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• Myoepithelial progenitors as founder cells of hyperplastic human breast lesions upon PIK3CA transformation

  The myoepithelial (MEP) lineage of human breast comprises bipotent and multipotent progenitors in ducts and terminal duct lobular units (TDLUs). We here assess whether this heterogeneity impacts on oncogenic PIK3CA transformation. Single cell RNA sequencing (scRNA-seq) and multicolor imaging reveal that terminal ducts represent the most enriched source of cells with ductal MEP markers including a-smooth muscle actin (a-SMA), keratin K14, K17 and CD200. Furthermore, we find neighboring CD200high and CD200low progenitors within terminal ducts. When sorted and kept in ground state conditions, their CD200low and CD200high phenotypes are preserved. Upon differentiation, progenitors remain multipotent and bipotent, respectively. Immortalized progenitors are transduced with shp53 and mutant PIK3CA. Upon transplantation, CD200low MEP progenitors distinguish from CD200high by the formation of multilayered structures with a hyperplastic inner layer of luminal epithelial cells. We suggest a model with spatially distributed MEP progenitors as founder cells of biphasic breast lesions with implications for early detection and prevention strategies.

  Study EGAS00001005933

• 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 >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

• Genome-wide DNA methylation sequencing identifies epigenetic perturbations in the upper airways under long-term exposure to moderate levels of ambient air pollution

  While the link between exposure to high levels of ambient particulate matter (PM) and increased incidences of respiratory and cardiovascular diseases is widely recognized, recent epidemiological studies have shown that low PM concentrations are equally associated with adverse health effects. As DNA methylation is one of the main mechanisms by which cells regulate and stabilize gene expression, changes in the methylome could constitute early indicators of dysregulated signaling pathways. So far, little is known about PM-associated DNA methylation changes in the upper airways, the first point of contact between airborne pollutants and the human body. Here, we focused on cells of the upper respiratory tract and assessed their genome-wide DNA methylation pattern to explore exposure-associated early regulatory changes. Using a mobile epidemiological laboratory, nasal lavage samples were collected from a cohort of 60 adults that lived in districts with records of low (Simmerath) or moderate (Stuttgart) PM10 levels in Germany. PM10 concentrations were verified by particle measurements on the days of the sample collection and genome-wide DNA methylation was determined by enzymatic methyl sequencing at single-base resolution. We identified 231 differentially methylated regions (DMRs) between moderately and lowly PM10 exposed individuals. A high proportion of DMRs overlapped with regulatory elements, and DMR target genes were involved in pathways regulating cellular redox homeostasis and immune response. In addition, we found distinct changes in DNA methylation of the HOXA gene cluster whose methylation levels have previously been linked to air pollution exposure but also to carcinogenesis in several instances. The findings of this study suggest that regulatory changes in upper airway cells occur at PM10 levels below current European thresholds, some of which may be involved in the development of air pollution-related diseases.

