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• Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma

  SOX11 is overexpressed in the highly aggressive conventional mantle cell lymphoma (MCL) but rarely in the indolent non-nodal MCL subtype. We performed RNA-seq of SOX11+ and SOX11- MCLs to search for SOX11-regulated genes that contributed to MCL clinical evolution, identifying Musashi-2 (MSI2) stem cell-related gene. By performing RNA-seq upon MSI2 knockdown or inhibition in MCL, we identified MSI2 as a potential target to inhibit drug resistance in aggressive MCLs.

  Study EGAS00001006613

• National Eye Institute (NEI) Genetic Epidemiology of Age-Related Macular Degeneration in the Old Order Amish

  Identifying genetic risk loci for Age-Related Macular Degeneration is important. Most of the loci identified to date have been found through the interrogation of common variants. This study initiates the identification of rare variants in a founder population, the Amish, and will use genotyping of known risk loci and ultimately use the whole exome chip to assess the association of Age-related Macular Degeneration with coding variants. We will further refine the Age-Related Macular Degeneration phenotype through the use of modern imaging, the OCT, to visualize the early anatomic signs of Age-Related Macular Degeneration. We hypothesize there are endophenotypes associated with specific genotypes that can be used to determine Age-related Macular Degeneration progression. These endophenotypes are hypothesized to be influenced by a combination of common and rare variants. We will relate these endophenotypes to genotypes to define the role of genetics in the progression of Age-Related Macular Degeneration and a new risk profile incorporating genotypic information.

  Study phs001361

• ENCORAFENIB COMBINED WITH BINIMETINIB FOR BRAFV600E-MUTATED RELAPSED/REFRACTORY MULTIPLE MYELOMA: THE PHASE II GMMG-BIRMA TRIAL (Hipo_K08K)

  Activating BRAF mutations are rare events in multiple myeloma but have been shown to be promising therapeutic targets in small case studies. This multicenter phase II trial assessed the efficacy and safety of the BRAF/MEK inhibitors, encorafenib and binimetinib, in patients with relapsed/refractory multiple myeloma (RRMM) carrying an activating BRAFV600E mutation. Twelve RRMM patients with a median of five prior lines of therapy were enrolled. The study met its primary endpoint with 10 patients achieving at least a partial response according to IMWG criteria (overall response rate 83.3%). Responses occurred rapidly within the first cycle and deepened over time. The median progression-free survival (PFS) was 5.6 months and overall survival was 55% at 24 months. Genomic profiling revealed RAS mutations and structural variants involving the BRAF locus to be drivers of resistance to BRAF/MEK inhibition in RRMM. This trial demonstrates the value of translationally driven clinical trials in selected patient populations.

  Study EGAS00001005973

• Rapid Early Action for Coronary Treatment (REACT-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: This multicenter controlled community study developed and evaluated the impact of a community educational intervention program on participant delay time from onset of symptoms of an acute myocardial infarction (AMI) to arrival at a hospital emergency department.Background: Although early reperfusion or thrombolytic therapy can reduce morbidity and mortality following an AMI, delayed access to medical care in participants is relatively common. Mean delay times from symptom onset to hospital arrival range from more than 4 hours to 24 hours, and the largest component of prolonged delay is participant recognition and action.Participants: A total of 20 communities from 5 field centers in the U.S. were pair-matched (10 pairs) according to geographic proximity and demographic characteristics. After initiation of a 4 month baseline surveillance period, one community in each pair was randomly selected to receive the intervention. The baseline surveillance period was followed by an 18 month community intervention and surveillance period. The community surveillance captured a total of 59,944 adults aged 30 years or older presenting to hospital emergency departments with chest pain, of whom 20,364 met study criteria for suspected acute coronary heart disease (CHD) at admission and discharged with a CHD diagnosis.Conclusions: Delay times were decreased in the intervention and reference communities. The results showed that the multicomponent community intervention program did not differentially reduce delay time from onset of AMI symptoms to arrival at a hospital, but did significantly increase the use of Emergency Medical Services by these participants in the intervention communities. (PMID:10872014).

  Study phs003885

• UK10K_RARE_NEUROMUSCULAR

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The neuromuscular disorder samples are part of the “rare disease” group, and will undergo exome sequencing. For further information with regard to this cohort please contact Francesco Muntoni (f.muntoni@ucl.ac.uk).

  Study EGAS00001000101

• UK10K_RARE_FIND

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Raymond samples will be part of the “rare disease” group, and will undergo exome sequencing. For further information with regard to this cohort please contact Lucy Raymond (flr24@cam.ac.uk).

