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• Rapid Acceleration of Diagnostics - Tech Program (RADx-Tech) Collection of General Research Use Datasets

  This individual-level collection of datasets contains all the RADx® Tech Programs (RADx-Tech) studies in dbGaP for General Research Use (GRU) and have no further limitations beyond those outlined in the model RADx Data Use Certification Agreement. Access to this study collection will include additional authorized individual-level GRU datasets that become available. Renewal of this study collection is required annually. Access to studies in this collection is on the RADx® Data Hub. To request access to this study collection, select phs003831 in the dbGaP when submitting a data access request.

  Study phs003831

• Rapid Acceleration of Diagnostics - Radical (RADx-rad) Collection of General Research Use Datasets

  This individual-level collection of datasets contains all the RADx® Radical (RADx-rad) studies in dbGaP for General Research Use (GRU) and have no further limitations beyond those outlined in the model RADx Data Use Certification Agreement. Access to this study collection will include additional authorized individual-level GRU datasets that become available. Renewal of this study collection is required annually. Access to studies in this collection is on the RADx® Data Hub. To request access to this study collection, select phs003834 in the dbGaP when submitting a data access request.

  Study phs003834

• Reconstruction of the personal information from human genome reads in gut metagenome sequencing data

  Human DNA present in fecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is currently unclear how much personal information can be reconstructed from such reads and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable the efficient use of human genetic information in stool samples, such as for research and forensics. Here, we used genomic approaches to reconstruct personal information from fecal metagenomes of 343 Japanese individuals with associated human genotype data.

  Study JGAS000600

• ESGI_Identification_of_novel_genes_and_mechanisms_leading_to_Primary_Ciliary_Dyskinesia

  Approximately 80% of clinically clearly diagnosed patients suffering from primary ciliary dyskinesia (PCD) cannot be assigned to a specific gene defect. Despite extensive research on PCD and despite the increasing number of PCD genes and knowledge about their sites of action as e.g structural component or cytoplasmic pre-assembly factor, the biology of motile cilia and the pathomechanism leading to PCD is largely unknown. The aim of this study is to identify novel PCD related genes and processes relevant for motile cilia function.We will perform exome sequencing, aiming on the analysis of family trios. In these families, the diagnosis of PCD is secured, but the underlying gene defects has so far not been identified.

  Study EGAS00001000523

• Rapid Acceleration of Diagnostics - Digital Health Technologies (RADx-DHT): NIH Digital Health Solutions for COVID-19: IBM Covid19 Contact Tracing and Data Exchange Tools

  The goal of this project is to develop both contact tracing and secure data exchange tools. The contact tracing solution securely combines data from a variety of sources (including manual self-report data and mobile device surveys) to enable tracing of contacts with individuals that have tested positive for COVID-19 or have been exposed to COVID-19. The data exchange solution is a secure mechanism that empowers users to control the data they share in the course of their return to work, including the ability to provide a verifiable health status claim. These tools are being used by an employer to evaluate the risk of allowing individuals to return to normal activities, and also the ability to trace user contact with individuals diagnosed with or suspected of having contracted COVID-19. DOI: https://rapids.ll.mit.edu/10.57895/h0an-m559

  Study phs002516

• Using_genetics_to_identify_cell_types_and_mechanisms_underlying_susceptibility_to_primary_sclerosing_cholangitis

  Primary sclerosing cholangitis (PSC) is a T-cell mediated, chronic inflammatory condition of the biliary tree that is strongly associated with inflammatory bowel disease. Genome-wide association studies have identified 22 non-HLA genetic risk variants associated PSC. Identifying the genes impacted by these variants has proven difficult as the majority lie in non-coding regions of the genome. Knowledge of the genes and biological pathways these non-coding variants are perturbing is vital to understanding the disease biology. One means of assessing the impact of non-coding variants within disease associated loci upon genes is via colocalisation with eQTL. Many eQTL are cell-type specific, requiring the analysis of disease relevant cell types to detect colocalisation. We have collected PSC-relevant T-cell-subtypes from the peripheral blood of PSC patients via fluorescence activated cell sorting in preparation for RNA sequencing and mapping of eQTL. Samples were collected at the Norfolk and Norwich University Hopital, for which local ethical approval has been granted. Lysed cell samples will be transferred to WTSI and DNA/RNA will be extracted from lysed cell samples by T143 before genotyping (DNA) and custom library preparation and sequencing (RNA). This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002643

• Using_genetics_to_identify_cell_types_and_mechanisms_underlying_susceptibility_to_primary_sclerosing_cholangitis