  Study EGAS00001007374

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

  The ~52,000 sample Type 2 Diabetes Exome Sequencing project is a collaboration of six consortia with various funding mechanisms that have joined together to investigate genetic variants for type 2 diabetes (T2D) using the largest T2D case/control sample set compiled to date. This includes samples from: Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) Genetics of Type 2 Diabetes (GoT2D) Exome Sequencing Project (ESP) Slim Initiative in Genomic Medicine for the Americas: Type 2 Diabetes (SIGMA T2D) Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCAMP) Progress in Diabetes Genetics in Youth (ProDIGY) This data generated from the SIGMA Diabetes in Mexico Study (DMS) was part of the Slim Initiative in Genomic Medicine for the Americas: Type 2 Diabetes (SIGMA T2D), which is an international research consortium funded by the Carlos Slim Foundation that seeks to identify the genetic risk factors for type 2 diabetes (T2D) in Mexico and Latin America and translate those findings into improved treatment and prevention of diabetes. The SIGMA T2D project has sequenced and genotyped more than 13,000 samples from Mexican and Mexican Americans. The individuals were obtained from over 20 cohorts across the 6 consortia that are listed in Table 1. The strategy was to perform deep exome sequencing of individuals, 24,991 with T2D and 24,953 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. The T2D-GENES, ProDIGY and SIGMA studies, sequencing was performed at the Broad Institute using the Agilent v2 capture reagent or Illumina Rapid Capture on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, two of the cohorts below are not in dbGaP, due to the samples not being consented for deposition. This includes the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study and Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) study. The Exome Sequencing Project (ESP) was deposited in dbGaP as part of their initial study and the phs numbers for that project can be found here: https://esp.gs.washington.edu/drupal/dbGaP_Releases. Table 1. 52,000 sample T2D Case/Control Whole Exome Sequencing Studies Ancestry Consortia Study Countries of Origin # Cases # Controls African American T2D-GENES Project 1 Jackson Heart Study US 500 526 African American T2D-GENES Project 1 Wake Forest School of Medicine Study US 518 530 African American ESP Exome Sequencing Project (ESP) US 467 1374 African American T2D-GENES Follow up study BioMe Biobank Program (BioMe) US 1297 1256 East Asian T2D-GENES Project 1 Korea Association Research Project Korea 526 561 East Asian T2D-GENES Project 1& Follow up Study Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 1486 1568 East Asian T2D-GENES Follow up study Korea SNUH South Korea 450 475 East Asian T2D-GENES Follow up study Research Studies in Hong Kong (Hong Kong) Hong Kong 493 485 European T2D-GENES Project 1 Ashkenazi US, Israel 506 355 European T2D-GENES Project 1 Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European GoT2D Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European GoT2D Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European GoT2D UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European GoT2D Malmo-Botnia Study Finland, Sweden 478 443 European LuCamp Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) Denmark 997 997 European ESP Exome Sequencing Project (ESP) US 390 2843 European T2D-GENES Follow up study Genetics of Diabetes and Audit Research Tayside Study (GoDARTS) Scotland, UK 960 966 European T2D-GENES Follow up study Framingham Heart Study (FHS) US 396 596 Hispanic T2D-GENES Project 1 San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 218 Hispanic T2D-GENES Project 1 & SIGMAv2 Starr County, Texas US 1762 1738 Hispanic SIGMAv1 Mexico City Diabetes Study Mexico 281 549 Hispanic SIGMAv1 & v2 Multiethnic Cohort (MEC) US 1476 1443 Hispanic SIGMAv1 & v2 UNAM/INCMNSZ Diabetes Study (UIDS) Mexico 1998 1977 Hispanic SIGMAv1 & v2 Diabetes in Mexico Study (DMS) Mexico 1522 1546 Multi ethnic ProDIGY Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) US 3097 0 Multi ethnic ProDIGY SEARCH for Diabetes in Youth (SEARCH) US 553 0 South Asian T2D-GENES Project 1 London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 531 538 South Asian T2D-GENES Project 1 & Follow up study Singapore Indian Eye Study Singapore (Indian Asian) 1640 1478 South Asian T2D-GENES Follow up study Pakistan Genomic Resource (PGR) Pakistan 914 932 The Diabetes in Mexico Study (DMS) study contributed 1,522 cases and 1,546 controls to the 52k T2D exome sequencing study.

  Study phs001388

• Characterization of Neoantigen-reactive T cells by Single-Cell Analysis

  Through CITE-seq and TCR-seq analysis of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TIL), we developed a neoantigen-reactive T-cell signature based on clonotype frequency and CD39 protein and CXCL13 mRNA expression. There are four datasets from four NSCLC cases. Each dataset includes (1) Transcriptome of tumor infiltrating lymphocytes (TIL), (2) Cell surface protein expression on TIL by Feature barcoding, (3) T-cell receptor analysis of TIL, and (4) Reference file for feature-barcoding antibodies.

  Study phs002792

• Spatial multiomic analyses reveal carcinogenic pathways in end-stage renal disease

  Patients with end-stage renal disease (ESRD) are at increased risk for acquired cystic kidney disease (ACKD) and renal tumours, but the molecular basis of such disorders remains elusive. Here, we performed spatial immunogenomic analyses on specimens from 43 patients with ACKD and associated tumours. In this study, we characterized the genomic and transcriptomic features of renal tumours in ESRD. Second, we elucidated the genetic background and microenvironment of cysts in ACKD via comprehensive spatial transcriptomics.

  Study JGAS000855

• Policy Documentation

  Policy Documentation The following policy documentation is required to be prepared and submitted to the EGA, together with your data files and associated metadata. Data Access Agreement (DAA) The Data Access Agreement is a contract made between Data User and Data Access Committee. The agreement should be drafted by the DAC and includes, but is not limited to, details of data use, publication embargoes and storage. Completion of a DAA by the applicant/s should form part of the application process to the DAC. 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 template Alternate (harmonised) DAA template

  Documentation access/data-access-committee/policy-documentation

• Comprehensive pharmacogenomic characterization of gastric cancer

  Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments. To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers. We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib. Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.