  Study EGAS00001000128

• UK10K_RARE_CILIOPATHIES

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Ciliopathies samples will be part of the rare disease group, and will undergo exome sequencing. For further information with regard to this cohort please contact Phil Beales (p.beales@ich.ucl.ac.uk).

  Study EGAS00001000126

• UK10K RARE CHD

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The CHD (congenital heart disease) samples will be part of the “rare disease” group, and will undergo exome sequencing.For further information with regard to this cohort please contact Shoumo Bhattacharya (shoumo@me.com).

  Study EGAS00001000125

• Somatic Mutation in Normal Bladder Study

  Adult human somatic tissues are landscapes of mutant clones, but little is known about how these landscapes are shaped by known cancer risk factors. The goal of this study was to determine how the main bladder cancer risk factors (sex and smoking) change the mutational landscape of the normal urothelium. We collected normal urothelium from 45 donors at autopsy by brushing ~2cm² of the surface epithelium in the upper part (dome) and lower part (trigone) of the bladder (79 samples total). To identify mutations with high sensitivity we employed ultradeep (~5000x) DNA error-correcting duplex-sequencing on a panel of 15 protein coding genes and the TERT promoter, previously described to be under positive selection in normal urothelium or relevant to bladder cancer. We identified thousands of clonal driver mutations, which demonstrate pervasive positive selection in the normal urothelium. Males showed a significantly higher number of driver truncating mutations in RBM10, CDKN1A and ARID1A, despite similar rates of non-coding mutations, indicating stronger positive selection and clonal expansion in the male urothelium. We also discovered clonal expansions driven by activating TERT promoter mutations in the normal bladder, which were strongly associated with age and smoking. These results demonstrate that sex and smoking shape the clonal landscape of the normal bladder and indicate that the high mutational content of normal tissues might be leveraged to study the effect of mutations in vivo (i.e. natural saturation mutagenesis). We will deposit in dbGaP de-identified relevant clinical information from the 45 donors and the fastq files derived from duplex sequencing of the 79 samples in the study. We will also deposit fastq files derived from duplex sequencing of 3 control cord blood samples.

  Study phs004105

• Studying the single cell characteristics of pancreatic cancer

  Pancreatic cancer is a dangerous malignancy in the pancreas. In this study we use single-cell RNA sequencing technique to help understand the transcriptome characteristics of pancreatic tumor cells. This study help understands the complex microenvironment of pancreatic tumors and will likely to benefit clinical research of pancreatic cancer treatments.

  Study EGAS00001003889

• National Cancer Institute (NCI) Adding Hispanics to Ongoing GWAS in Colorectal Cancer

  Genome-wide association studies (GWAS) of colorectal cancer (CRC) have been instrumental in identifying a number of common susceptibility loci in Non Hispanic (NH)-White populations, and a NCI priority is to extend GWAS findings to other populations to address racial/ethnic disparities in cancer susceptibility. Currently, GWA studies of CRC in NH-Whites, Japanese and African-Americans are ongoing. We propose a complementary study to address this critical research area in Hispanics. Hispanics represent the fastest growing ethnic population in the U.S. and have been largely understudied in terms of genetic susceptibility to cancer. There are noted differences in incidence, survival and mortality in CRC by ethnic/racial groups. Hispanics often present with CRC at a younger age and have a significantly greater incidence of stage IV tumors or metastatic disease compared to NH-Whites. We propose to conduct a large, cost-efficient, population-based GWAS in Hispanics by building upon existing NIH-funded resources, the Colon Cancer Family Registry (Colon CFR) and the Multiethnic Cohort Study (MEC). We plan to recruit 2,500 Hispanic men and women diagnosed with CRC between 01/2008 to present using cancer registries in California, physican referrals and familial referrals. Risk factor/diet questionnaires, pathology reports, Oragene saliva samples (for genotyping), optional blood samples (for genotyping and biometric analysis) and tumor blocks (for MSI testing) will be collected using methodologies developed in the Colon CFR/MEC. Cases of CRC in the MEC (currently 473; anticipated 600 at end) will also be included. Population-based Hispanic individuals without a diagnosis of CRC participating in other GWA studies in the MEC (n=3,900, U01HG004726, Haiman) will be used as controls. We will genotype all 3,100 cases using the Illumina 1M array and use available genotype and epidemiologic data collected on 3,900 controls. Our statistical analyses will include: single-SNP and haplotype effects, gene-environment interactions and heterogeneity by MSI, tumor subtype and family history of CRC. We will replicate findings in a second-stage using CRC cases and controls from Mexico (1,000 cases and 1,000 controls, EU FP7 funding, CHIBCHA, Carvajal-Carmona/Tomlinson). We will also examine heterogeneity of the risk estimates by ethnicity/race by leveraging GWA data on NH-Whites (2,142 cases, 1,909 controls, U01 CA122839, Casey), (4,000 cases, 6,000 NH-White controls, UK-CHIBCHA, Tomlinson), Colombians (2,000 cases and 2,000 controls, CHIBCHA), Japanese (1,000 cases and 1,000 controls) and African-Americans (1,500 cases and 1,500 controls, R01CA126895, Le Marchand). We will genotype replicated significant SNPs in our main and combined analysis in several Hispanic populations (note: studies funded by EU or NIH for data collection but not GWAS), including 800 Puerto Ricans, 2,000 Brazilians, 2,000 Argentineans and 3,000 Spanish/Portuguese, to assess generalizability of findings. We will examine the differences in inflammatory gene transcription dynamics in leukocytes (from blood sample collection) by fatigue level (as assessed from study questionnaire data). This study will have a high impact by addressing the key question of racial/ethnic disparities related to genetic susceptibility to CRC, will provide translational guidelines on biological mechanisms during the cancer survivorship period to increase quality of life among cancer survivors, and will enable further growth and investment into research among Hispanics by providing a resource of genetic data and biospecimens, which is lacking.