  Primary sclerosing cholangitis (PSC) is a T-cell mediated, chronic inflammatory condition of the biliary tree that is strongly associated with inflammatory bowel disease. Genome-wide association studies have identified 22 non-HLA genetic risk variants associated PSC. Identifying the genes impacted by these variants has proven difficult as the majority lie in non-coding regions of the genome. Knowledge of the genes and biological pathways these non-coding variants are perturbing is vital to understanding the disease biology. One means of assessing the impact of non-coding variants within disease associated loci upon genes is via colocalisation with eQTL. Many eQTL are cell-type specific, requiring the analysis of disease relevant cell types to detect colocalisation. We have collected PSC-relevant T-cell-subtypes from the peripheral blood of PSC patients via fluorescence activated cell sorting in preparation for RNA sequencing and mapping of eQTL. Samples were collected at the Norfolk and Norwich University Hopital, for which local ethical approval has been granted. Lysed cell samples will be transferred to WTSI and DNA/RNA will be extracted from lysed cell samples by T143 before genotyping (DNA) and custom library preparation and sequencing (RNA). This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002642

• Genome Variation among HIV-Resistant People with Hemophilia

  Rare individuals are highly resistant to infection with human immunodeficiency virus (HIV). Studies of candidate genes resulted in the discovery of a 32bp deletion in the CC-chemokine receptor 5 gene (CCR5Δ32), which rendered this critical co-receptor for primary HIV infection to be non-functional. Pharmacologic and vaccine-induced blockade of CCR5 is being pursued to treat and prevent HIV infection and other conditions. The allele frequency of CCR5Δ32 among persons of European ancestry is approximately 10%. CCR5Δ32/Δ32 homozygotes are almost totally resistant to HIV infection. People with severe hemophilia A require frequent replacement with clotting Factor VIII (FVIII) to control hemorrhage. Prior to the discovery of HIV in 1984 and licensure of recombinant FVIII in the late 1980s, people with severe hemophilia A were treated with plasma-derived FVIII and thus were intensively exposed to HIV. Only 5% of such patients were not infected with HIV. Of these, approximately 1/3 were CCR5Δ32/Δ32 homozygotes. The remaining 2/3 of these people who were highly resistant to HIV remain unexplained. This project seeks to discover genome variations among people who are highly resistant to HIV infection. Such variation is likely to serve as a target for reducing the morbidity and incidence of HIV.

  Study phs000445

• Automated system for scoring hematoxylin and eosin-stained ovarian cancer sections by identifying single cells uncovered that stromal cell ratio is a significant predictor for overall survival and progression-free survival.

  Concerted efforts in genomic studies have revealed profound insights in prognostic ovarian cancer subtypes. On the other hand, abundant histology slides have been generated to date, yet their uses remain very limited and largely qualitative. Our goal is to develop automated histology analysis as an alternative subtyping technology for ovarian cancer that is cost-efficient and do not rely on DNA quality. We develop an automated system for scoring hematoxylin and eosin-stained (H&E) primary tumour sections of 91 late-stage ovarian cancer to identify single cells including cancer and stromal cells. We demonstrated high accuracy of our system based on expert pathologists’ scores (cancer=97.1%, stromal=89.1%) as well as compared to immunohistochemistry scoring (correlation=0.87). Quantitative stromal cell ratio is significantly associated with poor overall survival after controlling for clinical parameters including debulking status and age (multivariate analysis p=0.0021, HR=2.54, CI=1.40-4.60) and progression-free survival (multivariate analysis p=0.022, HR=1.75, CI=1.09–2.82). We demonstrate how automated image analysis enables objective quantification of microenvironmental composition of ovarian tumours. Our analysis reveals a strong effect of the tumour microenvironment on ovarian cancer progression and highlights the potential of therapeutic interventions that target the stromal compartment or cancer-stroma signalling in the stroma-high, late-stage ovarian cancer subset.

