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• 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

• The chemotherapeutic CX-5461 is extremely mutagenic and may increase cancer risk

  The chemotherapeutic agent CX-5461 or pidnarulex has been fast-tracked by the US FDA for treatment of BRCA1-, BRCA2-, and PALB2-mutated cancers. It is under investigation in Phase I/II clinical trials. Here we find that although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, non-selective, collateral mutagenesis in all cells, to magnitudes that exceed known environmental carcinogens, raising public health concerns regarding its potential for promoting secondary cancers.

  Study EGAS50000000023

• INCLUDE: Down Syndrome Early Post-Natal Brain Multiome

  Neurodevelopmental deficiencies and neuronal dysfunction contribute to cognitive impairment in individuals with Down syndrome, but what molecular pathways underlie the defects that lead to intellectual disability remain unclear. Human brain development is precisely choreographed through tightly regulated transcriptional programs. Proper regulation of these transcriptional programs is necessary for developing the numerous functionally distinct regions, cell types, and connections of the brain, and forming the basis for human-specific social, cognitive, and motor abilities. These data establish a reference of molecular features of the DS developing brain. Such foundational information will provide not only a reference for any existing and future models, but also a basis for understanding disrupted neural development and impaired cognition in DS.Dataset 1 contains single-nucleus RNAseq and ATACseq from frozen postmortem human basal forebrain tissue. Dataset 2 contains single-nucleus RNAseq and ATACseq from frozen postmortem human dorsolateral prefrontal tissue. Dataset 3 contains single-nucleus RNAseq and ATACseq from frozen postmortem human caudate nucleus tissue.

  Study phs004098

• Colorectal cancer study

  Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and non-matrix proteins. Although most MMPs are secreted as inactive proenzymes and they are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11’s protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.

  Study EGAS00001006489

• NHLBI TOPMed: Early-Onset Atrial Fibrillation in the Estonian Biobank

  The Estonian Biobank is the population-based biobank of the Estonian Genome Centre of University of Tartu. The biobank is conducted according to the Estonian Gene Research Act and all participants have signed broad informed consent. The cohort size is currently 51,535 people from 18 years of age and up.

  Study phs001606

• Cerebrospinal fluid circulating tumour DNA allows the characterisation and monitoring of medulloblastoma

  The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. In this study we show that CSF ctDNA allows the molecular characterisation and monitoring of medulloblastoma. This can ultimately facilitate the clinical management of medulloblastoma patients.

  Study EGAS00001004651

• Parent-of-origin dependent DNA methylation and gene expression in the human placenta

  DNA methylation is globally reprogrammed after fertilization and the parental genomes have similar DNA methylation profiles after implantation except at the germline differentially methylated regions (gDMRs). We, and others, have previously shown that there are a large number of transient gDMRs in human blastocysts, whose differential methylation is lost in embryonic tissues after implantation. In this study we employed genome-wide allelic DNA methylation analyses of highly purified trophoblast cells from human placentas. ~40% of the transient-in-embryo gDMRs maintained their parent-of-origin-dependent biased allelic methylation. RNA sequencing-based allelic expression analyses revealed that some of the placental-specific gDMRs were associated with novel imprinted genes. This approach identified the first examples of X-linked gDMRs specific to the placenta. These findings highlight the unique regulation of allelic DNA methylation in the human placenta, which is important for understanding normal placental development and the pathogenesis of pregnancy complications.

  Study JGAS000038

• Profiles of Extracellular RNA in Cerebrospinal Fluid and Plasma from Subarachnoid Hemorrhage Patients

  Brain injury resulting from hemorrhagic stroke is clinically challenging to manage and results in high rates of morbidity and mortality. The pathophysiology of brain damage resulting from aneurysmal subarachnoid hemorrhage (aSAH) is largely unknown, and methods to treat and monitor patients are variable with no meaningful correlations to patient outcome. Prediction of patient risk for serious neurological complications is currently a significant clinical obstacle. An extracellular RNA (exRNA) biomarker to predict onset and severity of brain damage would improve patient outcomes. We sequenced plasma and CSF samples from adult patients with SAH. Samples were collected from post bleed day 1 to day 7. Total exRNA was isolated from each sample. In addition, we prepared a subset of 140 CSF samples, isolating the RNA contained within extracellular vesicles and vesicle-depleted biofluid.