  Study EGAS00001004106

• Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers

  Germline mutations in BRCA1 or BRCA2 exist in ~2-7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked for biomarkers that were predictive of response (assessed by residual cancer burden) after 6 months of therapy. We found that all resistant tumors exhibited either the loss of SHLD2, expression of a hypoxia signature, or expression of a stem cell signature. These results indicate that the deep analysis of pre-treatment tumors can identify biomarkers that are predictive of response to talazoparib and potentially other PARP inhibitors, and provides a framework that will allow for better selection of patients for treatment, as well as a roadmap for the development of novel combination therapies to prevent emergence of resistance.

  Study EGAS00001005676

• WES analysis of a mixed cohort of pituitary tumors

  BACKGROUND: Sporadic pituitary adenomas are the second most common primary brain tumor, but their genetics remains incompletely understood. We performed deep DNA sequencing of 42 pituitary macroadenomas, including hormonally active and atypical adenomas. METHODS: Pituitary adenomas representative of a spectrum of histopathologic subtypes, primary and recurrent tumors, and MIB-1 proliferative indices were profiled. Whole-exome sequencing was performed on tumors and paired blood followed by analysis of somatic copy number alteration and mutation. RESULTS: On the whole, the tumors harbored a low rate of mutations, similar to other benign brain tumors. However, almost one-third (29%) exhibited somatic copy-number alterations across large fractions of the genome (up to 99%). Despite such widespread genomic disruption, these tumors had few focal events, which is atypical among highly-disrupted cancers. The other 71% of tumors formed a distinct molecular class, with somatic copy-number alterations involving less than 6% of the genome. Among the highly-disrupted group, 92% were functional or atypical null-cell adenomas, whereas 87% of the less-disrupted group were clinically non-functional adenomas. The only significantly recurrent events were arm-level losses of chromosomes 1, 2, 11, and 18. No significantly recurrent mutations or insertion/deletion events were identified, suggesting no genes are altered by exomic mutations in >15% of pituitary tumors. CONCLUSIONS: Genomic characterization of a large series of sporadic pituitary adenomas reveals two classes of tumor, based on genomic disruption from arm-level copy-number alterations, which associate with hormonal and histologic subtypes.

  Study EGAS00001001714

• Cystic Fibrosis Nasal Epithelium Gene Expression by RNAseq

  Cystic fibrosis (CF) is a monogenic disorder leading to multi-organ system dysfunction, with the primary cause of morbidity and mortality being lung disease. Mutations in CFTR result in defective ion channel transport leading to hyperviscous mucus, airway infection, inflammation and lung function decline. While the Phe508del mutation is the most common CFTR mutation in North American people with CF, it is well known that there is a broad range of lung disease severity even amongst Phe508del homozygotes, including twins/siblings. Heritability analyses showing the relative contribution of non-CFTR modifier genes in such differences in phenotype, have led to our genomic and transcriptomic studies of gene modifiers in CF. Complementary to two international CF GWAS studies, this study was performed to a) determine differential expression of genes relative to a quantitative lung disease severity phenotype score (KNoRMA; as used in CF GWAS studies) and b) to assess expression quantitative trait loci. To better understand genetic modification of CF lung disease severity, we analyzed gene expression (transcriptomic) profiles by mRNA sequencing from nasal mucosal biopsy specimens of 134 people with CF. Each study participants was characterized for CF lung disease severity phenotype by averaging three years of lung function data (forced expiratory volume in 1 second; FEV1), normalized to a CF-specific reference population matching for age, sex, and height. Participants completed nasal lavage and nasal curettage mucosal sampling, with directed sampling to the inferior nasal turbinate, a well validated surrogate for cellular characteristics and CFTR function of the lower CF airways. Participants were further invited to complete a second set of these sampling procedures for validation analysis. Specimen and concurrent clinical data collection occurred across four North American study sites and nasal mucosal specimens were subjected to RNASeq analysis. These data were to be made available in the dbGaP. Our association analyses of gene expression relative to quantitative CF lung disease phenotype, taken together with previously identified GWAS signals, identified biological pathways correlated with CF lung disease pathogenesis. Our further association analyses of gene expression relative to single nucleotide polymorphism variation at significant CF GWAS loci further identified potential mechanisms of genetic variants associated with CF lung disease. This resource is intended to aid researchers in characterizing airway mucosal gene expression from the CF airways for the purpose of gene expression profiling in CF and in muco-obstructive airways disease.

