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• Epigenome-wide methylation analysis of colorectal carcinoma, adenoma and normal tissue reveals novel biomarkers addressing unmet clinical needs

  Studies about CRC biomarker discovery have focused on methylation patterns in normal and colorectal tumor tissue, leading to a lack of knowledge of methylation in adenomas. Therefore, we performed the first epigenome-wide study to compare the epigenomes of all three tissue types combined, and to identify discriminatory biomarkers. Public Illumina MethylEPIC® data was collected from 552 normal, 118 carcinoma and 116 adenoma samples. Pairwise analyses were performed for discovery of differentially methylated probes (DMPs). We identified 693 813, 620 643 and 558 897 DMPs when comparing normal vs carcinoma, normal vs adenoma and adenoma vs carcinoma respectively. To double evidence (DE) these DMPs, analysis of Illumina 450K data from public datasets was performed. Through this analysis, 13 DE DMPs with │Δβ│≥0.3 were identified for adenoma vs carcinoma. A binary logistic regression model was generated to evaluate the discriminatory potential of these DE DMPS. The model was validated in an in-house experimental methylation dataset of 13 adenoma and 9 carcinoma samples. Our classifier reached a cross-validated AUC of 0.996 and 0.855 in the discovery and validation datasets respectively. A sensitivity and specificity of 96% and 95% were reached, with an overall accuracy of 96%. Our analysis show that methylation biomarkers have the potential to discriminate between normal, precursor and carcinoma tissues of the colorectum. More importantly, we highlight the power of the methylome, showing that DMPs can be used as biomarkers in the clinic to identify colorectal adenoma and carcinoma. 

  Study EGAS00001007017

• 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

• Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis thymoma

  Myasthenia gravis (MG) is known to be epidemiologically associated with abnormalities of the thymus, an organ that maintains central tolerance. However, due to the complexity of the thymus, specific characteristics related to the pathogenesis of MG remain elusive. In our study, we attempted to narrow down the features associated with MG using spatial transcriptome analysis of thymoma and thymic hyperplasia samples. We found that the majority of thymomas were constituted by the cortical region, whereas the medullary region was localized in comparatively restricted areas. Moreover, the medullary region contained polygenic enrichment, MG-specific germinal center structures, and a supporting immune microenvironment. Additionally, neuromuscular medullary thymic epithelial cells (nmTECs), previously identified as MG-specific autoantigen-producing cells, were situated at the cortico-medullary junction. The immune microenvironment in the medulla was characterized by a specific chemokine pattern and specific immune cells, such as CCR7+ migratory dendritic cells (migDCs) and effector regulatory T (Treg) cells. Furthermore, similar germinal center structures and immune microenvironments were observed in the medulla during thymic hyperplasia. This study indicates that the medulla and junction areas are related to the pathology of MG, suggesting that these areas should be the focus of future studies on MG pathogenesis and drug targeting.

  Study JGAS000672

• Determination of Cross-Reactive Immunological Material (CRIM) status and longitudinal follow-up of individuals with Pompe disease

  Infantile-onset Pompe disease is an inherited disorder that is normally diagnosed within the first months of life. It is caused by lack of or defect in an enzyme (a special protein that carries out normal chemical reactions within the body) called acid alpha-glucosidase (GAA). GAA normally breaks down glycogen (stored sugar) in lysosomes (the part of the cell that digests food and other chemicals). Pompe disease is one of many lysosomal storage diseases (LSDs). LSDs are diseases caused by the malfunction of the lysosome or one of their digestive enzymes. Patients with Pompe disease cannot break down lysosomal glycogen. This causes glycogen to build up and damage cells throughout the body, especially in the heart and muscles. Current treatment for Pompe disease involves enzyme replacement therapy (ERT). In this treatment, the drug alglucosidase alfa (Myozyme) is put into your blood. The drug provides a form of the GAA enzyme to replace the enzyme that is missing or not working properly in the patient's blood. This treatment has allowed babies to live longer and achieve developmental milestones. In this study, researchers will learn about the patient's ability to tolerate ERT. Cross-Reactive Immunological Material (CRIM) is a measurement of natural GAA production. A patient's CRIM status (either positive or negative) is an important factor that affects how he or she responds to ERT with Myozyme. Children who produce some natural GAA are classified as CRIM+, while children who do not produce any natural GAA are classified as CRIM-. Children who are CRIM+ generally tolerate ERT well. But, children who are CRIM-, and some children classified as CRIM+, have a poor response to ERT. Patients who have a poor response to ERT have complications because their body sees Myozyme as "foreign" and triggers an immune response to try to remove it from the body. Treatments are currently being developed to stop this immune response and prevent complications from ERT. We will enroll patients with Infantile Pompe disease in this longitudinal natural history (observational) study. The specific aims of this study are: To determine and correlate Cross-Reactive Immunological Material (CRIM) status with the GAA gene mutations found on these patients To validate an approach for determining CRIM status from whole blood sample, with the gold standard determination of CRIM status by skin fibroblasts and mutation analysis To explore the clinical treatment response and natural history of CRIM-positive and CRIM-negative Pompe disease patients with and without immune modulation To investigate the role of immune response to treatment

