing a new connection to __EGA_INBOX_DOMAIN__ using your password as the logon method in FileZilla. The figure showcases the FileZilla version 3.52.2 operating on IOS v11.2.3. By following the depicted steps, users can create a secure and efficient connection to the inbox, ensuring seamless data transfers. It's worth noting that using a password for authentication can be less secure than using an SSH key, as passwords can be more easily compromised through various means. However, if you choose to use your password for authentication, selecting "Ask for password" as your Logon Type is a good way to do so securely via a GUI. Why is it better to use my key and not my password? SSH keys for authentication is generally considered to be more secure and convenient than using passwords. SSH keys are more difficult to crack than passwords, and they can be restricted to specific users and machines, giving you more control over access. Once you set up your SSH keys, you can use them to authenticate quickly and easily, without having to enter a password every time. This makes automation of tasks, such as uploading encrypted files, much simpler. Additionally, SSH keys provide better logging, allowing you to keep track of who is accessing your systems and when. All in all, using SSH keys is a good practice for improving security and convenience in your authentication process.

  Documentation submission/data/uploading-files/inbox

• GenomeEUtwin Data Access Committee

  Access to data generated by the GenomeEUtwin is available by emailing application to the data access committee and will be granted to qualified investigators for appropriate use.

  Dac EGAC00000000007

• Converging and evolving immuno-genomic routes towards immune escape in breast cancer

  Data access committe for the project: Converging and evolving immuno-genomic routes towards immune escape in breast cancer

  Dac EGAC50000000074

• Biomarker Data from KATHERINE: A Phase III Study of Adjuvant Trastuzumab Emtansine versus Trastuzumab in Patients with Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer

  Study EGAS00001006229

• Time course acetalax bisacodyl treatment

  RNA-Seq raw data of PDX treated with acetalaxor bisacodyl for 4h00 to 24h00.

  Dataset EGAD50000000875

• BelCovid_2_genotype

  Cohort: Raw genotype files for BelCovid2 cohort. Genotype Chip: Illumina Global Screening Array-24 v3.0 + Multi-Disease beadchip genomic build: b37

  Dataset EGAD00010002179

• PanCancer_Phosphoproteomics2024

  Pan-cancer phosphoproteomics profiling data for 1000 retrospective and prospective samples of the MASTER/INFORM cohort,Shotgun proteomics

  Dataset EGAD00010002730

• GEN_COVID_genotype

  Cohort: Raw genotype files for GEN_COVID cohort. Genotype Chip: Illumina Global Screening Array-24 v3.0 + Multi-Disease beadchip genomic build: b37

  Dataset EGAD00010002177

• Illumina BeadArray SNP arrays

  SNP measurement. Illumina BeadArray SNP arrays for the study "Molecular characteristics in Burkitt lymphoma over age groups"

  Dataset EGAD00010002137

• Gene Expression Profiling for study EGAS00001004165

  Gene Expression Profiling from 44 Mantle Cell Lymphoma cases

  Dataset EGAD00010001842

• mtDNA-Roma

  mtDNA variant positions vcf files for 86 human samples

  Dataset EGAD00010001844

• Reference epigenome CKD25_C_Podo_WGBS data generated from KEP study

  A CKD25_C_Podo_WGBS paired end data for Podocytes(CD90(-) Podocalyxin(+), kidney)

  Dataset EGAD00001003470

• Reference epigenome CKD24_C_Podo_WGBS data generated from KEP study

  A CKD24_C_Podo_WGBS paired end data for Podocytes(CD90(-) Podocalyxin(+), kidney)

  Dataset EGAD00001003469

• Reference epigenome OB57_D_PreA_WGBS data generated from KEP study

  A OB57_D_PreA_WGBS paired end data for Preadipocyte(fat)

  Dataset EGAD00001003480

• Reference epigenome IPS01_N_Fibroblast_mRNA-Seq data generated from KEP study

  A IPS01_N_Fibroblast_mRNA-Seq paired end data for iPSC(Oct4)

  Dataset EGAD00001003488

• Reference epigenome IPS04_X_Fibroblast_mRNA-Seq data generated from KEP study

  A IPS04_X_Fibroblast_mRNA-Seq paired end data for iPSC(Oct4)

  Dataset EGAD00001003491

• Reference epigenome IPS01_N_Fibroblast_smRNA-Seq data generated from KEP study

  A IPS01_N_Fibroblast_smRNA-Seq single end data for iPSC(Oct4)

  Dataset EGAD00001003501

• Reference epigenome IPS04_X_Fibroblast_smRNA-Seq data generated from KEP study

  A IPS04_X_Fibroblast_smRNA-Seq single end data for iPSC(Oct4)

  Dataset EGAD00001003504

• Hipo-032 Metastasome of Colorectal Cancer

  Whole genome sequencing of Control (blood), Tumor and metastasis triplets for 12 samples.