  Study phs001193

• Linguistic utterance counts for The admixture histories of Cabo Verde

  Datasets used in the article "The genetic and linguistic admixture histories of the islands of Cabo Verde" by Laurent R et al. eLife 2023 (DOI: https://doi.org/10.7554/eLife.79827 - URL: https://elifesciences.org/articles/79827) File name "eGAdeposit_225CaboVerde_FreeSpeech_Utterance_counts_FINAL_01062022.txt" Column 1 corresponds to individual alphanumeric codes as in the "eGAdeposit_233CaboVerde_GenotypeFile_FINAL_01062022.vcf" genotype file. Note that only 225 unrelated Cabo Verdean-born individuals are considered here, out of the 233 individuals in the genotype file. See Material and Methods in Romain Laurent et al. 2022 - doi pending Each 4831 other column correspond to the respective individual's utterance count in the free speech transcribed in ALUPEC and provided as column header. See See Material and Methods in Romain Laurent et al. 2022 - doi pendingColumn 1 corresponds to individual alphanumeric codes as in the "eGAdeposit_233CaboVerde_GenotypeFile_FINAL_01062022.vcf" genotype file. Note that only 225 unrelated Cabo Verdean-born individuals are considered here, out of the 233 individuals in the genotype file. See Material and Methods in Romain Laurent et al. 2022 - doi pending Each 4831 other column correspond to the respective individual's utterance count in the free speech transcribed in ALUPEC and provided as column header. See Material and Methods in Laurent R et al. eLife 2023

  Dataset EGAD00001008978

• Genetic Underpinnings of Ethnic Disparities in Bone Toxicities Between Hispanic and Non-Hispanic Children Treated for Acute Lymphoblastic Leukemia

  Acute lymphoblastic leukemia (ALL) is the most common malignancy among children and young adolescents. More than 90% of children are cured with a combination of multiple chemotherapeutic drugs. Some may suffer from debilitating toxicities due to the cytotoxic drugs, necessitating pharmacogenetic research to search for genetic markers predictive of treatment toxicities, so that treatment can be better tailored based on patients' genetic makeup. Bone toxicities, including osteonecrosis and fractures, most often due to glucocorticoids, are the most common complications in ALL, which have long-lasting detrimental impact on the still developing skeletons in children. In DFCI ALL Consortium Protocol 05-001, a multi-center clinical trial for childhood ALL conducted in Canada and the US, we found that Hispanic children had less drug toxicities to their bones than non-Hispanic children. Although reasons for the observed ethnic differences are largely unknown, patients' inherited genetic background may be at play. This study seeks to perform a novel pharmacogenomic study based on multi-site clinical trials DFCI ALL Consortium Protocol 05-001 and 11-001 to identify genetic underpinnings of ethnic disparities in bone toxicities.

