Search Results - EGA European Genome-Phenome Archive

Accurate detection of tumor-specific fusion genes reveals strongly immunogenic personal neo-antigens

Fusion genes arising from cancer-associated somatic mutations are a potential rich source for highly immunogenic neo-antigens. However, their exploitation as targets for personalized cancer immunotherapy is currently limited by the lack of computational tools allowing transcriptome-wide identification of unique fusion genes in an accurate and sensitive manner. Here, we present EasyFuse, a computational pipeline, to detect individual and cancer-specific fusion genes in next-generation-sequencing transcriptome data obtained from human cancer samples. Using machine learning, EasyFuse predicts personal fusion genes with high precision and sensitivity and outperforms previously described approaches as qualified by an unprecedented ground-truth dataset of >1500 verification experiments in relevant patient samples. By testing immunogenicity with autologous blood lymphocytes from cancer patients we detected pre-established CD4+ and CD8+ T cell responses for 10 of 21 (48%), and for 1 of 30 (3%) of identified fusion genes, respectively. In conclusion, we demonstrate accurate detection of cancer-specific fusion genes. The high frequency of T cell responses detected in cancer patients support the relevance of private fusion genes as neo-antigens for personalized immunotherapies, especially for tumors with low point mutation burdens.

Study EGAS00001004877

The impact of BNT162b2 mRNA vaccine against SARS-CoV-2 on adaptive and innate immune responses

The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 through induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. In the present study, we investigated the specific adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants, as well as its effects on the responsiveness of human immune cells upon stimulation with heterologous viral, bacterial, and fungal pathogens. BNT162b2 vaccination induced effective humoral and cellular immunity against SARS-CoV-2 that started to wane after six months. We also observed long-term transcriptional changes in immune cells after vaccination, as assessed by RNA sequencing. Additionally, vaccination with BNT162b2 modulated innate immune responses as measured by the production of inflammatory cytokines when stimulated with various microbial stimuli other than SARS-CoV-2, including higher IL-1/IL-6 release and decreased production of IFN-α. Altogether, these data expand our knowledge regarding the overall immunological effects of this new class of vaccines and underline the need of additional studies to elucidate their effects on both innate and adaptive immune responses.

Study EGAS00001006818

Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression

Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, we analyze 1,532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2,933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n=148) or the alternatively spliced isoform (n=9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal (https://cseminer.stjude.org/), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

Study EGAS00001007766

H3Africa - Kidney Disease Research Network

Chronic kidney disease (CKD) affects an estimated 14% of adults in sub-Saharan Africa but very little research has been done on the etiology, progression and prevention of CKD on the continent. As part of the Human Heredity and Health in Africa (H3A) Consortium, the H3Africa Kidney Disease Research Network was established to study prevalent forms of kidney disease in sub-Saharan Africa and increase the capacity for genetics and genomics research. The study is performing comprehensive phenotypic characterization with analysis of environmental and genetic factors from seven clinical centers in two African countries (Ghana and Nigeria) over a five-year period. Approximately 4,000 participants with specified kidney disease diagnoses and 4000 control participants will be enrolled in the four African countries. In addition, approximately 50 families with hereditary glomerular disease will be enrolled. The study includes both pediatric and adult participants ages <1 to 74yrs across a broad spectrum of kidney diseases secondary to hypertension, diabetes, human immunodeficiency virus, sickle cell disease, biopsy-proven glomerular disease and CKD of unknown origin. Clinical and demographic data with biospecimens are collected for assessment of clinical, biochemical and genetic markers of kidney disease.

Study EGAS00001006558

Transcriptome of (peripheral blood), from donor Sample B, replicate 1 time-course biological replicates; 10x lane replicate 1

time-course biological replicates; 10x lane replicate 1

Dataset EGAD00001010088

BLUEPRINT release August 2014, DNase-Hypersensitivity for macrophage

DNase-Hypersensitivity data for 1 macrophage sample(s). 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT release August 2014. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20140811/homo_sapiens/README_dnaseseq_analysis_20140811

Dataset EGAD00001000931

What is a DAC?