  Dataset EGAD00001003965

• BGI study for primary and metastatic Chinese lung adenocarcinomas

  We sequenced 205 patients who were suffering NSCLC with Exome sequencing method.

  Dataset EGAD00001001398

• ICGC PACA-CA Release21

  ICGC Release 21 for PACA-CA from OICR

  Dataset EGAD00001001956

• Premalignant SOX2 in ovarian cancer patients

  Whole Genome Sequencing data set for the study "Premalignant SOX2 in ovarian cancer patients"

  Dataset EGAD00001002734

• RNAseq BAM files

  RNAseq BAM files for Coding and non-coding mantle cell lymphoma driver mutations

  Dataset EGAD00001006268

• Follicular T cell lymphoma

  Paired-end RNA-seq of follicular T cell lymphoma for the discovery of fusion transcripts

  Dataset EGAD00001006379

• pilot

  Pilot study for genome-wide sequencing of cell-free DNA from nipple aspirate fluid and plasma of breast cancer patient

  Dataset EGAD00001010836

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

  Background Information: Primary open-angle glaucoma (POAG) is an age-related, intraocular pressure (IOP)-dependent progressive optic neuropathy that ultimately leads to irreversible blindness. Vision loss from POAG is a condition of public health significance. Current evidence suggests that POAG is a polygenetic disease modified by environmental influences. Despite the fact that a positive family history of disease is an important risk factor for POAG, conventional linkage and candidate gene approaches have revealed less than 5% of the genetic component of the disease. Furthermore, there is no consensus on environment risk factors for POAG. Elevated IOP is the only modifiable risk factor for POAG; yet, lowering IOP slows, but does not halt the disease process. Study Objectives: The overall goal of our research is to elucidate the pathogenesis of POAG so that cost-effective disease detection and primary prevention strategies can be implemented. The primary aim of the Glaucoma Gene Environment Initiative (GLAUGEN), funded by the Human Genome Research Institute (NHGRI), is to discover genetic loci associated with POAG. The secondary aim of GLAUGEN, funded by NHGRI and the National Eye Institute, is to discover gene environment interactions in POAG. Methods and study populations: For this study, we have assembled cases and controls from three studies: the Nurses&#39; Health Study (NHS), the Health Professionals Follow-up Study (HPFS) and the Genetic Etiologies of POAG (GEP) project based at Massachusetts Eye and Ear Infirmary (MEEI). This case-control group includes 1057 unrelated cases and 1272 controls. Members of the NHS and HPFS also have repeated environmental exposure data collected prior to a diagnosis of POAG. NHS - The Nurses Health Study started in 1976 under the direction of Dr. Frank E. Speizer. With funding from the NIH, registered nurses from 11 US states were invited to complete a detailed questionnaire regarding lifestyle and health biennially. Initially, 121,000 women responded to the baseline questionnaire. Currently, Dr. Susan Hankinson serves as the program director for the NHS. HPFS - The Health Professionals Follow-up Study began in 1986 under the direction of Drs. Walter Willett and Meir Stampfer. Under the auspices of the NIH, they enlisted 51,529 male health professionals from throughout the US to complete similarly designed biennial questionnaires. Beginning in 1990, questions regarding ocular health were added to biennial questionaires completed by health professionals participating in the NHS and HPFS. This allowed us to formulate (PI: S. Hankinson; NEI) and maintain (PI: L. Pasquale; NEI) a cohort at risk for POAG derived from the respective general cohorts who were under ophthalmic care. We then developed a definition of POAG that allowed us to identify cases from a population that was geographically dispersed. The centerpiece of this definition is the presence of reproducible visual field loss consistent with nerve fiber layer (NFL) dropout (the NFL contains the axons that comprise the optic nerve) on reliable tests. Reproducible visual field loss occurred in the context of anterior segment findings that did not suggest a secondary cause of elevated IOP and posterior segment findings that did not suggest a secondary cause of visual field loss. We selected controls from the cohort at risk for POAG on the basis of age, gender and time period when cases were identified. GEP - The Genetic Etiologies of POAG was initiated in 1996 with funding from the National Eye Institute under the direction of Dr. Janey Wiggs. The purpose of this work was to discover novel genetic loci associated with POAG. In the GEP, cases were derived predominantly from the Glaucoma Service at MEEI. The majority of cases had an examination by a glaucoma specialist and met the definition for POAG used in NHS and HPFS. Cases with only one reliable visual field consistent with NFL dropout were included if there was a cup-disc ratio of 0.7 or more. The majority of controls were patients who presented to the MEEI comprehensive ophthalmology service for routine eye examination or from spouses of MEEI patients with secondary forms of glaucoma. Other controls were identified from regional glaucoma screenings held throughout Massachusetts. Members of GEP have detailed ocular phenotype data but limited information on environmental exposures. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to primary open-angle glaucoma through large-scale genome-wide association studies of three well-characterized cohorts of cases and controls, some in matched pairs. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were performed at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000308