  Study phs001555

• Use_of_Deep_Sequencing_to_Dectect_Clonal_Mutations_In_Sun_Exposed_Skin_Epidermis

  This study aims to define the landscape of somatic mutations in sun exposed human skin by deep sequencing, analyse their frequency and use the data to infer the effect of mutations on proliferating cell behaviour. The frequency of each mutation will reflect the size of the clone of cells in the tissue sample. By analyzing small samples, clones with as few as 100 cells will be detectable. Allele frequency distributions for each mutation will be used to infer cell fate using published methods (Klein et al. 2010). This study will shed unprecedented light on the early clonal events that lead to the emergence of cancer.

  Study EGAS00001000515

• Use_of_Deep_Sequencing_to_Dectect_Clonal_Mutations_In_Sun_Exposed_Skin_Epidermis_PART2

  This study aims to define the landscape of somatic mutations in sun exposed human skin by deep sequencing, analyse their frequency and use the data to infer the effect of mutations on proliferating cell behaviour. The frequency of each mutation will reflect the size of the clone of cells in the tissue sample. By analyzing small samples, clones with as few as 100 cells will be detectable. Allele frequency distributions for each mutation will be used to infer cell fate using published methods (Klein et al. 2010). This study will shed unprecedented light on the early clonal events that lead to the emergence of cancer.

  Study EGAS00001000603

• Effects of 2DG, Galactose, or Oligomycin on the epigenome remodeling induce by T cells activation.

  T cell activation is known to require a metabolic shift towards glycolysis, triggered by TCR-engagement . To substantiate the role of glycolysis in transcriptional reprogramming during antigen-driven T cell activation, we utilized a well-established ex-vivo model to recapitulate the process of antigen stimulation without the requirement for additional antigen-presenting cells . We initially explored and validated the conditions for both metabolic and epigenetic reprogramming. Antigen-mediated CD4+ T cells activation initiates context-specific gene-expression programs that drive effector functions and cell fates through changes in the epigenetic landscape . To evaluate global changes in histone modifications, we isolated CD4+ T cells from peripheral blood (PB) of healthy control (HC) human donors and either maintained them in resting conditions or stimulated with anti-CD3/CD28 for 24h. Rapid changes in the CD4+ epigenome and transcriptome were observed within 24h as measured by RNA-sequencing (RNA-seq) and H3K27ac chromatin immunoprecipitation followed by DNA-sequencing (ChIP-seq).To explore the requirement for metabolic reprogramming in regulating transcriptional responses after initial TCR engagement, CD4+ T cells from PB of healthy donors were isolated and activated in either the presence or absence of oligomycin (inhibitor of ATP synthase blocking the production of ATP by OXPHOS), 2-deoxyglucose (2DG; competitively inhibiting production of glucose-6-phosphate from glucose), or replacement of glucose with galactose. Galactose is metabolized through glycolysis, utilizing the Leloir pathway which is energy neutral, forcing cells to use all the pyruvate production to sustain the TCA cycle for OXPHOS and ATP synthesis at the expense of lactate production. Employing ChIP-seq and RNA-seq, inhibition of OXPHOS-mediated ATP production by oligomycin had only a limited effect on H3K27-acetylation or activation-induced transcription during the first 24h of activation. In contrast, inhibition of glycolysis by 2DG treatment compromised both H3K27-acetylation and transcriptional changes. However, under conditions of galactose-metabolism where lactate production is abrogated, activated CD4+ T cells were still able to globally remodel H3K27 acetylation and reprogram the transcriptome.