What is a DAC? Given the complexity, scale, and diversity of global submitters and studies, the EGA operates a distributed data access model in which requests are made to the data controller, not to the EGA. The European Commission defines a data controller, in the General Data Protection Regulation (GDPR), as the person that determines the purposes for which and the means by which personal data is processed. A Data Access Committees, commonly referred to as DACs, comprise on or more individuals (or data controllers) that review data access requests and make decisions on who can access personally identifiable genetic, phenotypic, and clinical data deposited at the EGA. Therefore, the members of a DAC should be individuals who have the authority to approve data access requests. The animation describes how you can authorise access to your sensitive data with the help of Data Access Committee and Authorisation tool. Acknowledgement to CSC - IT Center for Finland, Elixir Finland, Elixir Europe. Frequently Asked Questions How can I create a Data Access Committee? How can I create a Data Access Committee? The members of a DAC can come from different areas of expertise, such as data management, data analysis, information technology, legal and compliance, subject matter experts, privacy and security, and representatives from the organisations or individuals that provide data to the DAC. The specific members of a DAC can vary depending on the needs of the organisation and the type of data being managed. The EGA strongly suggests checking with your organisation to align with its regulations How should a DAC be named? The chosen name must be informative to the applicant. For example, internal identifiers, such as grant numbers, should not be used. Individual PI names should also not be used. DAC's are often named after the organisation or department of the data source. Browse the full list of DAC names currently in the EGA. How can I become an EGA DAC contact? To register a DAC at the EGA you must create first as an EGA user. Once your EGA user has been approved by the Helpdesk team, you will be able to log in to the DAC Portal. How can I register a DAC? To register a DAC, follow the DAC Portal instructions. You will be required to provide a DAC name, name of the individual(s) that make up your DAC and contact details for your DAC including your Institutional email(s). Wherever possible, the DAC should make sure that all points of contact are readily available and able to answer any initial data requests/queries in < 2 weeks. Once your DAC is registered, you will have to wait upon the validation from our Helpdesk team. As soon as all the validations have been completed, your DAC will be activated. Alternatively, you can also establish a DAC at the EGA during a programmatic submission through Webin API. Which are the possible roles of a DAC contact? There are two possible roles for DAC contacts: member and admin. An admin has additional privileges compared to a member: An “admin” can manage data requests, create and edit policies, edit the content of the DAC, add or remove contacts, and decide the role of each contact. A “member” can manage data requests and create policies. However, a member does not have permission to modify DAC details, edit information from policies where they are not admins, or add/remove contacts. There is no limit to the number of admins in a DAC, and each admin is responsible for deciding who should have editing privileges. This allows for a more decentralised and democratic approach to managing the DAC. How can I modify the information of a DAC? To modify a DAC, follow the instructions here. Keep in mind that only DAC contact with an admin role can modify the information of a DAC. If your DAC was registered before the lauch of the DAC Portal, and its ID is EGAC0 (not EGAC5), you must use the programmatic submission to modify it. Please, do not hesitate to contact our Helpdesk team if you need help with this! To prevent potential data breaches and ensure adherence to GDPR regulations, it is essential that the European Genome-Phenome Archive (EGA) is informed via the Helpdesk team of any changes to the Data Access Committee (DAC). This should be done in addition to any changes being made on the DAC portal. Data Controllers (as per the definition in the DPA) are also responsible for notifying the previous DAC of any modifications. Without proper notification, changes might not be automatically updated in our system, leading to the risk of incorrect permissions being applied and potential data access issues. Therefore, it is imperative that all Data Controllers follow this protocol to maintain data integrity and security. What’s the link between DAC, policy and dataset? A dataset is linked to one single policy. At the same time, one policy has a one to one relationship with a DAC. In this example, you can see that in this dataset page, we are only showing the information of one DAC (1 dataset - 1 DAC). However, the ratio of objects does not work the same in the other direction. One DAC can own multiple policy objects. And each policy object can be reused in several datasets. Thus, one DAC can manage one or more datasets. In this example, you can see that in this DAC page, we are showing all the datasets that are managed by one DAC (1 DAC - >400 datasets). EGA Data Access Committee Best Practices Which are the EGA DAC best practices? Refer to DAC Best Practices What happens if a DAC member changes institutions? EGA is committed to the protection and ownership of the data stored in our systems. We respect the institution's ownership of the data, and as such, if a DAC member changes institutions, the ownership of the data will not be transferred to the new institution. Therefore, before changing institutions, we request that the DAC contact add a new member who will replace them once they no longer work at the institution. This ensures that the data remains protected and is accessible to authorised personnel at the institution. To prevent potential data breaches and ensure adherence to GDPR regulations, it is essential that the European Genome-Phenome Archive (EGA) is informed via the Helpdesk team of any changes to the Data Access Committee (DAC). This should be done in addition to any changes being made on the DAC portal. Data Controllers (as per the definition in the DPA) are also responsible for notifying the previous DAC of any modifications. Without proper notification, changes might not be automatically updated in our system, leading to the risk of incorrect permissions being applied and potential data access issues. Therefore, it is imperative that all Data Controllers follow this protocol to maintain data integrity and security. What happens if EGA detects an unresponsive DAC? EGA defines an unresponsive DAC as a DAC with one or more contacts who do not respond to data access requests. EGA has procedures in place to identify these types of DACs, escalate the issue, and attempt to reassign the DAC to a responsive contact. This is a crucial step in ensuring that data can be accessed and utilised by researchers. If EGA identifies an unresponsive DAC, the organisation will first try to resolve the issue by escalating it to the appropriate parties. This may involve attempting to reassign the DAC to a more responsive contact. Unfortunately, in situations where we cannot reassign the DAC, the dataset will be withdrawn from the public website and the files will be removed from our system. If an EGA ID is referenced in a publication, the EGA will take extra steps to ensure that the public is made aware of the data's unavailability. I don't want to receive an email notification for pending requests. How can I do that? If you are an EGA DAC with pending requests, you will always receive emails for new data access requests. However, the EGA understands that a request resolution can take some time, for this reason, if you add a comment (make sure you save it by clicking the APPLY button!) we will filter those requests at the time of sending the notification! How can I manage data access requests? What documentation does the DAC need to provide? Each dataset that is submitted to the EGA must be linked to a policy object. The policy is a Data Access Agreement (DAA), which defines the terms and conditions of using the dataset, such as how the data files should be stored once downloaded or details of publication embargoes that should be observed by the approved user. As part of the Data Access Agreement, information regarding the application can be captured to help inform the DAC when making its decision. For example, requestors could be asked to provide a proposed title for their research and a proposal of how the data will be used. By asking for provision of such information the DAC can be assured that the requestor fully understands any consents associated with the data. It is important that accounts created at the EGA, are created solely for those individuals that will be downloading the data from the EGA. As part of the data access request, we strongly encourage you to identify individuals that will need an account at the EGA in order to prevent sharing of login details, which is strictly prohibited under EGA user account policy. Such information can easily be captured in the DAA. NOTICE The data access agreement template below is provided for guidance only and should be adapted as you see fit to suit your own purpose. In the interest of promoting data sharing, we suggest that if an agreement cannot be met around clause 19 in this example that both parties should agree to remain silent, and that the clause should be removed from the agreement. Example DAA How can the DAC provide the DAA? The DAC should provide their own DAA when registering a policy. Data requestors will download this document and should fill it in and send it back to the DAC. Data access decisions should be based on such documentation. The DAA can be downloaded through the request data webpage. Once it has been filled in, the signed copy of the DAA can be uploaded back to the request data webpage and sent to the DAC for review. How can I grant access to the data? Once you receive a data access request, you can login to the DAC Portal. In this portal you will see all your pending requests and will be able to grant or decline access to the requestors. I am a member of the Data Access Committee. Could I approve somebody else to deal with the requests on my behalf? If you want to delegate data access decisions to someone else, make sure that the individual's account is officially registered as a member of the DAC. Remember that a DAC contact with an "admin" role can always add new members to an existing DAC, remove members, and modify contact details through the DAC Portal. Can I automatise the process of managing data access requests? The answer is yes! You can use a programmatic approach using our DAC API! Check out the DAC API specification! Data Breach What should a DAC do if they suspect a breach? If a DAC suspects a data breach of one or more of their datasets, they should immediately contact the EGA Helpdesk team at this link. The DAC must provide the following information when contacting the EGA Helpdesk team: A list of affected datasets An estimated date of the data breach (or interval of dates) A list of unauthorised users who accessed the data (if available). Otherwise, they can provide a list of authorised users for the affected datasets Any observations they would like to raise to the EGA team Once the DAC has contacted the EGA team, we will respond within 48 hours (please allow some leeway during peak times) and activate our data breach protocol. What can I expect from the EGA if they detect a breach? Once the EGA determines that a security incident has occurred, we will notify all DAC members that a data breach has been detected, and take steps to contain the incident. Containment approaches may include: Revoking a data provider's access to the EGA resources, such as by changing passwords. Removing affected EGA datasets from distribution, such as by withdrawing a dataset. Disabling certain functions or services, such as the EGA ingestion pipeline. Shutting down the system or disconnecting it from the network. After the incident has been contained, the EGA will determine whether it is necessary to eradicate components related to the incident. Finally, the EGA will enable recovery of the service to normal operation and confirm that all services are functioning normally.