  Study EGAS00001001694

• GCAT | Genomes for life

  The GCAT project is a prospective cohort study that was designed to recruit the general population of Catalonia, the north-east region of Spain. This study is a long-term genomic, environmental and lifestyle cohort project that aims to evaluate and track multiple pathologies as well as biologically related traits. By the end of 2017, the GCAT Study had recruited a total of 20 000 participants aged 40–65 years. Participants who agreed to take part in the study completed a self-administered computer-driven questionnaire, and underwent blood pressure, cardiac frequency and anthropometry measurements. For each participant, blood plasma, blood serum and white blood cells are collected at baseline. The GCAT Study has access to the electronic health records of the Catalan Public Healthcare System. Participants are followed biannually for/during, at least, 20 years after recruitment. Therefore, the GCAT Study offers a unique opportunity to integrate diverse data to allow the identification of novel relations among different biomarkers and conditions. Results may lead to the development of new genetic, genomic, epigenomic and proteomic diagnoses and screening tests, as well as new public health recommendations. The only currently available population-based prospective cohort study in Spain to the date, including more than 4899 genotyped participants and 800 whole genome sequences is now stored in the EGA archive under accession id EGAS00001003018.

  Blog gcat-genomes-for-life

• Anaplastic Meningioma WGS-X10

  Anaplastic meningiomas are a rare, malignant variant of meningioma. At present there is no effective treatment for this cancer. The aim of the study is to identify somatic mutations in anaplastic meningiomas. We plan to sequence a set of 500 known cancer genes in 50 anaplastic meningioma and corresponding peripheral blood DNA samples. Bioinformatics will be used to analyse the results to assess the probability of these mutations being causal and so likely of critical importance for the tumour growth. Identification of these mutations will guide selection of appropriate compounds to effectively treat the disease.

  Dataset EGAD00001001267

• eMERGE: Northwestern (NUgene) WGS

  The NUgene Project is a biorepository with longitudinal medical information from participating patients at Northwestern Medicine affiliated hospitals and outpatient clinics. Participants' DNA samples are coupled with data from a self-reported questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 3 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated enterprise data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. The electronic MedicalRecords and Genomics (eMERGE) Network is a consortium of 9 clinical sites with EMR linked DNA biobanks, including Northwestern University and its NUgene biobank, funded by the NHGRI (National Human Genome Research Institute) to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 100,000 individuals using EMR-derived phenotypes and DNA from linked biorepositories. Using electronic phenotyping methods, the consortium has been and is using DNA samples from all participating sites to explore the genetic determinants of approximately 80 phenotypes, including both diseases and traits, for which the electronic phenotyping algorithms have or are being published on PheKB.org. Thus, for the eMERGE network, ~900 NUgene subjects were selected, as described in the study inclusion/exclusion criteria section below, to be genotyped using whole genome sequencing (WGS), for use in the eMERGE network as eMERGE subjects. The criteria used below were selected so that these subjects will likely meet the criteria to be cases and/or controls, of diverse races and/or ethnicities, for at least 1 of the ~80 phenotypes being studied within eMERGE, and could be recontacted for future research if needed.

  Study phs001191

• The Surveillance Monitoring for ART Toxicities (SMARTT) and the Women and Infants Transmission Study (WITS)

  Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor (NRTI) which competitively inhibits HIV reverse transcriptase and is incorporated into the viral DNA, resulting in DNA chain termination. It was the first approved antiretroviral medication used for preventing HIV transmission from mother to child. However, in vitro and animal studies have suggested genotoxicity of ZDV and no study has evaluated potential impact of in utero ZDV exposure using genomic sequencing technologies. In this study, we investigate markers of genomic damage detected in peripheral blood mononuclear cell samples obtained from 91 ZDV-exposed and, for comparison, 94 NRTI-unexposed HIV-uninfected children born to HIV-infected mothers during the first week after birth. We utilize high-throughput DNA sequencing (whole exome sequencing) and genotype array methods to comprehensively identify potential clonal somatic single nucleotide variants (SNVs) and large acquired copy number alterations (SCNAs) related to ZDV exposure.

  Study phs002061

• NHLBI TOPMed: My Life Our Future (MLOF) Research Repository of Patients with Hemophilia A (Factor VIII Deficiency) or Hemophilia B (Factor IX Deficiency)

