Search Results - EGA European Genome-Phenome Archive

National Eye Institute (NEI) Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study

The purpose of the POAAGG study is to investigate the genetic architecture of primary open-angle glaucoma (POAG) in African Americans. This population is up to eight times more likely to develop glaucoma than non-Hispanic whites, yet no large-scale genetics studies have specifically addressed this ethnic group. The POAAGG study aims to enroll 7765 patients, consisting of a discovery cohort of 5500 subjects (2000 cases and 3500 controls) and a validation cohort of 2265 subjects (1000 cases and 1265 controls). The study population consists of self-identified blacks (African Americans, African descent, or African Caribbean), 35 years or older, identified from the Philadelphia region. Subjects are recruited from the Scheie Eye Institute and its research sites in Philadelphia, PA, as well as from the Penn Medicine Biobank. Fellowship-trained glaucoma specialists classify each subject as a case, control, or glaucoma suspect based on specified criteria. As of 02/01/2017, a total of 8187 subjects have been recruited to the POAAGG study, including 2522 cases, 4545 controls, and 1120 suspects. A comprehensive genetic analysis of POAG, including a genome-wide association analysis, is currently underway. The GWAS was conducted on the Illumina Infinium Multi Ethnic Genotyping Array (MEGA), which contained custom content tailored to POAG and African Americans. A comprehensive genetic analysis of quantitative traits associated with POAG is also in progress. Over 90% of cases have full phenotypic information, including intraocular pressure, cup-to-disc ratio, central corneal thickness, retinal nerve fiber layer thickness, visual acuity, and visual fields.

Study phs001312

Identification of driver oncogenes in scirrhous-type gastric cancer cell lines

Scirrhous type gastric cancer (SGC) is one of the most intractable cancer subtypes in human, and its therapeutic targets have been rarely identified to date. Exploration of somatic mutations in the SGC genome with the next generation sequencers has been hampered by low tumor contents by the markedly increased fibrous tissues. Thus, SGC cell lines may be useful resources to search for novel oncogenes in. Here we have conducted whole exome sequencing and RNA sequencing on two SGC cell lines, OCUM-8 and OCUM-9. Interestingly, most of the mutations thus identified have not been reported. In OCUM-8 cells, a novel CD44-IGF1R fusion gene is discovered, the protein product of which ligates the amino-terminus of CD44 to the transmembrane and the tyrosine-kinase domains of IGF1R. Further, both of CD44 and IGF1R are markedly amplified in the OCUM-8 genome and abundantly expressed. CD44-IGF1R has a transforming ability, and the suppression of its kinase activity leads to rapid cell death of OCUM-8. On the other hand, OCUM-9 seems to possess multiple oncogenic events in its genome. The MET gene is highly amplified, and the treatment of OCUM-9 with crizotinib, a MET inhibitor, results in cell death. Further, a novel BORCS5-ETV6 fusion gene is identified in the OCUM-9 genome. BORCS5-ETV6 possesses oncogenic activity, and suppression of its message partially inhibits cell growth. Prevalence of these novel fusion genes among SGC awaits further investigation, but we validate the significance of cell lines as appropriate reagents for detailed genomic analyses of SGC.

Study JGAS000179

Nanopore sequencing of blood, saliva, buccal mucosa samples of patients with inherited retinal disorders

X-linked genetic disorders typically affect females less severely than males due to the presence of a second X chromosome not carrying the deleterious variant. However, the phenotypic expression in females is highly variable, which may be explained by an allelic skew in X chromosome inactivation. Accurate measurement of X inactivation skew is crucial to understand and predict disease phenotype in carrier females, with prediction especially relevant for degenerative conditions. We propose a novel approach using nanopore sequencing to quantify skewed X inactivation accurately. By phasing sequence variants and methylation patterns, this single assay reveals the disease variant, X inactivation skew, its directionality, and is applicable to all patients and X-linked variants. Enrichment of X-chromosome reads through adaptive sampling enhances cost-efficiency. Our study includes a cohort of 16 X-linked variant carrier females affected by two X-linked inherited retinal diseases: choroideremia and RPGR-associated retinitis pigmentosa. As retinal DNA cannot be readily obtained, we instead determine the skew from peripheral samples (blood, saliva and buccal mucosa), and correlate it to phenotypic outcomes. This revealed a strong correlation between X inactivation skew and disease presentation, confirming the value in performing this assay and its potential as a way to prioritise patients for early intervention, such as gene therapy currently in clinical trials for these conditions. Our method of assessing skewed X inactivation is applicable to all long-read genomic datasets, providing insights into disease risk and severity and aiding in the development of individualised strategies for X-linked variant carrier females.