Documentation access/data-access-committee/what-is-dac

Submission 6 - study_title 1 - edited

Submission 6 - description 1 -edited

Study EGAS50000000748

Characterization_of_individual_foci_of_multicentric_multifocal_breast_cancer_using_targeted_next_generation_sequencing

Multifocality or multicentricity in breast cancer may be defined as the presence of two or more tumor foci within a single quadrant of the breast or within different quadrants of the same breast, respectively. This original classification of the breast cancer as multicentric or multifocal was based on the assumption that cancers arising in the same quadrant were more likely to arise from the same ductal structures than those occurring in separate areas of the breast. The problem with these definitions is that the “quadrants” of the breast are arbitrary external designations, as no internal boundaries do exist. This project will therefore focus both on synchronous multifocal and multicentric tumors. The incidence of multifocal and multicentric breast cancers was reported to be between 13 and 75% depending on the definition used, the extent of the pathologic sampling of the breast and whether in situ disease is considered evidence of multicentricity (1). Although this incidence is variable, those figures show that it is a frequent phenomenon. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic management of the cancer. Multifocality or multicentricity has been associated with a number of more aggressive features including an increased rate of regional lymph node metastases and adverse patient outcome when compared with unifocal tumors (2-3), and a possible increased risk of local recurrence following breast conserving surgery (4). For the moment, the literature is divided on whether there is a corresponding impact on survival outcomes. Today, the current convention to stage and to treat multifocal and multicentric tumors is the classical tumor-node-metastasis (TNM) staging guidelines with which tumor size is assessed by the largest tumor focus without taking other foci of disease into consideration. If some papers, as the recent one from Lynch and colleagues, support the current staging convention (3), others, however, as Boyages et al. suggested that aggregate size and not the size of the largest lesion should be considered in order to refine the prognostic assessment of those tumors (5). On the top of that, the question whether multifocal/multicentric carcinomas are due to the spread of a single carcinoma throughout the breast or is due to multiple carcinomas arising simultaneously has been a matter of debate. Some studies suggested that multifocal breast cancer may result from either intramammary spread from a single primary tumor or multiple synchronous primary tumors; whereas others suggest that multiple breast carcinomas always arise from the same clone (6-8). Recently, Pietri and colleagues analyzed the biological characterization of a series of 113 multifocal/multicentric breast cancers (8) which were diagnosed over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. Interestingly, this heterogeneity among foci has led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor. This study therefore showed that differences in biological characteristics of multifocal/multicentric lesions play a crucial role in the adjuvant treatment decision making process. In this study, we will concentrate on a larger series of patients with multifocal invasive ductal breast cancer lesions. We aim at: 1. Evaluating the incidence of multifocality according to the different breast cancer molecular subtypes (ER-/HER2-, HER2+, ER+/HER2-). 2. Evaluating the incidence of multifocality in patients with hereditary breast cancer disease (presence of germline BRCA1 or BRCA2 mutations). Moreover, we would like to investigate if multifocal lesions with BRCA1 or BRCA2 mutations exhibit a characteristic combination of substitution mutation signatures and a distinctive profile of deletions as demonstrated recently by Nik-Zainal and colleagues (9). 3. Correlating multifocality with clinical information in order to define its influence on patients’ survival (DFS and OS). 4. Carrying high coverage targeted gene sequencing of driver cancer genes and genes whose mutation is of therapeutic importance in order to compare clinically-relevant genetic differences between several multifocal breast cancer lesions. 5. Evaluating the impact of the distance between the different lesions on the clinical outcome but also on the genetic differences. 6. Comparing gene expression patterns between several multifocal breast cancer lesions and correlate them with the results of the targeted genes screen. 7. Characterizing the genomic and transcriptomic status of cancer related genes in metastatic lesions (local recurrence, positive lymph node or distant metastatic sites) from the same multifocal invasive ductal breast cancer patients in order to evaluate the consequence of genomic and transcriptomic heterogeneity of multifocal lesions on metastatic lesions. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic choice. This project has the potential to identify genetic/transcriptomic differences existing between several lesions constituting multifocal breast cancers, which in the routine clinical practice are usually considered to be homogeneous among them. We foresee validating significant results in a larger series of patients and this, in turn, could have a remarkable impact on the treatment and clinical management of multifocal breast cancers. Indeed, we hope to provide some evidence whether or not each focus matters in multifocal and multicentric breast cancer to define the adequate therapeutic approach, especially in the context of targeted therapies. The work to be done at Sanger will be target gene screen pooling of 1400 samples.