• GeneSTAR (Genetic Study of Atherosclerosis Risk) NextGen Consortium: Functional Genomics of Platelet Aggregation Using iPS and Derived Megakaryocytes

  The causal mechanisms of common diseases and their therapies have been only marginally illuminated by genetic variants identified in genome wide association studies (GWAS) utilizing single nucleotide polymorphism (SNPs). Platelet activation pathways reflecting hemostasis and thrombosis are the underlying substrate for many cardiovascular diseases and related acute events. To overcome GWAS limitations, genomic studies are needed that integrate molecular surrogates for platelet-related phenotypes assayed in cell-based models derived from individuals of known genotypes and phenotypes. In our GWAS study of native platelet aggregation phenotypes and aggregation in response to low dose aspirin in 2200 subjects (GeneSTAR, Genetic Study of Aspirin Responsiveness), important genome wide "signals" (p&lt;5x10-8) associated with native platelet aggregation and important "signals" associated with platelet responsiveness to aspirin were identified and replicated. Although we are currently performing functional genomics studies to elucidate our most promising findings in known genes (PEAR1, MET, PIKC3G), most "signals" occurred in intergenic regions or in introns. Mechanistic interpretation is limited by uncertainty as to which gene(s) are up- or down-regulated in the presence of most SNP modifications. In this 3 phase proposal, we will (1) create pluripotent stem cells (iPS) from peripheral blood mononuclear cells, and then differentiate these stem cells into megakaryocytes (2) develop an efficient strategy to produce iPS and megakaryocytes using a novel pooling method, and (3) produce iPS and megakaryocytes from 250 subjects in GeneSTAR (European Americans and African Americans), selected based on specific hypotheses derived from GWAS signals in native and post aspirin platelet function; characterize genetic mRNA transcripts using a comprehensive Affymetrix array; measure protein expression for transcripts of interest using mass spectrometry; examine mRNA and protein expression patterns for each GWAS signal to determine the functional pathway(s) involved in native platelet phenotypes; and examine the functional genomics of variations in responsiveness to aspirin using our prior genotyped and phenotyped population. Precise information about the exact functional processes in megakaryocytes and platelets may lead to innovative and tailored approaches to risk assessment and novel therapeutic targets to prevent first and recurrent cardiovascular and related thrombotic events.

  Study phs001074

• A New Reference Panel to Boost African American Genotype Imputation

  Modern genetic studies have been conducted predominantly in cohorts of individuals of European ancestry. By 2010, there were approximately ten times as many published genome wide association studies (GWAS) in people of European ancestry than studies in people of all other ancestries combined. This research disparity has led to an uneven understanding of the genetic basis underlying disease in Europeans and non-Europeans. 23andMe's web-based, large scale research model is ideal for scaling genetics research within non-European populations and thereby bringing more parity to genetics research. Our database is composed of genotypes and phenotypes of over 1,000,000 consenting customers, including over 200,000 individuals with non-European ancestry. The data derived from non-European individuals represent a particularly valuable resource for genetic discovery of novel variants that may not be found in the European population. However, research studies in non-European populations are weakened by the lack of availability of large-scale reference datasets and, in particular, genotype imputation panels. Genotype imputation is a statistical methodology that uses observations of genotypes in a large reference panel to infer unobserved genotypes in a target dataset. This methodology is widely used within GWAS, and allows novel genetic associations to be identified and refined. Due to this utility, very large reference panels have been constructed, containing thousands or tens of thousands of whole genome sequences. Unfortunately, the largest imputation panels are composed of predominantly European genomes, reflecting the modern bias towards European studies in GWAS. This proposal aims to address this imbalance by constructing an imputation panel specifically for the African American population. In doing so, we will expand 23andMe's ability to perform genetic discovery in non-European populations, and improve the understanding of global genetic variation underlying diseases and traits. Key commercial outcomes of the research include the identification of novel genetic targets for internal and external therapeutic development. The long-term aim is to improve understanding of disease in minority populations, which we hope may eventually lead to improved treatments of disease in these historically medically understudied groups.