Study EGAS50000000440

C3 SNPs and outcome after lung transplantation

Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor. Methods: Since a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) is associated with long-term outcome after solid organ transplantation, we investigated this SNP in relation to LTx. In addition, we looked at local production of C3 by analyzing bronchoalveolar lavage fluid (BALF) of LTx patients using isoelectric focusing (IEF). Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients (p=0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival (p=0.044). Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation.

Study EGAS00001003843

Confirmation of a founder effect in a Northern European population (FRL) of a new beta-globin variant: HBB:c.23_26dup (codons 8/9 (+AGAA))

Beta-thalassemia is a genetic disease caused by a defect in the production of the beta-like globin chain. More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites. We recently described a duplication of 4 nucleotides in the first exon of beta-globin gene in several families of patients living in Nord-Pas-de-Calais (France). Using the genotypes at 12 microsatellite markers surrounding the beta-globin gene of four unrelated variant carriers plus an additional one recently discovered, we found that they shared a common haplotype indicating a founder effect that was estimated to have taken place 225 years ago (9 generations). In order to determine whether this variant arose in this region of Northern-Europe or was introduced by migrants from regions of the world where thalassemia is endemic, we genotyped the first 4 unrelated variant carriers and 32 controls from Nord-Pas-de-Calais for 97 European ancestry informative markers (EAIMs). Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations. Rare beta-thalassemia variants have already been described in patients sampled in non-endemic regions but it is the first proof of a founder effect in Northern Europe. The new genetic panel FRL is under registration in EGA.

Study EGAS00001000980

Biallelic tumor suppressor loss and DNA repair defects in de novo small cell prostate cancer

Small cell prostatic carcinoma (SCPC) is an aggressive pathology that is managed similar to small cell lung cancer. SCPC can evolve from prostatic adenocarcinoma in response to androgen deprivation therapy but in rare cases is present at initial cancer diagnosis. The molecular etiology of de novo SCPC is incompletely understood due to the scarcity of tumor tissue and the brief life expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology and the remainder had some admixed adenocarcinoma foci, but all were treated with first line platinum-based chemotherapy. Median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin embedded archival tumor tissue. We observed frequent biallelic deletion and/or mutation of tumor suppressors TP53, RB1 and PTEN, similar to treatment related SCPC. Indeed, at the RNA level pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes including BRCA1, BRCA2, ATM and MSH2/6: potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harbored ETS gene rearrangements to androgen-driven promoters, consistent with evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape underlies this unusual pathologic variant, and propose opportunities for targeted therapy strategies in a disease with few treatment options.

Study EGAS00001003007

A Single Complex Agpat2 Allele In A Patient With Partial Lipodystrophy

Genetic lipodystrophies are a group of rare syndromes associated with major metabolic complications - including severe insulin resistance, type 2 diabetes mellitus, and hypertriglyceridemia - which are classified according to the distribution of adipose tissue. Lipodystrophies can be present at birth or develop during life and can range from local to partial and general. With at least 18 different genes implicated so far, definite diagnosis can be challenging due to clinical and genetic heterogeneity. In an adult female patient with clinical and metabolic features of partial lipodystrophy we identified via whole genome sequencing a single complex AGPAT2 allele [V67M;V167A], functionally equivalent to heterozygosity. AGPAT2 encodes for an acyltransferase implicated in the biosynthesis of triacylglycerol and glycerophospholipids. So far homozygous and compound heterozygous mutations in AGPAT2 have only been associated with generalized lipodystrophy. A SNP risk score analysis indicated that the index patient is not predisposed to lipodystrophy based on her genetic background. The partial phenotype in our patient is therefore more likely associated to the genetic variants in AGPAT2. To test whether the resulting double-mutant AGPAT2 protein is functional we analysed its in vitro enzymatic activity via mass spectrometry. The resulting AGPAT2 double mutant is enzymatically inactive. Our data support the view that the current classification of lipodystrophies as strictly local, partial or generalized may have to be re-evaluated and viewed more as a continuum, both in terms of clinical presentation and underlying genetic causes. Better molecular understanding of lipodystrophies may lead to new therapies to treat adipose tissue dysfunction in common and rare diseases.