Study EGAS00001000407

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_BG_T=24hrs_RPMI_T=5days from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_BG_T=24hrs_RPMI_T=5days from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002904

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_BG_T=1hr from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_BG_T=1hr from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002906

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_BG_T=4hrs from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_BG_T=4hrs from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002910

BLUEPRINT September 2016, ATAC-seq for germinal center B cell from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for germinal center B cell from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002911

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_T=24hrs from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_T=24hrs from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002921

BLUEPRINT release August 2015, DNase-Hypersensitivity for Acute Myeloid Leukemia, on genome GRCh38

DNase-Hypersensitivity data for 1 Acute Myeloid Leukemia sample(s). 1 run(s), 1 experiment(s), 1 alignment(s) on human genome GRCh38. Part of BLUEPRINT release August 2015. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20150820/homo_sapiens/README_dnaseseq_analysis_20150820

Dataset EGAD00001001549

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_T=1hr from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_T=1hr from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002919

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_LPS_T=24hrs from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_LPS_T=24hrs from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002900

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_T=6days from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_T=6days from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002914

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_LPS_T=1hr from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_LPS_T=1hr from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002913

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_BG_T=24hrs from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_BG_T=24hrs from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002909

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_LPS_T=4hrs from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_LPS_T=4hrs from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002922

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_T=4hrs from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_T=4hrs from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002899

ARGO_GWAS

Osteoarthritis (OA) is the most common form of arthritis affecting ~40% of people over the age of 70. OA is characterised by cartilage degeneration in the synovial joints and presents one of the leading causes of chronic disability and impaired quality of life in the developed world.The ARGO study is an ongoing collection of well-phenotyped OA patients undergoing total joint replacement and is based in Greece.

Study EGAS00001000917

BLUEPRINT September 2016, ATAC-seq for monocyte RPMI_BG_T=24hrs_RPMI_T=5days_LPS_T=4hrs from venous blood, on Genome GRCh38

ATAC-seq data for 1 sample(s) for monocyte RPMI_BG_T=24hrs_RPMI_T=5days_LPS_T=4hrs from venous blood, on Genome GRCh38. 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002915

Surgical Treatment for Ischemic Heart Failure (STICH-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. ObjectiveTo compare medical therapy with coronary bypass surgery and/or surgical ventricular reconstruction for patients with congestive heart failure and coronary artery disease.BackgroundCoronary artery disease (CAD) is the most common cause of heart failure, which in turn is a major cause of death and disability globally. Evidence from previous clinical trials supports the use of coronary-artery bypass grafting (CABG) to relieve disabling symptoms of angina, particularly among high-risk subgroups with extensive CAD. However, the studies did not include patients with severe left ventricular dysfunction, and developments in medical therapy have since led to updated guidelines. In addition, the benefits of CABG in patients with ischemic cardiomyopathy had still not been clearly established at the time of this study. STICH sought to evaluate the role of CABG in the treatment of patients with CAD and left ventricular systolic dysfunction.Reduced left ventricular function may occur after myocardial infarction, often in conjunction with left ventricular remodeling, including left ventricular enlargement and changes in chamber geometry. Left ventricular remodeling is correlated with progression of heart failure and a poor prognosis. Therefore, a surgical approach to remodeling through left ventricular volume reduction could improve outcomes for patients with CAD and heart failure. Surgical ventricular reconstruction (SVR) has been shown to reduce the left ventricular volume, increase the ejection fraction, and improve ventricular function. There is also evidence that SVR performed with CABG may reduce the rate of hospitalization and improve ventricular function, as compared to CABG alone. As part of a second hypothesis, STICH additionally investigated whether SVR when added to CABG would improve outcomes in patients with heart failure and CAD.ParticipantsA total of 2,136 participants were enrolled in STICH. 1,212 were enrolled in the hypothesis 1 component of the trial, with 602 participants assigned to receive medical therapy alone, and 610 participants assigned to receive medical therapy plus CABG. 1,000 were enrolled in the hypothesis 2 component, with 499 participants assigned to receive medical therapy plus CABG, and 501 participants assigned to receive medical therapy plus CABG and SVR. 76 participants that were assigned to the CABG with medical therapy treatment were enrolled in both hypothesis components.DesignAfter initial determination of overall eligibility, participants were evaluated to determine which component of the STICH program was appropriate for them on the basis of suitable therapeutic options. All participants underwent cardiac imaging for assessment of left ventricular function and wall motion. Participants in the hypothesis 1 component were randomly assigned to receive either medical therapy alone or medical therapy plus CABG. Participants in the hypothesis 2 component were randomly assigned to receive either medical therapy plus CABG or medical therapy plus CABG and SVR.At baseline, demographic factors and clinical characteristics were assessed, including current medications and prior diagnostic and other cardiovascular procedures, and a physical examination was performed. Guideline-based recommendations for drug and device use were emphasized for all participants. All participants underwent follow-up evaluations at the time of discharge or at 30 days for participants still hospitalized, every 4 months for the first year, and every 6 months thereafter. The median length of follow-up was 56 months for hypothesis 1 and 48 months for hypothesis 2.For participants receiving CABG, arterial grafting for stenosis of the left anterior descending coronary artery was required for all participants without specific contraindications. The use of additional arterial conduits supplemented by vein grafts was recommended for revascularization of all major vessels with clinically significant stenoses. Concurrent mitral-valve surgery for regurgitation was performed at the discretion of the surgeon. For participants receiving SVR, the operation was most commonly performed during a single period of cardioplegic arrest after construction of bypass grafts. However, the procedure could also be performed with the heart beating in order to facilitate identification of the noncontractile zone of scarring. After an anterior left ventriculotomy was centered in the zone of anterior asynergy, a suture was placed in the interior of the ventricle to encircle the scar at the boundary between the akinetic and viable tissue. Visual inspection and palpation facilitated the judgment of whether a patch was needed to optimize the chamber size without deforming the left ventricle during closure of the ventriculotomy.The primary outcome for hypothesis 1 was the rate of death from any cause. The primary outcome for hypothesis two was a composite of death from any cause and hospitalization for cardiac causes.ConclusionsThere was no significant difference between medical therapy alone and medical therapy plus CABG for death from any cause, though participants that underwent CABG had lower rates of death from cardiovascular causes, death from any cause, or hospitalization for cardiovascular causes. Adding SVR to CABG reduced the left ventricular volume, as compared with CABG alone. However, this anatomical change was not associated with a greater improvement in symptoms or exercise tolerance, or with a reduction in the rate of death or hospitalization for cardiac causes.