  Study phs001798

• A Single Cell Atlas of Gene Regulatory Elements in the Human Heart

  Background: Cis-regulatory elements such as enhancers and promoters are crucial for directing gene expression in the human heart. Dysregulation of these elements can result in many cardiovascular diseases that are major leading causes of morbidity and mortality worldwide. In addition, genetic variants associated with cardiovascular disease risk are enriched within cis-regulatory elements. However, the location and activity of these cis-regulatory elements in individual cardiac cell types remains to be fully defined. Methods: We performed single nucleus ATAC-seq and single nucleus RNA-seq to define a comprehensive catalogue of candidate cis-regulatory elements (cCREs) and gene expression patterns for the distinct cell types comprising each chamber of four non-failing human hearts. We used this catalogue to computationally deconvolute dynamic enhancers in failing hearts and to assign cardiovascular disease risk variants to cCREs in individual cardiac cell types. Finally, we applied reporter assays, genome editing, and electrophysiogical measurements in in vitro differentiated human cardiomyocytes to validate the molecular mechanisms of cardiovascular disease risk variants. Results: We defined &gt;287,000 candidate cis-regulatory elements (cCREs) in human hearts at single-cell resolution, which notably revealed gene regulatory programs controlling specific cell types in a cardiac region/structure-dependent manner and during heart failure. We further report enrichment of cardiovascular disease risk variants in cCREs of distinct cardiac cell types, including a strong enrichment of atrial fibrillation variants in cardiomyocyte cCREs, and reveal 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Two such risk variants residing within a cardiomyocyte-specific cCRE at the KCNH2/HERG locus resulted in reduced enhancer activity compared to the non-risk allele. Finally, we found that deletion of the cCRE containing these variants decreased KCNH2 expression and prolonged action potential repolarization in an enhancer dosage-dependent manner. Conclusion: This comprehensive atlas of human cardiac cCREs provides the foundation for not only illuminating cell type-specific gene regulatory programs controlling human hearts during health and disease, but also interpreting genetic risk loci for a wide spectrum of cardiovascular diseases.

  Study phs002204

• NHLBI and NIDDK Sponsored GWAS in Benign Ethnic Neutropenia/Leukopenia (BEN) in African-Americans (age >45 yrs old) from the REGARDS

  Benign ethnic neutropenia (BEN) is a clinical condition more commonly observed in African-Americans. It is characterized by a relative reduction in neutrophil count by about 1000 cells per microliter, leading to a decrease in total leukocyte count by similar decrement. Previous reports of this condition showed that there was neither higher frequency nor increased severity of infections in affected individuals. Bone marrow examinations showed normal white cell maturation; and ex vivo culture of marrow cells showed low normal or slightly reduced number of myeloid colonies. Under physiologic stress, the increases in neutrophil and leukocyte counts of BEN individuals are slightly lower, compared to normal African-Americans or Caucasians. These clinical observations suggest that BEN results from a lower &#39;set point&#39; for cell number in the marrow. Additionally, case reports of familial BEN, the persistence of BEN over many decades in the US, UK, and Africa, and the recent report of Duffy antigen and chemokine receptor (DARC) being associated with neutropenia, all suggest a strong genetic association to neutropenia/leukopenia. Our initial look into microarray analyses in a pilot trial of subjects showed that there were no significant differences in mRNA signals between BEN and normal subjects. Therefore, we are now proposing a larger study, utilizing Illumina Omni Express chips, to look for genetic associations. We have partnered with the Reasons for Geographic and Racial Differences in Stroke study (REGARDS), where nearly half of the cohort are African-Americans. This will be one of the few GWAS being performed in only African-Americans, and will provide valuable genetic information to link with neutropenia and possibly other conditions/diseases. Genotyping was performed by the Johns Hopkins University Center for Inherited Disease Research (CIDR). Quality control of the genotypic and phenotypic data was performed through a collaboration between CIDR and the Genetics Coordinating Center, Department of Biostatistics at the University of Washington, which is funded by a federal contract supported by 14 NIH Institutes (HHSN268200782096C).

  Study phs000507

• Longitudinal Studies of Patients with Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM)

  FPDMM (OMIM #601399) is a rare autosomal dominant disease characterized by defective megakaryocytic development, thrombocytopenia, platelet functional defects, and a life-long risk of developing hematological malignancies. FPDMM is caused by germline mutations in the RUNX1 gene, which encodes a master regulator of hematopoiesis. The overall lifetime risk of hematological malignancies in FPDMM patients is 35 - 45%. It is hypothesized that mutations in other genes cooperate with the germline RUNX1 mutations for leukemia development. However, it is not clear which genes need to be mutated for leukemia to develop and which biomarkers or clinical tests can be used to predict which patients will progress to leukemia. Likewise, there are no treatments and/or preventative measures that can reduce or stop disease progression except for stem cell transplantation, which is not available for all patients and may be associated with significant complications. To address these questions, we launched a longitudinal natural history study of patients associated with RUNX1 germline mutations at the NIH Clinical Center in early 2019 (Trial Registration ID: NCT03854318). The goals of this study are to: (1) perform comprehensive longitudinal phenotyping of FPDMM patients to document the full spectrum of both hematopoietic and non-hematopoietic manifestations of the disease; and (2) perform extensive genomic analyses of FPDMM patient samples to identify cooperating genomic variants, which may confer growth advantage that leads to clonal expansion of affected hematopoietic cells that may serve as the precursor to malignancies. The data available through dbGaP include exome sequencing and RNA-seq data from these patients. Diverse germline mutation types were identified in the RUNX1 gene, including splice site mutations and large deletions, in addition to nucleotide substitutions and small indels. Somatic mutations, especially in genes associated with clonal hematopoiesis of indeterminate potential (CHIP), were found in a substantial proportion of FPDMM patients who were leukemia-free. The findings suggest that the genomes in these patients are prone to somatic mutations and monitoring the dynamic changes of these somatic mutations prospectively may provide a way to predict progression to malignancies.