  Study phs002254

• Chromothripsis in Patient WHIM-09

  We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. We have identified a patient born with WHIM syndrome and the WHIM mutation CXCR4R334X who has been disease-free for 20 years and who lacks CXCR4R334X in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele CXCR4R334X and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective Cxcr4 haploinsufficiency (inactivation of one copy of Cxcr4 and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that CXCR4 knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.

  Study phs000856

• A transcriptomic approach to understand patient susceptibility to pneumonia after abdominal surgery

  Rationale Nosocomial infections are a major healthcare challenge, developing in over 20% of patients aged 45 or over undergoing major-abdominal surgery, with postoperative pneumonia associated with an almost five-fold increase in 30-day mortality. Objectives To describe immune-pathways and gene-networks altered following major-abdominal surgery and identify transcriptomic patterns associated with postoperative pneumonia. Methods and Measurements From a prospective consecutive cohort (n=150) undergoing major-abdominal surgery whole-blood RNA was collected preoperatively and at three time-points postoperatively (2-6, 24 and 48hrs). Twelve patients diagnosed with postoperative pneumonia and 27 matched patients remaining infection-free were identified for analysis with RNA-sequencing. Main Results Compared to preoperative sampling, 3,639 genes were upregulated and 5,043 downregulated at 2-6hrs. Pathway-analysis demonstrated innate-immune activation with neutrophil-degranulation and Toll-like-receptor signalling upregulation alongside adaptive-immune suppression. Cell-type deconvolution of preoperative RNA-sequencing revealed elevated S100A8/9-high neutrophils alongside reduced naïve CD4 T-cells in those later developing pneumonia. Preoperatively, a gene-signature characteristic of neutrophil-degranulation was associated with postoperative pneumonia acquisition (P=0.00092). A previously reported Sepsis Response Signature (SRSq) score, reflecting neutrophil-dysfunction and a more dysregulated host response, at 48hrs postoperatively, differed between patients subsequently developing pneumonia and those remaining infection-free (P=0.045). Analysis of the novel neutrophil gene-signature and SRSq scores in independent major-abdominal surgery and polytrauma cohorts indicated good predictive performance in identifying patients suffering later infection. Conclusions Major-abdominal surgery acutely upregulates innate-immune pathways while simultaneously suppressing adaptive-immune pathways. This is more prominent in patients developing postoperative pneumonia. Preoperative transcriptomic signatures characteristic of neutrophil-degranulation and postoperative SRSq scores may be useful predictors of subsequent pneumonia risk.

  Study EGAS00001007229

• Two lung cancer cell lines with EGFR mutations, PC-9 and KHM-3S, were either treated with Tarceva for 24 hours or left untreated. The gene expression profiles were examined by RNAseq, and the genome wide binding profiles of total STAT3 and pSTAT3 were characterized by ChIPseq.

  Lung cancers harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as Tarceva. However, nearly all patients show relapse within 1 year after initial treatment. To investigate the early signaling switches that are involved in the formation of drug resistance, and the role of STAT3 in the early signaling switches involved in the formation of drug resistance, we have treated two lung cancer cell lines with EGFR mutations, PC-9 and KMH-3S, with Tarceva for 24hours. The RNA samples with and without treatment were collected in triplicate for RNAseq experiment.The total STAT3 and pSTAT3 chromatinIP were done on samples with and without treatment for ChIPseq.

  Study EGAS00001000793

• Pancreatic Cancer Case Control Association Study

  Pancreatic cancer is the fourth leading cause of cancer death in the United States. This is in large part due to the rapidly fatal course of this disease, as the vast majority of patients die within months of diagnosis and the five-year survival rate is less than 5. We have brought together over 8000 participants from 9 studies of pancreatic cancer, to conduct a GWAS of pancreatic cancer. The studies were drawn from the Pancreatic Cancer Case-Control consortium and include case-control studies from the United States, Europe and Australia. Sites include: Johns Hopkins National Familial Pancreas Tumor Registry, Mayo Clinic Biospecimen Resource for Pancreas Research, Ontario Pancreas Cancer Study (OPCS), Yale University, MD Anderson Case Control Study, Queensland Pancreatic Cancer Study, University of California San Francisco Molecular Epidemiology of Pancreatic Cancer Study, International Agency of Cancer Research and Memorial Sloan Kettering Cancer Center.