Study phs003493

DIAMOND PCR : plasma DNA LINE-1 targeted bisulfite sequencing, a new non-invasive multi-cancer detection marker

The detection of circulating tumor DNA, which allows non-invasive tumor molecular profiling and disease follow-up, promises optimal and individualized management of patients with cancer. However, detecting small fractions of tumor DNA released when the tumor burden is reduced remains a challenge. We developed a PCR-based targeted bisulfite method coupled to deep sequencing to detect methylation patterns of L1PA elements,which we named DIAMOND (for Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA). We used sodium bisulfite chemical conversion to achieve base-pair resolution analysis and designed a multiplexed PCR based on 8 amplicons covering L1PAs .

Dataset EGAD50000000646

RNA-seq FASTQ files from newborn screening dried blood spot samples

Paired-end RNA-seq FASTQ files from 21 newborn screening dried blood spot (DBS) samples. These DBS samples were obtained from extremely low gestional age newborns, where 10 of them were affected by a fetal inflammatory response (FIR) before birth, and 11 were unaffected. Total RNA was sequenced using an Illumina NextSeq-500 instrument. The sample preparation protocol included the depletion of rRNA and globin mRNA using the Globin Zero Gold rRNA Removal Kit from Illumina. Libraries were prepared using the NebNext Ultra TM II Directionl RNA LIbrary Prep Kit (New England Biolabs). Each sample was sequenced in 4 lanes, leading to 8 FASTQ files per sample and a total of 21x8=168 FASTQ files. There is an additional number of 8 FASTQ files corresponding to sample BS13, which was downsampled to 1/4 of its original depth (see BS13_README file for details).

Dataset EGAD00001004991

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

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

Dataset EGAD00001015413

Acral Melanoma PDXs from the admixed Brazilian Population- Human RNA expression data from Patient Derived Xenograft samples - htseq count files

Files containing the read counts obtained with obtained with HTSeq for all the genes in Ensembl v103 annotation for GRCh38 human reference genome. This dataset contains the files for all the Patient Derived Xenograft samples. Counting was performed using filtered BAM files after the removal of mouse reads with XenofilteR. Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like in Latin America, it can account for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing was performed on both tumours and patient-derived xenograft (PDX) samples. The PDX were obtained from a comprehensive collection of patient-derived xenograft (AM-PDX) models that we established which faithfully retained the histopathological and genomic features of the original tumours.

Dataset EGAD00001015747

Somatic L1 retrotransposition in normal colorectal epthelium

Throughout an individual’s lifetime, genomic alterations accumulate in somatic cells. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome, is poorly understood in normal cells. Here, we explored the whole-genome sequences of 406 normal colorectal clones, 12 MUTYH-associated adenomatous clones, and 19 matched colorectal cancer tissues. In addition, we analyzed promoter DNA methylation status of retrotransposition-competent L1 (in 139 clones) and read-through RNA expression profiles (in 116 clones) to investigate the epigenetic regulation of L1 activity.

Dataset EGAD00001010183

Ither2 WXS dataset - Implementation of pediatric precision oncology into clinical practice: The individualized Therapies for Children with cancer program “iTHER”

iTHER is a prospective national precision oncology program aiming to define tumor molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory pediatric tumors in order to identify relevant aberrations to inform treatment.

Dataset EGAD00001010178

Single cell transcriptional consequences of leukaemogenic SETBP1 mutations

The SETBP1 gene encodes a DNA-binding nuclear protein that regulates gene expression across multiple tissues. Precise control of SETBP1 dosage is essential for normal cellular function, as both loss- and gain-of-function variants of SETBP1 can lead to severe phenotypic consequences. De novo germline gain-of-function point mutations that prolong SETBP1 half-life result in Schinzel-Giedion syndrome (SGS), an ultra-rare and severe congenital disorder associated with extensive developmental abnormalities and health complications. These SGS-associated variants cluster within a hotspot in the SKI-homology domain of SETBP1, overlapping with somatic mutations recurrently observed in myeloid leukaemia with poor prognosis. Thus far, the precise mechanisms by which these SETBP1_mutations drive disease remain largely unclear. Here, through single-cell and single-nucleus mRNA sequencing of a rare collection of primary patient samples with SGS, we examined the transcriptional consequences of _SETBP1 gain-of-function variants in haematopoietic cells from natural variation.

Dataset EGAD00001015829

Genomic and transcriptomic landscape of T-cell lymphoblastic lymphoma compared to T-cell acute lymphoblastic leukemia: similar subtypes and different fusions

Due to the lower incidence of T-LBL and difficulties in obtaining diagnostic T-LBL material, extensive research on T-LBL has been hampered whereas genetic aberrations in T-ALL are thoroughly characterized. Given the similarities and differences between T-LBL and T-ALL, the question has been raised whether T-LBL and T-ALL represent two different diseases or different manifestations of the same disease. This study aims to identify the genomic and transcriptomic landscape of T-LBL and compare the findings to what is found T-ALL. Comparison of the molecular aberrations between T-LBL and T-ALL can provide insights into the overlap and differences in malignant development between the two entities, which could lead to improved risk stratification in T-LBL in order to eventually adapt T-LBL treatment protocols based on molecular-genetic prognostic factors.