  Study phs003075

• National Institute of Mental Health (NIMH) Duke Cognition Cohort

  The overall goal is to identify genetic variants influencing normal variation between humans, with a focus on cognitive and neurosensory traits. Because of the focus of funding agencies on disease, very few studies of the genetics of non-disease traits have been performed. The genetic variation underlying the vast majority of differences between humans therefore remains not only undiscovered, but also unexplored. We have assessed &#62;1,200 healthy volunteers for &#62;70 diverse, non-disease phenotypes, with a focus on cognitive and neurosensory traits that are understudied and seem to have a strong biological basis. Our study includes measurements of face recognition, night vision, cognitive performance, auditory pitch discrimination, contagious yawn susceptibility, time perception, sense of direction, taste preferences, personality, sexual behaviors, sleep habits, acne, headache locations, synesthesia, and teeth sensitivity. This method is very different from the focus of most studies on collecting cohorts of patients with disease and controls with minimal phenotypic information. Because we phenotype the same healthy volunteers for multiple highly variable yet heritable traits, we can perform genetic analyses on a large number of phenotypes by just investing once in sequencing the DNA of these participants. An additional &#62;2,000 participants in our cohort have been measured just for cognitive performance instead of for the more extensive phenotyping. Most of the genetic studies in this cohort have been about cognitive perfromance. The number of participants with genetic data generated who have undergone the more extensive phenotyping is limited. Our studies of the more novel traits like contagious yawning have therefore focused more on correlations between different phenotypes until we have a sufficient sample size to truly attempt to make genetic discoveries. . The dataset also includes two small challenge studies. In one study, the cognitive performance of 150 healthy volunteers was measured before and after an acute dose of the antiepileptic drug topiramate. In the other study, the cognitive performance of 13 healthy volunteers was measured before and after 24 hours of sleep deprivation.

  Study phs001406

• Exceptional Responders Initiative

  The Exceptional Responders Initiative is a pilot study to investigate the underlying molecular factors driving exceptional treatment responses of cancer patients to drug therapies. Study researchers will examine molecular profiles of tumors from patients either enrolled in a clinical trial for an investigational drug(s) and who achieved an exceptional response relative to other trial participants, or who achieved an exceptional response to a non-investigational chemotherapy. An exceptional response is defined as achievement of either a complete response or a partial response for at least 6 months duration in a trial or treatment where the overall response rate is &#60; 10%. The hope is to discover underlying molecular features that can be further investigated and may eventually predict benefit from a given drug or class of drugs for a particular patient. This pilot project will successfully characterize approximately 100 cases of tumor tissue and, when available, case-matched germline DNA. All samples will undergo whole exome sequencing, and cases with sufficient nucleic acids will undergo additional analyses (e.g. whole genome sequencing, mRNA-sequencing, mi RNA sequencing, promoter methylation analysis, SNP etc). Each case will be annotated with demographic and clinical information, along with follow-up information minimally sufficient to correlate molecular profiles with response. Both retrospective and prospective collections will be considered. The project will also accept sequencing data and clinical data from patients who have had sequencing performed outside of this project. All data will be de-identified and placed in a controlled access database so other investigators may use them for additional insights. Clinically annotated tissue specimens meeting the criteria will be provided by groups participating in the Exceptional Cases Initiative to a Biospecimen Core Resource (BCR), which will perform quality control on the tissues, and will use a standard operating procedure to isolate nucleic acids. The nucleic acids will be shipped to a sequencing center to perform whole exome sequencing and analysis. These findings will be made available to the broader cancer research community in a controlled access database.

  Study phs001145

• Bacterial Vaginosis, Cervical Immune Cells and HIV Susceptibility

  This was a cross-sectional study to characterize cervical immune cell composition and activation status in the presence versus absence of bacterial vaginosis (BV) using bulk messenger RNA sequencing (mRNA-Seq). Women enrolled in a longitudinal, open cohort study and engaged in a sex work in Mombasa, Kenya, were eligible. On the day of enrollment, participants self-collected vaginal swabs for generation of Gram-stained slide. The slides were scored from 0-10 using the method of Nugent and Hillier; in this system, women with scores of 0-3 are considered to have normal vaginal flora, those with scores of 4-6 are considered to have intermediate flora, and those with scores of 7-10 are considered to have BV. For this study, only women with normal flora (Nugent scores 0-3) or BV (Nugent scores 7-10) were eligible. Participants underwent speculum-assisted pelvic examination and collection of cervical biopsy specimens using Tischler forceps. Biopsies were placed immediately in ice cold medium and transferred to the laboratory where they were weighed and transferred to freezing medium (10% DMSO + fetal bovine serum) and cooled slowly overnight. Samples were shipped from Kenya to the United States in liquid nitrogen dry shippers, collagenase digested into single cell suspensions, and sorted on a FACS aria to enrich for a population of live, CD45+ cells. Sorted samples (N=17 with BV and N=13 without BV) were immediately lysed and processed using the Takara SMART-Seq v4 Ultra Low Input RNA Kit for sequencing. Library generation was completed using the manufacturer's instructions and sequencing performed on an Illumina NextSeq500 platform using Illumina NextSeq 500/550 High Output v2.5 (150 Cycles). The FASTQ files generated and BV status (N=9 with BV and N=12 without BV that passed quality control) of the donor sample will be available on dbGaP. We identified over 1000 differentially expressed genes between women with versus without BV at an adjusted p-value of <0.05 (listed under "gene names" below).