  Study EGAS00001007115

• The Intestinal Bacterial Metagenome in Pediatric Non-Alcoholic Fatty Liver Disease (NAFLD)

  Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children in the United States. NAFLD is associated with obesity and metabolic syndrome; however, there is limited understanding of the development and progression of NAFLD. There is evidence of abnormalities of bacterial colonization, and intestinal bacterial product-induced inflammation associated with NAFLD and disease progression. The goal of this study was to characterize the intestinal microbiome in pediatric participants with NAFLD and in both obese and normal weight controls to determine the relationship between alterations in the intestinal microbiome, inflammation, and the development of NAFLD. We hypothesized that alterations in the intestinal microbiome are associated with increased systemic inflammation and the development and severity of NAFLD.

  Study phs001837

• Maturation of Human Intestinal Epithelial Cell Layers Fortifies the Apical Surface against Salmonella Attack

  Pathogen invasion of intestinal epithelial cells (IECs) is a key gut infection event. The dynamics of this process in intact epithelia and the factors governing IEC susceptibility remain underexplored. We present a resource for live-cell infection imaging in human enteroid-/colonoid-derived IEC layers, across maturation states and in the presence or absence of soluble mucus production. Utilization of this resource shows how human IEC maturation fortifies the apical surface against invasion by Salmonella Typhimurium (S.Tm). Immature IEC layers appear permissive to S.Tm invasion, but maturation towards an enterocyte/colonocyte phenotype reduces the susceptibility by up to tenfold. This shift couples to downregulated expression of actin regulatory proteins exploited by the pathogen, an increased dependence on the S.Tm effector SipA, and the build-up of the apical IEC glycocalyx linked to surface-attached mucins like MUC13 and nullifiable by StcE-enzyme treatment. This underscores how the maturation state of human IECs governs susceptibility to bacterial invasion.

  Study EGAS50000001241

• Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome

  The transgenerational maternal effects of PCOS in female progeny have been revealed. As there are evidence that a male equivalent of PCOS may exist, we asked whether sons born to mother with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a Swedish nationwide register-based cohort and a clinical case-control study from Chile we found that PCOS-sons are more often obese and dyslipidemic. Their serum miRNAs are found to potentially regulate PCOS-risk genes. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in F1 male offspring are passed down to F3. Small non-coding RNAs (sncRNAs) sequencing of F1-F3 sperm revealed distinct differentially expressed (DE) sncRNAs across generations in the androgenized, obese, and obese and androgenized lineages, respectively. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism. These findings strengthen the translational relevance highlighting a previously underappreciated risk of reproductive and metabolic dysfunction via the male germline transmission and potential molecular markers to study in future generations.

  Study EGAS00001007079

• Tumor-derived exosomes modulate PD-L1 expression in monocytes

  In chronic lymphocytic leukemia (CLL), monocytes and macrophages are skewed toward protumorigenic phenotypes, including the release of tumor-supportive cytokines and the expression of immunosuppressive molecules such as programmed cell death 1 ligand 1 (PD-L1). To understand the mechanism driving protumorigenic skewing in CLL, we evaluated the role of tumor cell–derived exosomes in the cross-talk with monocytes. We carried out RNA sequencing and proteome analyses of CLL-derived exosomes and identified noncoding Y RNA hY4 as a highly abundant RNA species that is enriched in exosomes from plasma of CLL patients compared with healthy donor samples. Transfer of CLL-derived exosomes or hY4 alone to monocytes resulted in key CLL-associated phenotypes, including the release of cytokines, such as C-C motif chemokine ligand 2 (CCL2), CCL4, and interleukin-6, and the expression of PD-L1. These responses were abolished in Toll-like receptor 7 (TLR7)–deficient monocytes, suggesting exosomal hY4 as a driver of TLR7 signaling. Pharmacologic inhibition of endosomal TLR signaling resulted in a substantially reduced activation of monocytes in vitro and attenuated CLL development in vivo. Our results indicate that exosome-mediated transfer of noncoding RNAs to monocytes contributes to cancer-related inflammation and concurrent immune escape via PD-L1 expression.

  Study EGAS00001002377

• Exome_sequencing_in_patients_with_Calcific_Aortic_Valve_Stenosis

  The objective is to identify new genes involved in calcific aortic valve stenosis (CAVS) by screening the exome of at least 20 patients with familial CAVS. The recruitment of patients with CAVS has been achieved by l’institut du thorax (Nantes, France). DNA from the selected patients has been analysed by exome capture (Agilent SureSelect) and massively parallel sequencing (Illumina). The data generated by this project will lead to the identification of candidate genes involved in CAVS, which can be further screened for mutation in additional patients with CAVS.