  Study phs000648

• ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity

  Chronic inflammation in autoimmunity is driven by hyperactive T cells with dysregulated metabolism. ABHD11 is a mitochondrial hydrolase that supports alpha-ketoglutarate dehydrogenase function and has been associated with remission in rheumatoid arthritis. To explore its role in T cell function, we used CRISPR/Cas9 to knock down ABHD11 in Jurkat T cells and performed RNA-Seq analysis. Differential gene expression revealed widespread transcriptional changes, with sterol-related pathways among the most significantly enriched. These findings highlight ABHD11 as a potential regulator of metabolic programming in T cells with implications for autoimmunity.

  Study EGAS50000001297

• 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

• InterPregGen-GWAS-KAZ-3

  Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls. This dataset includes Infinium GSA genotyping of maternal, paternal and fetal PE cases and controls from Kazakhstan. This study is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator).

  Dataset EGAD00010001949

• InterPregGen-GWAS-KAZ-2

  Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls. This dataset includes OmniExpress genotyping of maternal and fetal PE cases and controls from Kazakhstan. This study is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator).

  Dataset EGAD00010001947

• InterPregGen-GWAS-KAZ-1

  Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls. This dataset includes lllumina 2.5-8 genotyping of maternal and fetal PE cases and controls from Kazakhstan. This study is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator).

  Dataset EGAD00010001945

• Early-onset Colorectal Cancer Study TOGETHER Data Access Committee

  The Early-onset Colorectal Cancer Study TOGETHER Data Access Committee (DAC) is responsible for reviewing requests to access sequencing and clinical data from the study. Access to the data is restricted to researchers with approved ethical clearance and scientifically valid research projects. Each request will be evaluated by the DAC to ensure compliance with participants’ informed consent and all applicable data protection regulations.

  Dac EGAC50000000752

• Next Generation Children project - WGS study of patients in NICU and PICU and their families

  With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations. Whole genome sequencing data.

  Study EGAS00001003002

• Solve-RD Solving the Unsolved Rare Dieseases

  Solve-RD – solving the unsolved rare diseases is a research project funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257 from 1 January 2018 to 31 March 2024. Six European Reference Networks (ERNs; ERN-RND, -ITHACA, -EuroNMD, -GENTURIS, -RITA and -EpiCare) contributed data and samples to one or more of the four cohorts for data re-analysis and novel omics. For more information see https://solve-rd.eu/results/solve-rd-data/.

  Study EGAS00001003851

• ctDNA quantification in Ewing sarcoma patients

  Background. Treatment stratification and response assessment in pediatric sarcomas has relied on imaging studies and surgical/histopathological evidence of vital tumor cells. Such studies and evidence collection processes often involve radiation and/or general anesthesia in children. Cell-free circulating tumor DNA (ctDNA) detection in blood plasma is one available method of so-called liquid biopsies that has been shown to correlate qualitatively and quantitatively to some extent with the existence of vital tumor cells in the body. Our clinical observational study focused on the utility and feasibility of ctDNA detection in pediatric Ewing sarcoma (EWS) as a marker of minimal residual disease (MRD). Patients and Methods. We performed whole genome sequencing to identify the exact breakpoints in tumors known to carry the EWS-FLI1 fusion gene. Patient-specific fusion breakpoints were tracked in peripheral blood plasma using digital droplet PCR (ddPCR) before, during, and after therapy in six consecutive children and young adults with EWS. Presence and levels of fusion breakpoints were correlated with clinical disease courses. The genetic changes in the tumors were defined, and inter- and intra-individual changes in the tumor DNA copy loads were observed over time. Results. We show that the detection of ctDNA in the peripheral blood of EWS patients i) is feasible in the clinical routine and ii) allows for the longitudinal real-time monitoring of MRD activity in children and young adults. Although changing ctDNA levels correlated well with clinical outcome within patients, between patients, a high variability was observed (inter-individually) for the six patients described here. Conclusions. ctDNA detection by ddPCR is a highly sensitive, specific, feasible, and highly accurate method that can be applied in EWS for follow-up assessments as an additional surrogate parameter for clinical MRD monitoring and, potentially, also for treatment stratification in the near future.

  Study EGAS00001006433

• Exome sequencing of patients with acute promyelocytic leukemia

  The dataset consists in 64 fastq files from 23 patients with acute promyelocytic leukemia. Exome sequencing was conducted on several stages (Diagnosis, Remission, Relapse) for each patient. For 5 patients, only Diagnosis and Relapse samples are available.

  Dataset EGAD00001004043