  Study phs002329

• Kids First: Whole Genome Sequencing in Recessive Structural Brain Defects

  Almost 5% of all live births in the US (1:20 births) display an inborn defect, including both structural and functional/metabolic abnormalities. These are among the most common causes of Infant mortality in the developed world and underlie nearly half of hospitalizations in the first 3 years of life. Of the 35 major defects observable at birth from the International Clearinghouse for Birth Defects Surveillance Program (www.icbdsr.org, external link), about half involve the nervous system. Many of these result in lifelong neurodevelopmental disorders. Structural Brain Defects (SBDs) result from errors in development of the central nervous system, including defects in the forebrain, midbrain and hindbrain. Many SBDs arise as the consequence of a single gene bi-allelic mutation, and for this reason, occur more commonly in populations or communities with elevated consanguinity.Our lab has identified dozens of novel SBD genes using WES/WGS in consanguineous SBD families. Importantly, the genes that we and others have identified in these unique families are then used to advance diagnosis in pediatric SBDs around the world. We have built an enormous cohort of SBD families, including newly recruited families not yet studied genetically, and previous families that were negative for cause following WES analysis. Here we propose to collaborate with the Gabriella Miller Kids First Pediatric Research Program (X01) to have sequencing performed in individuals from a total of 200 families with genetically undiagnosed SBDs. The Gleeson Lab team of researchers is dedicated to the field of SBDs, with an outstanding track record of high-impact science, and a collaborative approach to discovery. We have 150 newly recruited families that we propose to study by WES by sequencing blood-derived DNA from two affected patients, or the parents and one affected patient. We also have 50 families in which WES was negative, which we propose to study in a multi-omics approach combining WGS from blood-derived DNA. We anticipate that this study will lead to the identification of many new molecular causes of SBDs, as well as uncover new genotype-phenotype correlations and new disease mechanisms, paving the way for future breakthroughs in detection, treatment and prevention.

  Study phs002590

• Gabriella Miller Kids First Pediatric Research Program in Pediatric T-Cell Acute Lymphoblastic Leukemia

  The outcome for patients with relapsed T-ALL is dismal with 3-year event free survival of AALL0434 was a Children's Oncology Group-initiated phase 3 randomized clinical trial comparing Capizzi-style escalating methotrexate plus pegaspargase (CMTX) vs. high dose methotrexate (HDMTX), with/without six 5-day courses of nelarabine. Survival on this study was superior to any prior trial for de novo T-ALL, changing the standard of care. Yet, a substantial minority (~15%) of patients had relapsed or refractory (r/r) disease. Through the TARGET initiative, RNA sequencing (RNA-Seq), DNA copy number analysis, and whole-exome sequencing (WES) were performed on 264 T-ALL patients treated on AALL0434, demonstrating recurrent alterations could be grouped into 10 different potentially targetable functional pathways. This analysis was not powered to examine associations between genetic lesions with outcome, because too few patients with r/r disease were included. This project is dedicated to testing the hypothesis that comprehensive genomic profiling of the entire AALL0434 cohort will identify recurrent genetic alterations that can be segregated into biologically relevant deregulated pathways that can be combined with MRD to identify patients at risk for poor outcomes before they relapse and provide rationale for treatment with alternative therapies. In addition, a number of small recent studies demonstrated that many of the biologically relevant alterations in T-ALL occur in non-coding regions of the genome, but no large studies have performed whole genome sequencing (WGS) in T-ALL. This project also tests the hypothesis that WGS of a large cohort of patients with T-ALL will identify novel lesions in coding and non-coding regions that will be highly impactful in the understanding of T-ALL pathogenesis.These hypotheses are tested by performing comprehensive genomic profiling (WGS, WES, RNA-Seq, and copy number analysis) of the entire AALL0434 cohort with available samples with the following specific aims: (1) identify recurrent genetic alterations that predict poor outcome in T-ALL; (2) identify novel alterations, including non-coding alterations in T-ALL; and (3) identify germline genetic variants that predispose to T-ALL and to increased toxicity to chemotherapy.