Dataset EGAD00001015357

Genetics of gene expression in human macrophage response to Salmonella

Understanding how cells sense and respond to their environment, and how these responses are modulated by genetic variation, are fundamental biological problems, particularly for understanding how pathogenic organisms invade and manipulate the cells of the human immune system. Macrophages recognize and respond to many important human pathogens including HIV-1, Mycobacteria tuberculosis and Salmonella. This study will focus on the cellular response of human macrophages to Salmonella infection and how this response is modulated by the genetic bacground of the individual as well as additional pro-inflammatory stimulus (interferon-gamma priming). We will acquire 100 human induced pluripotent stem cell lines from the HipSci project, differentiate the cells in vitro into macrophages and expose them to four environmental conditions: (i) no stimulation, (ii) interferon-gamma (18h), (iii) Salmonella typhimurium SL1344 (5h), (iv) interferon-gamma (18h) + Salmonella (5h).Subsequently, we will isolate RNA from the samples for sequencing.

Dataset EGAD00001003204

Ither2 RNA-Seq dataset - Implementation of pediatric precision oncology into clinical practice: The individualized Therapies for Children with cancer program “iTHER”

iTHER is a prospective national precision oncology program aiming to define tumor molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory pediatric tumors in order to identify relevant aberrations to inform treatment.

Dataset EGAD00001010179

BLUEPRINT release August 2015, DNase-Hypersensitivity for alternatively activated macrophage, on genome GRCh38

DNase-Hypersensitivity data for 1 alternatively activated macrophage sample(s). 1 run(s), 1 experiment(s), 1 alignment(s) on human genome GRCh38. Part of BLUEPRINT release August 2015. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20150820/homo_sapiens/README_dnaseseq_analysis_20150820

Dataset EGAD00001001545

BLUEPRINT release August 2014, DNase-Hypersensitivity for CD34-negative, CD41-positive, CD42-positive megakaryocyte cell

DNase-Hypersensitivity data for 1 CD34-negative, CD41-positive, CD42-positive megakaryocyte cell sample(s). 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT release August 2014. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20140811/homo_sapiens/README_dnaseseq_analysis_20140811

Dataset EGAD00001000942

BLUEPRINT release January 2015, DNase-Hypersensitivity for CD34-negative, CD41-positive, CD42-positive megakaryocyte cell

DNase-Hypersensitivity data for 1 CD34-negative, CD41-positive, CD42-positive megakaryocyte cell sample(s). 1 run(s), 1 experiment(s), 1 alignment(s). Part of BLUEPRINT release January 2015. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20140811/homo_sapiens/README_dnaseseq_analysis_20140811

Dataset EGAD00001001161

Multiple_Malignancy_Familial_Comparison

Patient (who has had multiple malignancies) has previously been found to harbour a pathogenic p53 variant which is probably mosaic. This finding is based on exome sequencing performed elsewhere. In this study we will resequence the locus in question to ascertain whether the variant is indeed mosaic.

Study EGAS00001000333

Birth Defects: Moebius Syndrome and Related Congenital Facial Weakness Disorders

It is estimated that about 1 in every 33 infants in the United States is born with a birth defect. Among these, the subset of birth defect syndromes associated with facial weakness and lack of facial expression can have profound implications for social interactions and psychosocial development. Moebius syndrome is defined by congenital and non-progressive facial weakness and limited eye abduction, and most cases are believed to result from dysfunction of cranial nuclei/nerves VI and VII. Although rare, this syndrome causes significant impairment because of facial weakness and associated intellectual disabilities, autism, hearing loss, difficulty swallowing and breathing, peripheral neuropathy, muscle hypotonia, heart defects, chest wall abnormalities, and limb malformations. The phenotypic spectrum and the associated genetic and environmental factors underlying Moebius syndrome are poorly understood. The goal of this research is to identify causative gene mutations for Moebius syndrome and related conditions, such as Moebius-Poland or -Robin sequence, hereditary congenital facial paresis (HCFP), and oculoauriculovertebral dysplasia (Goldenhar syndrome). This proposal builds on an ongoing collaboration among researchers at Mount Sinai Medical Center, Boston Children's Hospital, NHGRI intramural program, and the Moebius Syndrome Foundation, but aims to greatly extend that work by collaboration with investigators in the NIH Clinical Center (CC). Our groups have already defined a new autosomal dominant syndrome with Moebius syndrome, Kallmann syndrome, cyclic vomiting resulting from a TUBB3 E410K substitution. We have also identified a new autosomal recessive Moebius-related syndrome with bilateral facial palsy, hearing loss, and strabismus resulting from a HOXB1 R207C substitution. Through collaborative efforts of these extramural teams with intramural investigators, whole exome sequencing (WES) has been conducted for four families with Moebius-like features, and data analyses are ongoing. The overall goal of this new grant application will be to conduct extensive phenotype analysis on approximately 24 families per year with Moebius and other undefined syndromes with facial weakness. Studies to be conducted at the CC include neurology, psychiatry, neurocognitive, rehabilitation medicine (muscle strength, speech/language pathology), ophthalmology, audiology, and genetics evaluations; autism screening; electromyography, nerve conduction, and blink reflex studies; videoscopy of quantitative eye movement recordings; 3D-CT craniofacial imaging; MRI of the brain, orbit, internal auditory canals, posterior fossa including brain diffusion tensor imaging for tractography; and genetic counseling. Jointly with the extramural teams, WES analysis and variant confirmation will be performed. A more comprehensive definition of the phenotypic and genotypic spectrum of these birth defects will have a significant impact on our understanding of the molecular pathways underlying dysmorphologies, cranial nerve development, and more common childhood disorders such as autism. Thus, this project will lead to strategies for prevention and treatment of birth defects.