  Study EGAS00001000049

• ICGC Oesophageal adenocarcinoma - 100 tumour samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000724

• Defining the metastasome in colorectal cancer: Implications for hypotheses on metastasis evolution and personalized therapy (HIPO-032)

  Personalized cancer therapy aims at individual genetic changes characterizing primary cancers. Still, however, metastasis is the major clinically unmet problem, also due to an incomplete understanding of its molecular evolution.This study is the first to define the metastasis-specific whole genome landscape of human colorectal primary vs. matched metastatic lesions.Protein coding, ncRNA genes and 3’UTRs harbored about a third each of single nucleotide variations (SNVs)/indels, 19% of them being metastasis-specific. We found novel mutational hills among ncRNAs and 3’UTRs, copy number changes able to explain changes in microRNA expression in metastases, and novel metastasis-specific mutations in the 3’UTRs on important cancer signalling genes. Some metastatic lesions showed targetable mutations not detected in the primaries. Analysis of mutual exclusivity patterns supported a model that has progressive alterations in important colorectal cancer genes and revealed new partners. Metastatic lesions were enriched in SNVs, specific structural variations, and alterations in genes affecting cell adhesion and extracellular matrix interaction.Furthermore, a hepatic stellate activation cascade was enriched in metastases, suggesting genetic programs for site-specific colonization. Allele frequency distribution and mutational signature analysis suggests a common ancestor clone to both the primary tumor and the metastasis, with additional mutagenesis ongoing in both sites independently. Taken together, our results significantly add to hypothesis generation on metastasis evolution, and suggest novel metastasis-specific genomic changes which would be missed by current personalized therapy concepts. (HIPO-032)

  Study EGAS00001002717

• MSI_Cancer_Models___RNAseq

  The study will use RNAseq to aid in define determinants of WRN dependency in MSI Cell lines.

  Study EGAS00001004180

• Genome-Wide Association Study in Systemic Sclerosis

  The Scleroderma Family Registry and DNA Repository (Registry) was initially developed as a registry and bio-specimen repository of patients with systemic sclerosis (scleroderma), family members and unaffected healthy controls. A case-control design was later adopted due to the lack of availability of many parents in this adult-onset disease, which precluded a linkage approach. In addition to collecting demographic data, the registry included the collection of disease-pertinent, cross-sectional, clinical information from medical records of affected participants. Registry participants were >/= 18 years of age at enrollment. On the basis of medical record review, all cases were verified by the principal investigator to meet the eligibility criteria. 800+ blood samples from verified affected cases of European ancestry were selected for a Genome Wide Association Study (GWAS). These genetic data, as well as phenotypic data, are available in dbGaP. DNA, serum and plasma from Registry participants, which are currently being stored in the University of Texas Health Science Center - Houston, Scleroderma Registry Genetic Repository, are available for research purposes. However, not all of the 800+ registry participants who submitted a blood sample currently have DNA available due to depletion of some samples. In addition to including SNP data from the genome-wide (first study release) and immunochip (second study release) scan on the 800+ samples, the dbGaP database provides a set of data tables with phenotypic information collected from the participants in the registry.

  Study phs000357

• Genome sequencing identifies splice-disrupting variants in childhood heart disease

  We used genome sequencing (GS) to identify cardiac specific splice disrupting variants that were subsequently validated in a subset of participants. In turn, we developed a heart-specific model for canonical and non-canonical splice variants, which was applied to patients with congenital heart disease (CHD). These included patients with two of the most common forms of cyanotic CHD i.e. tetralogy of Fallot (TOF) and dextro-transposition of the great arteries (TGA). In addition to identifying canonical splice-disrupting variants in known CHD-related genes in 1% cases, this approach identified putatively damaging non-canonical splice-disrupting variants in 11% of isolated CHD, with deeply intronic variants representing 53% of non-canonical splice-disrupting variants in CHD genes. GS was critical for the identification of variants that would not be captured by routine clinical genetic tests including exome sequencing, while cardiac RNA-Seq allowed for high specificity in the interpretation of splice-disrupting effects in the heart.