  Study phs002276

• Psychophysiological Investigation of Myocardial Ischemia (PIMI-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To investigate psychophysiological factors related to both symptomatic and asymptomatic cardiac ischemia.Background: An important hypothesis has been generated from current research in this area: manifestations and expressions of cardiac ischemia are influenced by specified psychophysiological mechanisms.Participants: The study population consisted of 196 participants recruited from four clinical units, all of which were clinical units for the Asymptomatic Cardiac Ischemia Pilot (ACIP). Participants eligible for PIMI were identified throughout the screening process established for the enrollment of participants in ACIP.Design: The primary goal of PIMI was to test the hypothesis, "Manifestations and expressions of cardiac ischemia are influenced by specific psychophysiological mechanisms." The specific relationships investigated were:Patients who are susceptible to mental stress ischemia (indexed by new left ventricular wall motion abnormalities) would display more ischemia during daily activities and would have ambulatory ischemia at lower heart rate and activity level thresholds than patients who are not susceptible. Cardiovascular and catecholamine reactivity to mental stress would be a predictive of severity of mental stress ischemia and of ambulatory ischemia. &#914;-edorphin responses to mental stress and to exercise would be predictive of asymptomatic ischemia. Patients with systematic ischemia and those with asymptomatic ischemia would show differences in each of the following at rest and after response to stresses (exercise and/or mental tests). Mental stress would produce different hormonal and perceptual responses than exercise. Asymptomatic ischemia would be associated with a lesser severity of ischemia than symptomatic ischemia. The location of the ischemic myocardium would be inferior in a higher proportion of patients with asymptomatic ischemia than of patients with symptomatic ischemia. The latency internal that would be the onset of ST segment depression and the onset of ischemic pain would be related to somatic sensory perception, autonomic nervous system reflux control of the heart, &#914;-endorphin responses, and psychosocial characteristics.

  Study phs004183

• UK10K NEURO IOP COLLIER

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Genetics and Psychosis (GAP) set consists of samples from subjects with schizophrenia, ascertained as a new-onset sample. This set is of UK origin, with data on cognition, brain imaging and other endophenotypes. The Maudsley twin series consists of probands ascertained from the Maudsley Twin Register, defined as patients of multiple birth who had suffered psychotic symptoms. This set is of UK origin, with data on cognition, brain imaging and other endophenotypes, with DNA available from an MZ or DZ affected or unaffected co-twin. The Maudsley family study (MFS) consists of over 250 families who have a history of schizophrenia or bipolar disorder Within the Maudsley Family Study, biological markers of psychosis include neuropsychological tests, Evoked Response Potentials Tests (ERPs), MRI scans, dermatoglyphics and eye tracking. Early risk factors for psychosis and clinical symptoms are also investigated. This set is of UK origin, with DNA available from both affected and unaffected relatives in many of the probands. For further information on this study please contact David Collier (david.collier@kcl.ac.uk).

  Study EGAS00001000121

• Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial

  Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements most patients die of their disease. While immune checkpoint blockade has become part of the standard of care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment in the early disease setting remain largely unknown. We hypothesized a higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with non-metastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n=21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by 4 cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well-tolerated, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent PD-L1 blockade and the subsequent combination with chemotherapy on the tumor microenvironment. A total of 21 patients were included, of whom 20 patients underwent surgery and were evaluable for the secondary pathologic response and survival endpoints, while 19 were evaluable for exploratory translational analyses. A major pathologic response (MPR, ≤10% residual viable tumor) was observed in 14/20 (70%; 95% CI 46-88%) patients, including 9 (45%; 95% CI 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13/14 responders were alive and disease-free, while 5/6 nonresponders had died due to disease recurrence. Notably, baseline PD-1+CD8+ T cell infiltration was significantly higher in responders than in nonresponders, and comparison of the tumor microenvironment alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy revealed that increased immune activity was achieved upon single-agent PD-1/L1 axis blockade. Based on these data, anti-PD-L1 plus chemotherapy warrants further exploration in patients with non-metastatic G/GEJ cancer, and these results call for validation in a larger cohort.