  Hemophilia A and B are X-linked bleeding disorders resulting from a deficiency in coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Hemophilia affects approximately 1/5000 male births worldwide, and results in premature death and disability due to bleeding if coagulation factor replacement therapy is not used effectively. Hemophilia is clinically categorized by coagulation factor activity levels and ranges in severity from mild (6% to 30%) to moderate (1-5%) to severe (<1%). Many female "carriers" of hemophilia also have decreased factor activity and morbidity from bleeding. Hemophilia A and B are almost always caused by identifiable mutations in the F8 and F9 genes, respectively, and these mutations are found throughout the structural genes. Although the hemophilias are monogenic disorders, there are wide variations in disease severity and therapeutic outcomes which are not readily explained by the disease causing mutations alone. The My Life Our Future (MLOF) project (www.mylifeourfuture.org) is a national resource developed by a partnership of BloodworksNW (BWNW, formerly the Puget Sound Blood Center), the American Thrombosis and Hemostasis Network (ATHN), the National Hemophilia Foundation (NHF) and Bioverativ, to provide free F8 and F9 gene variant analysis to patients with hemophilia A or B, and to establish a research repository of DNA sequence, DNA, RNA, buffy coat, serum and plasma. The sequence analysis and serum samples are linked to a phenotypic database hosted by ATHN, with samples submitted and clinical data entered at ~100 hemophilia treatment centers (HTCs) nationwide. (See ATHN Research Report Brief in the resource center at www.athn.org). MLOF has become the largest hemophilia genetic project worldwide. The roles of the MLOF partners are: BWNW, to serve as the central laboratory for the project and house the research repository; ATHN, to support and provide the administrative link with HTCs, to facilitate the collection of accurate phenotypic data, to conduct research review and approval for use of the repository and with BWNW to provide samples and data for research projects; NHF, to provide consumer education and facilitate consumer input into the project; and Bioverativ, to provide financial support and scientific input. The project is governed by a Steering Committee consisting of one representative from each organization. Subject samples chosen from the MLOF parent study for TOPMed and WGS were drawn from those who gave (or parents gave) informed consent for the Research Repository and included patients of all severities and type, but with an emphasis on those with severe hemophilia and others at increased risk of neutralizing antibody (inhibitor) formation and who had samples in the Research Repository (plasma, serum, RNA) for potential additional -omic studies. Also included were samples from subjects where a likely causative variant for hemophilia was not found in the F8 or F9 coding region, intron-exon boundaries or immediate upstream and downstream regions. Since hemophilia is an X-linked disorder, the majority of subjects are male. Racial distribution is similar to the overall population distribution.

  Study phs001515

• 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

• Targeted sequencing (paired) of HR genes in primary and metastatic patient-derived xenografts (PDXs) of colorectal cancer (CRC)

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we leveraged a comprehensive collection of 69 molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. Genetic analyses revealed that treatment sensitivity was marked by genomic scars indicative of BRCAness, suggesting homologous recombination (HR) deficiency as a key determinant. Accordingly, we surveyed a manually curated panel of 44 genes with a documented role in HR for the potential presence of pathogenic mutations. We did not observe a specific enrichment of HR gene mutations based on response to FOLFIRI. This result, combined with the absence of widespread biallelic inactivation of the analyzed genes and the predominance of mutations categorized as variants of unknown significance, suggests that FOLFIRI sensitivity is not primarily governed by underlying mutations in HR genes responsible for mitigating the genotoxic effects of this therapeutic regimen.

  Study EGAS50000000075

• Shallow Whole Genome Sequencing of Patient Derived Xenografts

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we leveraged a comprehensive collection of 27 molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. Genetic analyses revealed that treatment sensitivity was marked by genomic scars indicative of BRCAness, suggesting homologous recombination (HR) deficiency as a key determinant. Accordingly, we surveyed a manually curated panel of 44 genes with a documented role in HR for the potential presence of pathogenic mutations. We did not observe a specific enrichment of HR gene mutations based on response to FOLFIRI. This result, combined with the absence of widespread biallelic inactivation of the analyzed genes and the predominance of mutations categorized as variants of unknown significance, suggests that FOLFIRI sensitivity is not primarily governed by underlying mutations in HR genes responsible for mitigating the genotoxic effects of this therapeutic regimen.

  Study EGAS50000000191

• German early-onset prostate cancer cohort of the Pan-Prostate Cancer Genome (PPCG) project