  Study EGAS50000000586

• Rare occurrence of Aristolochic Acid Mutational Signatures in Oro-Gastrointestinal Tract Cancers

  Aristolochic Acids (AAs) are a family of carcinogenic phytochemical compounds commonly found in plants of Aristolochia and Asarum genus. Comprehensive genomic profiling of genitourinary and hepatobiliary cancers has highlighted the widespread prevalence of Aristolochic Acid (AA) signatures in cancer patients across parts of Asia, particularly in Taiwan. The aim of our study was to determine in Oro-Gastrointestinal Tract (OGITC) cancers, the prevalence, role and significance that AA plays as a driver of tumorigenesis as AA containing products are commonly administered orally. This would suggest a possible etiological relationship between cancers of OGITC. However, in this study the rarity of AA mutational signatures in OGITC suggests that AA is unlikely to drive carcinogenesis in OGITC through direct exposure. Our study is valuable to show that AA exposure is not an equal driver of tumorigenesis in different organs and represents an important piece of information in the field.

  Study EGAS00001005909

• Molecular_risk_stratification_in_patients_with_T1_colorectal_cancer_WES

  The introduction of bowel cancer screening has led to a significant increase in the proportion of patients being diagnosed with asymptomatic, early-stage colorectal cancer (CRC). Although the majority of these patients are successfully treated with surgery alone, a small proportion of patients have ‘born-to-be-bad’ aggressive lesions with early dissemination leading to distant metastases. Current standard of care histological assessment is unable to distinguish between these aggressive versus non-aggressive early lesions which is essential to provide appropriate clinical management decisions. This study aims to carry out molecular and histological profiling of approximately 300 T1 CRCs in order to develop a molecular stratifier based on the risk of relapse in early-invasive CRC. This novel T1 cohort will represent the world’s largest molecularly characterised T1 cohort of samples, with digital pathology assessment alongside whole exome sequencing, copy number variation analysis and 3’ RNA-seq. This data will be used to generate a robust panel of molecular and/or histological markers applicable to formalin-fixed paraffin embedded (FFPE) archival tissue which discriminates between T1 lesions based on risk of relapse, which will ultimately be used to inform clinical management of CRC at the earliest stages of the disease.

  Study EGAS00001005734

• Distribution of ctDNA levels in plasma of early-stage non-small cell lung cancer patients measured using personalised ctDNA analysis

  Blood-based assays have shown increasing ability to detect circulating tumour DNA (ctDNA) in patients with early-stage cancer. However, detection of ctDNA in patients with non-small cell lung cancer (NSCLC) has continued to prove challenging. We performed retrospective analysis to quantify ctDNA levels in a cohort of 100 patients with early-stage NSCLC prior to treatment with curative intent. Where tumour tissue was available for whole exome sequencing, mutations identified were used to define patient-specific sequencing assays. For those 90 patients, plasma cell-free DNA was sequenced to high depth across capture panels targeting a median of 328 mutations specific to each patient. Data was analysed using Integration of Variant Reads (INVAR), detecting ctDNA in 66.7% of patients, including 52.7% (29 of 55) patients with stage I disease and >88% detection for patients with stage II and III disease (16/18 and 15/17). ctDNA was detected in plasma at fractional concentrations as low as 9.1x10-6, and in patients with tumour volumes as low as 0.23 cm3. A 36-gene sequencing panel (InVisionFirst-LungTM) was used to analyse plasma DNA in 27 samples including the 10 cases without tumour exome data, and detected ctDNA in 59% of samples tested (16 of 27). Across the entire cohort, detection rates were higher in squamous cell carcinoma patients compared to adenocarcinoma patients (81% vs. 59%). Detection of ctDNA prior to treatment was associated with significantly shorter time free from relapse, across all patients and in patient subgroups, with Hazard Ratios ranging from 2.25 to >11. Our analysis indicates that for patients with stage I NSCLC, the median ctDNA fraction in plasma is approx. 12 parts per million (0.0012%). This indicates the limits of detection that would be required for ctDNA-based liquid biopsies to detect ctDNA in the majority of patients with early-stage NSCLC.

  Dataset EGAD00001006230

• Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer

  Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identified five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reasoned that their strong selection should prioritise them as key biomarkers for targeted therapies. We used primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number was associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC was statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway was independently observed in squamous lung cancer and triple negative breast cancer. These results suggest that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.