Study phs001383

Defective Homologous Recombination DNA Repair as Therapeutic Target in Advanced-Stage Chordoma (HIPO_021)

HIPO project: HIPO_021 Importance: Chordomas are rare tumors of the axial skeleton and skull base with few therapeutic options and no clinically validated molecular drug targets. The value of comprehensive genomic analyses for guiding medical therapy of patients with advanced-stage chordoma is unknown.Objective: To identify therapeutically tractable genetic lesions in a cohort of chordoma patients within a genomics-guided precision oncology program and to document the outcome of individualized, molecularly targeted chordoma therapy.Design, Setting, and Participants: We performed whole-exome sequencing of tumor and matched germline control samples from seven patients with locally advanced or metastatic chordoma who were enrolled in a cross-institutional molecular stratification registry trial for younger adults with advanced-stage cancer across all histologies and patients with rare tumors. All patients were heavily pretreated and had progressive disease prior to molecular analysis.Interventions: Individualized medical therapy was administered according to the patients’ molecular profiles.Main Outcomes and Measures: Candidate therapeutic targets identified by whole-exome sequencing and response to genotype-directed therapy.Results: All patients harbored alterations of two or more genes known to be involved in DNA repair via homologous recombination (HR), including heterozygous deletions of ERCC6, FANC family members, RAD51L (n = 6), BRCA2 (n = 5), ATR, CHEK2, RAD18, RAD51B, and XRCC3 (n = 4); inactivating PTEN mutations coupled with loss of heterozygosity (n = 2); and pathogenic germline variants in BRCA2 (n = 1), NBN (n = 1), and CHEK2 (n = 1) that were accompanied by somatic deletion of the corresponding wild-type alleles. Consistently, a mutational signature associated with defective HR was enriched in all samples and co-occurred with extensive genomic instability, as evidenced by HR deficiency scores and high numbers of large-scale state transitions. These results prompted off-label treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib in a patient whose tumor was refractory to irradiation and systemic treatment with imatinib, which led to a prolonged response and substantial clinical improvement.Conclusions and Relevance: Advanced-stage chordomas are frequently characterized by genomic imprints of defective HR DNA repair. HR deficiency represents a new therapeutic opportunity in this intractable disease through repositioning of PARP inhibitors that warrants further exploration in clinical trials.

Study EGAS00001002720

BLUEPRINT release August 2016, DNase-Hypersensitivity for CD4-positive, alpha-beta T cell, on genome GRCh38

DNase-Hypersensitivity data for 1 CD4-positive, alpha-beta T cell sample(s). 1 run(s), 1 experiment(s), 1 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_dnaseseq_analysis_20160816

Dataset EGAD00001002480

BLUEPRINT release August 2016, DNase-Hypersensitivity for CD8-positive, alpha-beta T cell, on genome GRCh38

DNase-Hypersensitivity data for 1 CD8-positive, alpha-beta T cell sample(s). 1 run(s), 1 experiment(s), 1 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_dnaseseq_analysis_20160816

Dataset EGAD00001002285

BLUEPRINT release August 2015, DNase-Hypersensitivity for CD8-positive, alpha-beta T cell, on genome GRCh38

DNase-Hypersensitivity data for 1 CD8-positive, alpha-beta T cell sample(s). 1 run(s), 1 experiment(s), 1 alignment(s) on human genome GRCh38. Part of BLUEPRINT release August 2015. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20150820/homo_sapiens/README_dnaseseq_analysis_20150820

Dataset EGAD00001001475

Foregut Microbiome in Development of Esophageal Adenocarcinoma

The distal esophagus is an important anatomical area where gastric acid reflux can cause reflux esophagitis (RE), Barrett's esophagus (BE) (intestinal metaplasia), and esophageal adenocarcinoma (EA). The incidence of EA has increased 6-fold in the U.S. since the 1970s, parallel to a significant increase in the prevalence of gastroesophageal reflux diseases (GERD). Although specific host factors might predispose one to disease risk, such a rapid increase in incidence must be predominantly environmental. The cause remains unknown. Our hypothesis is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in the GERD sequence. We will conduct a case control study to characterize the microbiome in every stage of the GERD sequence as well as analyze the trend in changes in the microbiome along disease progression toward EA. Specific Aim 1. To conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence, by a 16S rRNA gene survey. We will analyze samples of the foregut microbiome at three anatomic loci: mouth, distal esophagus, and gastric corpus. Changes of the microbiota in the distal esophagus will be correlated with the phenotypes. Spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined. Specific Aim 2. To define distal esophageal metagenome and demonstrate its association with GERD sequence, by shotgun metagenomic analysis. We will first classify samples of the metagenome into metagenotypes by between-sample k-mer distance and correlate the metagenotypes with the four phenotypes. Subsequent detailed analyses will include pathway-disease and gene-disease associations. DNA viruses and fungi, if identified, also will be correlated with the phenotypes. A significant association between the foregut microbiome composition and GERD sequence, if demonstrated, will be the first step for eventually testing the causal hypothesis that an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microbial ecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiome through use of antibiotics, probiotics, or prebiotics. Causative therapy for GERD could prevent its progression and reverse the current trend of increasing incidence of EA.