  Study phs002317

• Clonally selected lines after CRISPR/Cas editing are not isogenic

  The CRISPR-Cas9 system has enabled researchers to precisely modify/edit the sequence of a genome. A typical editing experiment consists of two steps: (i) editing cultured cells and (ii) selection of clones, which are presumed to be isogenic, with and without the intended edit. The application of the CRISPR-Cas9 system may result in off-target edits, while cloning would reveal culture-acquired mutations. We analyzed the extent of the former and of the latter by whole genome sequencing (WGS) involving separate genomic loci in three experiments conducted by three independent laboratories. In all experiments we hardly found any off-target edits, while we detected hundreds to thousands of single nucleotide mutations unique to each clone after relatively short culture of 10-20 passages. Notably, clones also differed in copy number alterations that were several kb to several mb in size, representing the largest source of genomic divergence among clones. This study in dbGaP includes data from experiments carried out by investigators at the Oklahoma Medical Research Foundation and Baylor College of Medicine (OMRF/BCM) involving an iPSC line derived from fibroblasts of a female patient (line c7) carrying a constitutional heterozygous variant (chr1:1,464,679 C>T; GRCh37) in exon 15 of the ATPase family, AAA domain containing 3A (ATAD3A) gene. The parental line was edited by introducing a double stranded break at the variant allele to correct the variant by homology directed repair. Two unedited control clones (clone7 and clone8) and one edited clone (SC20) were selected for WGS.

  Study phs003110

• Differential gene expression in the colon mucosa of irritable bowel syndrome patients with diarrhea-predominant symptoms

  The aim of this study is to characterize the pathophysiology of the irritable bowel syndrome (IBS) on the functional level and in parallel on the gene expression level. For this purpose RNAseq of mucosal biopsies was performed. The data from the differential expression analysis will be further processed by Ingenuity Pathway Analysis (IPA) software to gather Information on activated or inhibited signaling pathways in the disease.

  Study EGAS50000000046

• Differential gene expression in the colon mucosa of irritable bowel syndrome patients with mixed type symptoms

  The aim of this study is to characterize the pathophysiology of the irritable bowel syndrome (IBS) on the functional level and in parallel on the gene expression level. For this purpose RNAseq of mucosal biopsies was performed. The data from the differential expression analysis will be further processed by Ingenuity Pathway Analysis (IPA) software to gather Information on activated or inhibited signaling pathways in the disease.

  Study EGAS00001004835

• Rare germline sequence variants, copy number variations, expression alterations, methylation variations and disease susceptibility in familial melanoma

  Although a number of high-risk melanoma genes have been identified, they account for melanoma risk in less than 40% of melanoma-prone families. The major goals of our research are to identify novel high-penetrance genes for familial melanoma in melanoma-prone families without known mutations and to identify modifier factors, including genetic and epigenetic, in melanoma-prone families with and without known major mutations. We are using whole exome sequencing to identify additional high-risk susceptibility genes and using targeted sequencing to follow up on the top genes in additional family members and in population-based melanoma cases and controls. We are also using RNASeq to investigate genome-wide allele-specific expression and eQTLs in these families to identify genes with expression alteration, which will provide additional information for gene discovery. In addition, we also conducted genome-wide copy number variation (CNV), methylation, and miRNA expression profiling analyses in our melanoma families with the goal of identifying genetic and epigenetic factors as disease modifiers.

  Study phs001177

• Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Victorian Collaborative AuTism Study (CATS): Family and Community Study of the Genetics of Autism Spectrum Disorder

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs002044

• The Jerusalem Perinatal Study (JPS) aimed to examine the developmental origins of cardiometabolic risk.

  The Jerusalem Perinatal Study (JPS) aimed to examine the developmental origins of cardiometabolic risk and explore the mechanisms underlying the associations between perinatal characteristics and the development of risk for adult chronic disease. In other words, the cohort has enabled the examination of associations between maternal and paternal characteristics with cardiometabolic risk variables in offspring at various points in the life course, as well as the effect of longitudinal changes in characteristics in both parents and offspring.

  Study EGAS00001004075

• HELIUS cohort

  The gut microbiota composition is unique to every individual but is shaped by common factors including diet, lifestyle, medication use, early-life determinants, living environment or genetics. Most of these factors may be influenced by ethnicity. This study explored variations in fecal microbiota composition in 6048 individuals with different ethnic backgrounds living in the same geographical area (Amsterdam, the Netherlands). The HELIUS data are owned by the Amsterdam University Medical Centers, location AMC in Amsterdam, The Netherlands. To allow sharing of microbiome data collected in HELIUS with (inter)national researchers, 16s rRNA sequence analysis has been stored at the European genome-phenome archive (EGA; accession code EGAD00001004106). This requires that access needs to be granted, also because the HELIUS data are stored with relevant phenotypical variables. Access is granted to all researchers affiliated with an internationally recognized research institution who request to use the HELIUS data within the EGA context, after having signed the data transfer agreement. Any researcher can request the data by submitting a proposal to the HELIUS Executive Board as outlined at http://www.heliusstudy.nl/en/researchers/collaboration, by email: heliuscoordinator at amsterdamumc dot nl. The HELIUS Executive Board will check proposals if they do not conflict with ethical approvals and informed consent forms of the HELIUS study.