Study EGAS00001003177

Dilgom_Exome

The Finrisk sample sets are part of the National FINRISK Study. It is a large population survey on risk factors of chronic, noncommunicable diseases. The survey is carried out since 1972 every five years using independent, random and representative population samples from different parts of Finland. The main results from the previous FINRISK 2007 survey are published.The National FINRISK Study Survey was carried out in 5 areas in Finland and 2000 inhabitants aged 25-75 years were invited to participate in each year. Among findings were that Finns continue to gain weight.Data from FINRISK surveys are used for many different research projects and for national health monitoring needs. The recent research activities deal, in addition to cardiovascular diseases and the classical risk factors, also with e.g. asthma and allergy, alcohol, socioeconomic factors and genetic epidemiology.The FINRISK study is part of the MORGAM Project (MONICA Risk, Genetics, Archiving and Monigraph), sponsored by the EU and MDECODE (Molecular Diversity and Epidemiology of Common Disease) program coordinated by the University of Michigan.The exome sequencing study will be part of the Dilgom study, which is a part of the larger Finrisk population based health study performed in Finland. It consists of 5000 individuals with a prospective aspect of metabolic traits. The cohort has been extensively phenotyped for their cardiovascular and metabolic status. So far, we have performed a 660K Illumina GWAS and a full genome wide expression study from peripheral blood cells of 500 individuals. The cohort has also been in total genotyped by the cardiometabochip

Study EGAS00001000086

Single-cell DNA amplicon sequencing reveals clonal heterogeneity and evolution in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia that is most frequent in children and is characterized by the presence of few chromosomal rearrangements and 10 to 20 somatic mutations in protein-coding regions at diagnosis. The majority of T-ALL cases harbor activating mutations in NOTCH1 together with mutations in genes implicated in kinase signaling, transcriptional regulation or protein translation. To obtain more insight in the level of clonal heterogeneity at diagnosis and during treatment, we used single-cell targeted DNA sequencing with the Tapestri platform. We designed a custom ALL panel and obtained accurate single-nucleotide variant and small insertion-deletion mutation calling for 305 amplicons covering 110 genes in about 4400 cells per sample and time point. A total of 108,188 cells were analyzed for 25 samples of 8 T-ALL patients. We typically observed a major clone at diagnosis (>35% of the cells) accompanied by several minor clones of which some were less than 1% of the total number of cells. Four patients had >2 NOTCH1 mutations some of which present in minor clones, indicating a strong pressure to acquire NOTCH1 mutations in developing T-ALL cells. By analyzing longitudinal samples, we detected the presence and clonal nature of residual leukemic cells as well as clones with a minor presence at diagnosis that evolved to clinically relevant major clones at later disease stages. Single-cell DNA amplicon sequencing is a sensitive assay to detect clonal architecture and evolution in T-ALL.

Study EGAS00001004440

Healthspan and lifespan extension by fecal microbiota transplantation in progeroid mice

The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease or cancer, but its precise role in aging remains to be elucidated. Here, we characterize the gut microbiome profile of accelerated aging and show that its external modulation is sufficient to extend healthspan and lifespan. We found that two different mouse models of progeria present with intestinal dysbiosis, which is characterized, among other alterations, by an increment in proteobacteria, cyanobacteria and a loss in verrucomicrobia, whereas long-lived humans (i.e., centenarians) exhibit a remarkable increase in verrucomicrobia and a reduction in proteobacteria. Fecal microbiota transplantation proved to be effective to enhance healthspan and lifespan in both progeroid mouse models and, more importantly, the solely transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Our results demonstrate that intestinal dysbiosis is a phenotype associated with accelerated aging and its correction provides health benefits. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial outcome of reestablishing a healthy microbiome. Our results suggest the existence of a link between gut aging and the microbiota, and can help to gain insight into the rationale for microbiome-based interventions against age-related diseases. Mouse sequence data have been deposited in ENA (https://www.ebi.ac.uk/ena) under accession number PRJEB34214

Study EGAS00001003656

Colorectal adenomas, carcinomas and adjacent normal NKI-AvL TGO series NGS-ProToCol

Cancer is caused by changes in the genome of cells, resulting in aberrant transcripts and proteins. In order to understand why normal cells become cancer cells and how we can identify and destroy them, the CTMM-NGS-ProToCol project aimed to understand prostate and colorectal cancer through DNA and RNA molecular profiling, to further improve diagnosis, prognosis and treatment.The state-of-the-art within the field of genome sequencing makes it possible to identify all the modifications in our genome that encode for RNA and of the transcripts themselves. The latest development in RNA sequencing is that if one does not select for polyA RNA, but first removes rRNA from the total RNA and then performs ‘random’ RNA sequencing, 30-60% of the reads are intronic. Since about 40% of the genome consists of genes (and only 1.6% is exonic), deep RNA sequencing will cover not only the exons, but also a large portion of the introns and therefore much of the genome. The power of the combined sequencing of genome and transcriptome is the full view of copy number aberrations (CNA), exon mutations and the consequence and relevance of the mutations at the RNA level in the form of differential gene expression, alternative splicing, alternative promoter usage, novel transcripts, fusion transcripts, read-through transcripts and mutations. For the colorectal (tumor) tissue dataset, we applied molecular profiling to 30 colorectal adenomas, 30 colorectal carcinomas and 18 normal adjacent colon tissues.