  Study EGAS50000000168

• Targeted sequencing of genes recurrently mutated in AML

  Background Massively parallel sequencing technology has transformed cancer genomics. It is now feasible, in a clinically relevant time-frame, for a clinically manageable cost, to screen DNA from patient tumours for mutations essentially genome-wide. The challenge for personalised medicine will be to increase the sample size to thousands or tens of thousands of well-characterised cases in order to attain sufficient statistical power to stratify patients accurately across the complexity and genomic heterogeneity expected for most of the common tumour types. Currently, whole genome sequencing on this scale is not feasible, and targeted sequencing of relevant portions of the genome will be required. Pilot data We have developed protocols for large-scale, multiplexed sequencing of 100-200 genes in thousands of samples. Essentially, using robotic technology, genomic DNA from the cancer specimen is processed into sequencing libraries with unique DNA barcodes, thereby allowing sequencing reads to be attributed to the sample they derive from. Currently, these sequencing libraries can be generated in a 96-well format using fully automated protocols, and we are exploring methods to expand this to a 384-well format. The sequencing libraries are pooled and hybridized to custom sets of RNA baits representing the genomic regions of interest. Sequencing of the pulled-down libraries is done in pools of 48-96 samples per lane of an Illumina Hi-Seq. This protocol is already implemented at the Sanger Institute. We have published proof that somatic mutations in novel cancer genes can be identified from exome-wide sequencing. In unpublished pilot data, we have established the feasibility of robotic library production, custom pull-down, and multiplexed sequencing of barcoded libraries for 100 known myeloid cancer genes across 760 myelodysplasia samples. Highlights of the data thus far analysed reveal that the coverage is remarkably even between samples; when 96 samples are run, average coverage per lane of sequencing is ~250, with 90-95% of targeted exons covered by &gt;25 reads; known mutations can be discovered in the data set; and the protocol is amenable to whole genome amplified DNA. The bioinformatic algorithms for identification of substitutions and indels in pull-down data are well-established; we have pilot data proving that copy number changes, LOH and genomic rearrangements in specific regions of interest can also be identified by tiling of baits across the relevant loci. Proposal We propose to apply this methodology to 10000 samples from patients with AML enrolled in clinical trials over the last 10-20 years. Oncogenic point mutations and potentially genomic rearrangements will be identified, and linked to clinical outcome data, with a view to undertaking the following sorts of analyses: ? Identification of co-occurrence, mutual exclusivity and clusters of driver mutations. ? Correlation of prognosis with driver mutations and potentially gene-gene interactions ? Exploration of genomic markers of drug response Ultimately, we would like to be in a position to release the mutation data together with matched clinical outcome data to genuine medical researchers via a controlled access approach, possibly within the COSMIC framework (www.sanger.ac.uk/genetics/CGP/cosmic/). The vision here is to generate a portal whereby a clinician faced with an AML patient and his / her mutational profile can obtain a ?personalised? prediction of outcome, together with a fair assessment of the uncertainty of the estimate. With a sufficient sample size, there would also be the potential to develop decision support algorithms for therapeutic choices based on such data.

  Dataset EGAD00001000606

• Small RNA Sequencing across Diverse Biofluids Identifies Optimal Methods for exRNA Isolation

  We tested the efficiency and reproducibility of 10 RNA isolation methods on 5 different biofluids. Pooled human plasma and serum, bile and urine were used along with cell culture supernatants from human embryonic stem cells (hESC), primary neonatal rat ventricular myocytes (NRVM) and human cholangiocarcinoma cells (KMBC). 4 RNA isolation methods designed to isolate total RNA from bio fluids without enrichment of exRNA carriers were used. 6 methods that preferentially enriched for exRNA carriers were also compared. Small RNA libraries were constructed using the NEBNext small-RNA library prep. The efficiency and reproducibility of the different RNA isolation methods was compared using small-RNA seq.

  Study phs002143

• Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) Center for Environmental Health Disparities

  MADRES is a prospective pregnancy cohort based in urban Los Angeles, recruiting predominantly low income Hispanic mothers-to-be as part of a children's health study, funded by Environmental Influences on Child Health Outcomes (ECHO). Participants were measured for a number of chemical exposures and biomarkers. Two epigenetic markers will be available through dbGaP: miRNA expression in pregnancy (measured via Nanostring human assay, v3) and DNA methylation from pregnancy and children's cord blood (measured via EPIC array). Principal findings of this research described differences in miRNA expression profiles between early and late pregnancy, as well as miRNA expression affected by psychosocial stress.

  Study phs003194

• Development of Novel Histiocytic Sarcoma Organoid Model for Drug Discovery

  Histiocytic sarcoma is an extremely rare and aggressive hematopoietic malignancy. Its pathogenesis remains poorly understood and effective treatments are lacking. We treated a patient with histiocytic sarcoma of soft tissue in Osaka International Cancer Institute and established an organoid culture from a resected tumor specimen using a modified air���liquid interface method. After serial passaging, the organoid was successfully xenografted into NOD-scid IL2Rgnull (NSG) mice. The established organoid retained key histological features and genetic characteristics of the original tumor. This organoid model offers a novel and reliable platform for studying the biology of histiocytic sarcoma and may contribute to the development of future therapeutic strategies.

  Study JGAS000807

• Whole-genome bisulfite sequencing for high-grade glioma

  We conducted whole-genome bisulfite sequencing to delineate base-resolution methylomes of gliomas harboring G34R mutation as well as those harboring K27M and no mutations in H3F3A. Comparative analysis of these three glioma subgroups revealed that G34 subgroup exhibited lower global methylation levels, comparable CpG island (CGI) methylation levels, and compromised hypermethylation of telomere-proximal CGIs, compared to the other two subgroups. Genomic regions specifically hypermethylated in G34 subgroup were enriched for CGIs. CGIs with G34V-mutated histone H3.3 in the glioma cell line KNS-42 were hypermethylated compared to those without it, suggesting a correlation between G34-mutated histone H3.3 in CGI hypermethylation.

  Study JGAS000197