  Study phs001759

• National Eye Institute (NEI) Age-Related Eye Disease Study (AREDS)

  The Age-Related Eye Disease Study (AREDS) was initially designed as a long-term multi-center, prospective study of the clinical course of age-related macular degeneration (AMD) and age-related cataract. In addition to collecting natural history data, AREDS included a clinical trial of high-dose vitamin and mineral supplements for AMD and a clinical trial of high-dose vitamin supplements for cataract. AREDS participants were 55 to 80 years of age at enrollment and had to be free of any illness or condition that would make long-term follow-up or compliance with study medications unlikely or difficult. On the basis of fundus photographs graded by a central reading center, best-corrected visual acuity and ophthalmologic evaluations, 4,757 participants were enrolled in one of several AMD categories, including persons with no AMD. The clinical trials for AMD and cataract were conducted concurrently. AREDS participants were followed on the clinical trials for a median time of 6.5 years. Subsequent to the conclusion of the clinical trials, participants were followed for an additional 5 years and natural history data were collected. The AREDS research design is detailed in AREDS Report 1. AREDS Report 8 contains the mainline results from the AMD trial; AREDS Report 9 contains the results of the cataract trial. Blood samples were also collected from 3,700+ AREDS participants for genetic research. Genetic samples from 600 AREDS participants (200 controls, 200 Neovascular AMD cases, and 200 Geographic Atrophy cases) were selected using data available in March 2005 and then were evaluated with a genome-wide scan. These data, as well as selected phenotypic data, were made available in the dbGaP. DNA from AREDS participants, which is currently being stored in the AREDS Genetic Repository, is available for research purposes. However, not all of the 3,700+ AREDS participants who submitted a blood sample currently have DNA available. In addition to including the data from the genome-wide scan on the 600 original samples, this second version of the AREDS dbGaP database provides a comprehensive set of data tables with extensive clinical information collected for the 4,757 participants who participated in AREDS. The tables include information collected at enrollment/baseline, during study follow-up, fundus and lens pathology, nutritional estimates, quality of life measures and measures of morbidity and mortality. In November 2010, over 72,000 high quality fundus and lens photographs of 595 AREDS participants (of the original 600 selected for the genome-wide scan) were made available in the AREDS dbGaP. In addition to the genome-wide scan data, the fundus and lens grading data for these participants are also available through the AREDS dbGaP. Details about the ocular photographs that are available may be found in the document "Age-Related Eye Disease Study (AREDS) Ocular Photographs". In January 2012, a measure of daily sunlight exposure was added in a separate "sunlight" table. Furthermore, the "followup" table has been revised. The visual acuity for the right eye was inadvertently missing at odd-numbered visits (01, 03, 05, etc.). This data is now part of the table. In February 2014 over 134,500 high-quality fundus photographs (macular field F2) of 4613 AREDS participants were added to the existing AREDS dbGaP resource. The AREDS dbGaP image archive already contains over 72,000 high quality fundus and lens photographs of 595 AREDS participants for whom dbGaP-accessible genotype data exist. Information about the available ocular photographs found in the document "Age-Related Eye Disease Study (AREDS) Ocular Photographs" has been updated with an addendum. It is hoped that this resource will better help researchers understand two important diseases that affect an aging population. These data may be applied to examination and inference on genetic and genetic-environmental bases for age-related diseases of public health significance and may also help elucidate the clinical course of both conditions, generate hypotheses, and aid in the design of clinical trials of preventive interventions. Definitions of Final AMD Phenotype Categories Please see phd001138.1 for a detailed description of how AREDS participants' final AMD phenotype was categorized. User's Guide for AREDS Phenotype Data A detailed User's Guide for the AREDS phenotype data is available. This User's Guide is meant to be a comprehensive document which explains the complexities of the AREDS data. It is recommended that all researchers using AREDS phenotype data make use of this User's Guide.

  Study phs000001