  Prostate cancer is the most frequent malignant tumor in males and the second most frequent cause of cancer-related death. Currently, in Germany, more than 60,000 prostate cancers are diagnosed every year. Although most of these patients are treated in a curative attempt, more than 10,000 German men die from prostate cancer annually. Owing to the demographic changes of our society, a further doubling of prostate cancer incidences during the next 20 years is expected. Prostate cancer is generally considered a tumor of elderly men. However, a fraction of prostate cancers are diagnosed at the age of 55 years or less. For several reasons, these “early onset prostate cancers” may represent a key entity for the understanding of prostate cancer biology. First, it is likely that early onset prostate cancers represent a distinct molecular subgroup of prostate cancer (PCa), potentially characterized by relatively small numbers of genetic changes, some of which may be particularly strong driver mutations for PCa development. Second, a fraction of prostate cancers in young individuals could represent classical prostate cancers that are detected at a very early stage and might therefore have accumulated molecular changes/mutations occurring that are most instrumental for prostate cancer early detection. Third, PCa with hereditary backgrounds are likely to accumulate in the age group below 55 years. A comparison with other sample sets (e.g. from other ICGC consortia), a systematic genomic analysis of young men with PCa could therefore lead to the detection of mechanisms for hereditary PCa. Fourth, a better understanding of these tumors is particularly relevant as finding optimal treatment regimens is most critical in young cancer patients. We are analyzing the entire genomic DNA sequences of at least 200 PCas (and matched non-tumorous DNA) of young men (≤ 55y), to at least 30 fold coverage, and integrate single-nucleotide variants and genomic structural variations with differential methylation, mRNA and miRNA expression data.Tissues were collected at the University Medical Center Hamburg-Eppendorf. Sequencing was performed at DKFZ and NCT (Heidelberg), EMBL (Heidelberg), and MPIMG (Berlin). Data management and bioinformatic data analyses is being conducted at DKFZ.

  Study EGAS00001003373

• NEI CIDR Methylation Profiling of Primary Open Angle Glaucoma in GLAUGEN Samples

  This is a case-control study of Primary Open Angle Glaucoma (POAG). POAG is a progressive optic neuropathy that eventually leads to blindness. More than 30 million people worldwide have Primary Open Angle Glaucoma (POAG), of which greater than 3 million are blind. Gene expression changes in the retina have been observed for POAG. Several recent studies, including the GLAUGEN (Glaucoma Gene Environment) initiative have used GWAS to identify correlative regions of the genome. Despite this, the genetic basis of Glaucoma is not well understood. Epigenetic variation may account for low heritability and environmental effects on human disease. Despite the significant advances being made in understanding the role of epigenetics in gene regulation in other fields, little is known about the relationship between DNA methylation patterns, retinal gene expression, and retinal disease. The goal of this study is to identify differentially methylated regions in the peripheral blood of patients with POAG. The case identification is as per the GLAUGEN description: Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. POAG and control samples come from Massachusetts Eye and Ear Infirmary (MEEI). These samples were collected and genotyped as part of the GLAUGEN study. From the MEEI, 50 patients were selected from POAG pedigrees, to include all the probands genotyped by CIDR and are currently undergoing exome sequencing, and to include additional genotyped probands who belong to pedigrees of sufficient size and structure that parent of origin effects could be evaluated. Additional individual-level phenotype and genotype data may be obtained through the authorized access portal of phs000308 (Geneva - Glaugen GWAS Study).

  Study phs000461

• Airway Epithelial Cell Culture RNA Expression

  This study seeks to characterize airway epithelial mRNA and miRNA expression under a variety of experimental conditions. Samples are available from primary human cell cultures as well as cell lines grown under a variety of experimental conditions as documented in the phenotype and conditions associated with each individual sample. For some experiments, cells on plastic were exposed to cigarette smoke condensate to evaluate the effects of smoking. FOSL1 is a target gene for regulation by MIR34A family microRNAs.

  Study phs002472

• Creatine in Huntington's Disease (HD) (CREST-E)

  This is a multi-center, randomized, double-blind, placebo-controlled trial of creatine monohydrate involving 553 ambulatory subjects with HD who are not requiring skilled care or institutionalization. Eligible subjects were randomized to receive up to 40 grams daily of creatine monohydrate or matching placebo. Randomization will be followed by a Titration Phase, a Maintenance Phase, an Optional Extended Maintenance Phase, and Washout. During the Titration Phase, which may last up to six months, study drug will be initially escalated in 5-gram increments starting at 5 g/day until the 40 g/day target dose is reached. Should subjects be unable to reach or stay at the maximum dose during the Titration Phase, they will remain on the highest tolerated dose (HTD) for which they have no significant side effects. During the Maintenance Phase, subjects will be followed prospectively and systematically. Subjects completing 36 months of follow-up on study drug will be eligible to continue in the study for an additional twelve months of follow-up in the Extended Maintenance Phase. The primary measure of efficacy is the annualized rate of change in TFC. The primary hypothesis of the study is that chronic treatment of early-stage HD subjects with creatine monohydrate will slow the progressive functional decline of HD.