Study phs000260

Genetic Factors associated with Conversion from Active Surveillance to Treatment for Prostate Cancer

This is a genome-wide association study (GWAS) of conversion from active surveillance (AS) for prostate cancer (PC) to treatment. AS is the monitoring with screening tests and/or biopsies over time of men usually with low-risk, early-stage PC to avoid harmful side effects of PC treatment. "Conversion" refers to patients who withdraw from AS (switch to active treatment) due to changes in their cancer development, anxiety about delayed treatment, or other reasons. Patients who converted because of anxiety alone were censored in the GWAS analysis. The overall goal of this study is to develop an easily measurable, germline-based panel of genetic variants to aid in selecting PC patients appropriate for AS and/or the intensity of monitoring. In total, 6,324 PC patients from 28 collaborating institutions are included in this study. Patients are those with PC who are either on AS or who have previously converted from AS to treatment. In this study, 70% of all subjects were diagnosed with very low-risk, low-risk, or low-volume intermediate-risk PC (Kryvenko and Epstein, 2016; PMID: 26709152) and have been enrolled in an AS program. DNA was extracted from blood, saliva, or formalin-fixed, paraffin-embedded (FFPE) tissue collected from the study subjects at the participating sites. Genotyping, quality control processes, and imputation were performed at the Center for Inherited Disease Research (CIDR) at Johns Hopkins University. CIDR used the Illumina Infinium Multi-Ethnic Global Array (MEGA) version 1, which included genome-wide tag SNPs and 10,000 SNPs selected with custom content. Quality control and assurance (QC/QA) checks on genotyped data involved four domains: sample-level checks, batch effects, SNP-level checks, and preliminary association tests. Samples and SNPs passing the QC/QA checks were imputed to appropriate reference panels (HRC r1.1 for patients of European ancestry) using the Michigan Imputation Server (PMID: 27571263). Unmeasured genetic variants were imputed using the Trans-Omics for Precision Medicine (TOPMed) Imputation Server, with 97,256 reference samples and 308,107,085 SNPs. Variants with imputation quality (INFO) score < 0.3 were excluded, leaving a total of 22,691,641 SNPs successfully imputed. After QC steps, a total of 5,936 samples genotyped at CIDR remained for inclusion in the GWAS.

Study phs002056

(Epi)genetic Risk Architectures of Opioid-Dependent Brain

With nearly 20,000 overdose deaths in 2014 alone, opioid addiction (OA) has emerged as one of the most pressing public health crises in recent US history. One-fifth of individuals who try heroin develop an addiction to opioids. Genetics is a major contributor to OA with an estimated 60% heritability, only somewhat less than schizophrenia (80%) which has recently seen substantial gains in identified underlying genetics. Yet, studies to date have failed to uncover most of the genes that predispose individuals to OA, leaving the overwhelming fraction of OA heritability unexplained. The proposed study takes a novel, integrated "omics-based" strategy to investigate the molecular basis of OA and uncover both genetic and epigenetic factors associated with opioid addiction. The premise for our approach is founded on studies from our labs, and others, implicating regulatory variation in common traits and diseases, including those associated with complex brain phenotypes like addiction. We have collected the largest known cohort of postmortem brains from addicts who overdosed on opioids, along with matched control brains from non-users. From both cases and control specimens, we will isolate cells from 2 regions of the brain closely implicated in the addiction phenotype: the Prefrontal Cortex (PFC) and the Nucleus Accumbens (NAc). In Aim 1, we propose ChIP-seq studies to identify regulatory elements that distinguish cases from controls and define the opioid addiction phenotype. The regulatory differences will be connected to their gene targets through high resolution in situ Hi-C. In Aim 2, we propose QTL-based approaches to identify genetic variants that underlie the regulatory differences (hmQTLs). We also propose eQTL analyses to identify genetic variants that underlie differences in transcript levels between cases and controls. Aim 3 leverages the largest heroin addiction GWAS meta-analysis to date to test the hypothesis that SNPs in regions associated with chromatin and expression differences between cases and controls define novel loci for predisposition to OA. Each Aim has the potential for discovery independent of the others (differential HM, RNAexp, QTLs, and variant-phenotype associations) but their synergy is the most powerful component of the proposed study: identifying regulatory pathways that generate, not only phenotype associations, but hypothesized mechanisms for those associations which can be the focus of new opioid addiction prevention and treatment development.

Study phs002724

UK10K RARE COLOBOMA

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. Ocular coloboma is the most common significant developmental eye defect with an incidence of ~1 in 5,000 live births. It results from failure of optic fissure closure during embryogenesis. The position and extent of the fusion failure dictates the clinical appearance and functional effect. ~30% of coloboma cases are associated with other systemic malformations. These UK10K samples will mostly comprise isolated coloboma cases without systemic involvement (aka non-syndromal coloboma). There is strong evidence from family studies that coloboma has a major genetic component with autosomal dominance being the most common pattern of inheritance. However, many cases are isolated or show complex patterns of familial clustering. The genes responsible for isolated coloboma are largely unknown, but in a small number of families mutations in SHH, CHX10, and PAX6 have been identified indicating marked genetic heterogeneity. Thus in addition to the clinical benefits of achieving a molecular diagnosis there are also major scientific advantages to identifying coloboma genes, as these are likely to provide insights into the complex process of optic fissure closure, that is critical to normal eye development. In the longer term, understanding the molecular basis of the disease may provide clues to therapeutic strategies.For further information with regard to this cohort please contact David Fitzpatrick (david.fitzpatrick@ed.ac.uk).

Study EGAS00001000127

Synthetic - GDI synthetic data

Synthetic - The Genomic Data Infrastructure (GDI) project is enabling access to genomic and related phenotypic and clinical data across Europe. It is doing this by establishing a federated, sustainable and secure infrastructure to access the data. In support of FAIRness in data sharing, this dataset is made freely available under the Creative Commons Licence (CC-BY). Please ensure the GDI project (funding: EC H2020 under grant agreement number 101081813) is acknowledged.

Study EGAS50000000678

EXCEED Study

EXCEED is a longitudinal population-based cohort which facilitates investigation of genetic, environmental and lifestyle-related determinants of a broad range of diseases and of multiple morbidity through data collected at baseline and via electronic healthcare record linkage. Recruitment has taken place in Leicester, Leicestershire and Rutland since 2013 and is ongoing, with approximately 10,000 participants aged 30-69 to date. The population of Leicester is diverse and additional recruitment from the local South Asian community is ongoing.

Study EGAS00001003499

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