Study EGAS00001002854

The Dutch Microbiome Project: Defining the (un)healthy gut microbiome

The Dutch Microbiome Project (DMP) data includes raw data generated by shotgun metagenomic sequencing of faecal samples of 8,208 Dutch individuals, processed microbiome data analysed using Biobakery2 tools (including taxonomy, pathway, virulence factors and antibiotic resistance gene profiles), and basic phenotypes (age and sex, BMI). Data is made available in two randomly assigned batches to facilitate the data access and maintenance. Access to this dataset requires a minimal access procedure (data access form at https://forms.gle/eHeBdXJMXbVvCJRc8 or email request to the data access committee (DAC) of this study, listed at DAC EGAC00001001996, https://ega-archive.org/dacs/EGAC00001001996). This access procedure is to ensure that the data is being requested for research/scientific purposes only and thus complies with the informed consent signed by Lifelines participants, which specifies that the collected data will not be used for commercial purposes. Submitted data access forms will be evaluated by the DAC and Lifelines, and a response to requests will be given within two weeks. For requests from verified academic parties, access will be given without further delay. For requests from commercial parties, Lifelines will perform a pre-DPIA (Data Privacy Impact Assessment) to assess the risks of the proposed processing of personal data (e.g. purpose, storage, access, archiving, etc.) with respect to the GDPR (EU privacy laws) subject rights. Based on the outcome of the pre-DPIA, Lifelines will decide whether sharing data with the commercial entity is allowed and/or whether additional measures have to be taken.

Study EGAS00001005027

A Machine Learning Tool Integrating Circulating Cell-Free DNA Methylation with Clinical Variables for Non-Invasive Diagnosis of Liver Graft Pathology

Liver Transplant Recipients (LTRs) with elevated liver enzymes can develop graft injury due to various etiologies, such as T-cell mediated rejection (TCMR) and NASH (NASH-LT). While liver biopsy is the gold standard method for diagnosis of graft pathology, it is invasive and is associated with risks. The goal of our study was to develop a Machine Learning (ML) tool integrating clinical variables with methylation patterns on circulating DNA in plasma as a non-invasive diagnostic tool of graft injury. We generated methylation profiles of circulating DNA in a pilot study of 43 LTRs (11 NASH-LT, 19 TCMR, and 13 Control-LT), and developed an L2 multinomial logistic regression ML approach across 101 bootstrapped models to distinguish between the graft conditions. NASH was associated with distinctive methylation patterns on genes involved in fatty acid metabolism, while methylation of platelet-derived growth factors was identified in patients with TCMR. Our ML model achieved a mean multi-classification accuracy of 0.91, with mean specificity and sensitivity of 0.94 and 0.91, respectively. The model was found to be particularly adept at detecting TCMR and Control-LT, with true positive rates (TPRs) of 95% and 90%, and areas under the curve (AUROC) of 0.992 and 0.985, respectively. For NASH-LT, the models achieved a performance with a TPR of 82% and an AUROC of 0.991. These preliminary results suggest that our newly developed ML tool, leveraging cell-free DNA methylation and clinical variables, is a promising non-invasive classifier of graft pathology.

Study EGAS00001007171

FHIR Test Study BETA

FHIR Test Study BETA. This study was created with 3 consent groups to simulate an actual study for FHIR API testing project. The data herein is simulated and are intended for development of FHIR representation of dbGaP phenotype data.

Study phs002410

Myelofibrosis Etiology and Transplant Outcomes

The Myelofibrosis Etiology and Transplant Outcomes study is a collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research (CIBMTR). The study aims to identify genomic factors affecting myelofibrosis pathogenesis and prognosis.

Study phs002635

Study of Lyme Immunology and Clinical Events (SLICE)

The overall objective of this study is to measure risk factors, symptom patterns and severity, longitudinal course, and associated biomarkers in patients who develop symptoms of post treatment Lyme disease (PTLD) in cohort studies.  

Study phs002793

COVID-19 ACTIV-4 ACUTE: A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19 (ACTIV4A)

This is a randomized, open label, adaptive platform trial to compare the effectiveness of antithrombotic strategies for prevention of adverse outcomes in COVID-19 positive inpatients.

Study phs002694

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