  Study EGAS00001006200

• Stressors and Health Study

  ObjectivesThe objectives of the Stressors and Health Study were to: (1) examine the prevalence of stressors and health outcomes and (2) assess differences in the associations between multi-level stressors and health outcomes, and (3) explore the protective and adaptive factors in the associations between multi-level stressors and health outcomes. Background Stressors have been posited to explain disparities in health. However, no surveys to our knowledge have simultaneously collected multiple stressors at various levels and the coping strategies used to deal with these stressors. Measuring these factors can provide a better understanding of the stressors experienced by specific groups and the impact that these experiences have on their health and health practices. In addition, exploring the various resilience and coping strategies employed to deal with stressors can help design appropriate interventions to reduce health disparities. Participants Participants included 1000 White, 1000 Black or African American, 1000 Latino or Hispanic, 1000 Asian, 500 American Indian or Alaska Native, 500 Native Hawaiian or Pacific Islander, and 500 mixed or multi-race adults (≥18 years) across the United States. Design The Stressors and Health Study is a cross-sectional online survey of adults across the US. A sampling frame (target population) of US residents based on the American Community Survey (ACS) was constructed using a rigorous two-step sampling matching approach to establish national representation.

  Study phs004019

• Study on the consequences of prenatal famine exposure on DNA methylation.

  The potential of the epigenome to undergo environmentally-induced changes during early development is central to its postulated role in human disease. Here, we report a genome-scale view of DNA methylation differences after early gestational malnutrition that was caused by the Dutch Hunger Winter, a severe famine at the end of World War II. We adopted an annotation guided analysis of reduced-representation bisulfite sequencing data generated in 24 middle-aged individuals who had been exposed to famine in utero and 24 unexposed sibling controls. We observed differential DNA methylation primarily at genomic regions with regulatory potential, including enhancers active during early development. In-depth annotation of 181 prenatally-induced differentially methylated regions (P-DMRs) showed that they were predominantly located in gene bodies and co-occurred with histone marks denoting an active state. In line with the early gestational timing of the exposure, the P-DMRs mapped to genes that were enriched for differential expression patterns during blastocyst development and early organogenesis. Validation and further explorative analyses of 6 P-DMRs mapping to SMAD7, CDH23, INSR, RFTN1, CPT1A and KLF13 highlighted the critical role of gestational timing, indicated that differential methylation extended along pathways involved in growth, development and metabolism, and suggested associations with birth weight and serum LDL cholesterol in adulthood and confirmed an enhancer function for the INSR and CPT1A P-DMRs. Our results point toward a link between prenatal malnutrition and epigenetic modulation of growth and lipid metabolism that may underlie the adverse metabolic phenotype of exposed individuals in later life.

  Study EGAS00001000668

• Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic

  Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks. "Reprinted from doi:10.1016/j.ebiom.2014.12.003, with permission from EBioMedicine."

  Study phs000942

• Genome Diversity in Africa Project: Benin (2021-02-16)

  Globally, human populations show structured genetic diversity as a result of geographical dispersion, selection and drift. Understanding this genetic variation can provide insights into the evolutionary processes that shape both human adaptation and variation in disease. Populations from SSA have the highest levels of genetic diversity. This characteristic, in addition to historical genetic admixture, can lead to complexities in the design of studies assessing the genetic determinants of disease and human variation. However, such studies of African populations are also likely to provide new opportunities to discover novel disease susceptibility loci and variants and refine gene-disease association signals. A systematic assessment of genetic diversity within SSA would facilitate genomic epidemiological studies in the region. The Genome Diversity in Africa Project (GDAP) aims to produce a comprehensive catalogue of human genetic variation in SSA, including single nucleotide polymorphisms (SNPs), structural variants, and haplotypes. This resource will make a substantial contribution to understanding patterns of genetic diversity within and among populations in SSA, as well as providing a global resource to help design, implement and interpret genomic studies in SSA populations and studies comprising globally diverse populations, complementing existing genomic resources. Specifically, we plan to carry out high depth whole genome sequencing of up to 2000 individuals across Africa (25 individuals from each ethnolinguistic group). Our scientific objectives are to: 1) develop a resource that provides a comprehensive catalogue of genetic variation in populations from SSA accessible to the global scientific community; 2) characterise population genetic diversity, structure, gene flow and admixture across SSA; 3) develop a cost-efficient, next-generation genotype array for diverse populations across SSA; and 4) facilitate whole genome-sequencing association studies of complex traits and diseases by developing a reference panel for imputation and resource for enhancing fine-mapping disease susceptibility loci. These scientific objectives will be supported by cross-cutting operational activities, including network and management of the consortium, research ethics, and research capacity building in statistical genetics and bioinformatics 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/ . This dataset contains all the data available for this study on 2021-02-16.

  Dataset EGAD00001006970