  Study phs001488

• Feasibility study of enzymatic methylation sequencing of cell-free DNA from cerebrospinal fluid of pediatric brain tumors for classification

  Array-based DNA methylation profiling is the gold standard for molecular classification of brain tumors. However, it relies on significant amount of input DNA extracted from surgical tissue, thus limiting its use for tumors where biopsy is challenging or limited in quantity. Cell-free tumor DNA (cfDNA) in cerebrospinal fluid (CSF) presents alternative opportunities for brain tumor diagnosis and disease monitoring following treatment. Novel enzymatic DNA methylation sequencing (EM-seq) methods may allow us to overcome input DNA limitations and accurately quantify methylation from cfDNA for tumor classification.

  Study EGAS50000000871

• Whole exome sequencing to discover genetic variation associated with aortopathy in Turner Syndrome

  Turner syndrome is a disorder affecting only girls and women, which is caused by a complete or partial loss of the second sex chromosome. Girls and women with Turner syndrome have a variety of phenotypes. Of interest to this study is aortopathy, including bicuspid aortic valve (BAV) and thoracic aortic dilation (TAD) in which we know that 25 - 50% of girls with Turner syndrome are born with. The aorta is the main artery that conducts the blood out of the heart. The aortic valve guards the entrance to the aorta. When the aortic valve has two leaflets instead of the usual three it is called a BAV. BAV is more common than all other congenital heart defects combined. BAV commonly causes obstructions to blood flow out of the heart or become leaky over time. BAV often occurs in combination with TAD. In Turner syndrome, TADs are increased 50-100 fold compared to the general population. Currently, there are no effective approaches or pre-surgical treatments for aortic disease. Therefore, progression of aortic disease in individuals with BAV/TAD can result in catastrophic aortic dissection, rupture, and death. Our goal is to leverage DNA sequencing and carefully curated patient samples to gain a better understanding of the molecular mechanisms that cause these inter-related aortic diseases.

  Study phs001531

• Plasma MicroRNA Signatures of Aging

  Background. MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally and show differential expression in various tissues with aging phenotypes. Detectable in circulation, extracellular microRNAs reflect (patho)physiological processes and hold promise as biomarkers for healthy aging and age-related diseases. This study aimed to explore plasma extracellular microRNAs as biological aging indicator and their associations with health outcomes using population-level data. Methods. We quantified plasma expression levels of 2,083 extracellular microRNAs using targeted RNA-sequencing in 2,684 participants from the population-based Rotterdam Study cohort. The training and test sets included 1,930 participants from the advanced-aged initial and second subcohort (RS-I/RS-II; median age: 70.6), while the validation set comprised 754 participants from the middle-aged fourth subcohort (RS-IV; median age: 53.5). Based on 591 microRNAs well-expressed in plasma, we examined differential expression of microRNAs with chronological age, PhenoAge –a composite score of age and nine multi-system blood biomarkers–, the frailty index, and mortality. Next, elastic net models were employed to construct composite microRNA-based aging biomarkers predicting chronological age (mirAge), PhenoAge (mirPA), frailty index (mirFI), and mortality (mirMort). The association of these aging biomarkers with different age-related health outcomes was assessed using Cox Proportional Hazard, linear regression, and logistic regression models in the test and validation sets. Results. We identified 188 microRNAs differentially expressed with chronological age within the RS-I/RS-II advanced-aged population (ntraining=1158, ntest=772), of which 177 microRNAs (94.1%) were replicated in the middle-aged RS-IV subcohort (nvalidation=754). Moreover, 227 miRNAs showed robust associations with PhenoAge, 61 with FI, and 16 with ten-year mortality independent of chronological age. Subsequently, we constructed four plasma microRNA-based aging biomarkers: mirAge with 108, mirPA with 153, mirFI with 81, and mirMort with 50 miRNAs. Elevated scores on these microRNA-based aging biomarkers were associated with unfavorable health outcomes, including lower subjective physical functioning and self-reported health and increased mortality and frailty risk, but not with first- or multi-morbidity. Overall, larger effect estimates were observed for mirPA, mirFI, and mirMort compared to mirAge. Conclusions. This study describes distinct plasma microRNA-aging signatures and introduces four microRNA-based aging biomarkers with potential to identify accelerated aging and age-related decline, providing insights into the intricate process of human aging.

  Study EGAS00001008117

• Transcriptomics of human olfactory mucosa

  The olfactory gene repertoire is largely species-specific, shaped by the nature and necessity of chemosensory information for survival in each species' niche. We are intrigued by this interspecific variation and started to investigate the olfactory transcriptome in primates for evidence of selection at the level of receptor gene choice. Having collected this data from two primates, we now wish to extend the analysis to humans. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001003213