  Study EGAS00001002969

• Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.

  Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

  Study EGAS00001001179

• Genetic_profiling_of_mucosal_melanoma

  Primary mucosal melanomas (MMs) arise from melanocytes located in mucosal membranes lining the respiratory, gastrointestinal and urogenital tracts. MMs frequently present late and have a poor prognosis; the 5-year survival rate is only 14%. MM makes up only ~1.4% of all melanomas and it is this rarity that makes knowledge of the genetic changes that contribute to its pathogenesis limited to a small number of exome/genome studies and other targeted studies. Thus to investigate the somatic alterations and mutation spectra in MM genomes, we have extracted genomic DNA from formalin-fixed, paraffin-embedded (FFPE) human MMs, and subjected them to whole exome sequencing. Given the propensity of MM to metastasize, we will also be sequencing metastatic MM lesions; primary and metastatic lesions from the same individual represent an excellent opportunity to identify potential drivers of metastasis in MM. Finally we will sequence ‘normal’ DNA from the same individual, where possible, to exclude germline variations.

  Study EGAS00001001115

• The Vaginal Microbiome: Disease, Genetics and the Environment

  The vagina is an interactive interface with the environment, and as such is covered by a protective epithelial surface. This surface is colonized by a biofilm consisting of bacteria and other microorganisms, which through a variety of mechanisms serve to protect the host from invasion by pathogens. Alterations in the normal vaginal microflora; i.e., dysbioses, particularly those associated with bacterial vaginosis, the most common disorder of the female reproductive tract, contribute to risk of sexually transmitted infections, infection by HIV, and are associated with increased risk of adverse pregnancy outcomes including but not limited to spontaneous preterm birth. Physiologic alterations in the host (e.g., menopause and pregnancy), which are beginning to be investigated as potential selective conditions for change in the "normal" vaginal flora, and their impact on disease susceptibility and transmission, remain to be more definitively elucidated. The effects of chronically abnormal physiologic states (e.g., diabetes mellitus) on normal vaginal flora have not been well described or studied. Finally, an almost unexplored area of inquiry is the genetic contribution, including race/ethnicity, to the establishment and maintenance of a "normal" vaginal flora, under normal and physiologically altered circumstances. Our research will shed light on how the vaginal microbiome contributes to adverse obstetrical outcomes and sexually transmitted infections in diverse populations. This project addresses the following questions: First: Do the genes of the host contribute to the composition of the vaginal microbiome? We hypothesize that a woman's genetic composition significantly affects the ability of certain commensal, parasitic and pathogenic microbes to colonize and/or infect the genital tract. Thus, we will compare and quantify the microbial populations inhabiting the vaginas of monozygotic and dizygotic twins from the Mid Atlantic Twin Registry, and, in the process, address the question of whether there is a relationship between the microbiomes of the vagina, mouth and GI tract. Second: What changes in the vaginal microbiome are associated with common physiological perturbations or non-infectious pathological states of the host?We hypothesize that "altered" physiologic (pregnancy, menopause) and pathologic (chronic disease, hysterectomy) conditions, or environmental "exposures" (exogenous hormones, antibiotics, chronic immunosuppressant, smoking; douching) can predictably alter the vaginal microenvironment. These alterations will lead to changes in microbial populations within the vagina. Changes in the microbial populations may have impacts, positive or more likely negative, on the spontaneous and future well-being of the affected individual. We are characterizing the effects of these "altered" physiologic and pathologic conditions, and environmental exposures, on the composition of the vaginal microbiome. Finally, we are examining the impact of the important physiological changes incurred during pregnancy on the composition of the microbiome of the female reproductive tract. Third: What changes in the vaginal microbiome are associated with relevant infectious diseases and conditions? We are testing the hypothesis that infectious diseases predictably alter the vaginal microbiome, and that these changes have an impact on the disease susceptibility, process, and outcome. A predilection for bacterial vaginosis, vaginitis, HIV infection, or other sexually transmitted diseases, is likely associated with a women's vaginal microbial composition. Thus, we will characterize samples from women with a variety of these infectious conditions to determine the contribution of their microbiomes to the disease process and susceptibility. We are addressing these questions using a combination of high throughput 'nextgen' sequencing technologies. Early studies were performed using the Roche 454 FLX and the first generation Illumina Genome Analyzer II instruments and more recently employing Illumina MiSeq and HiSeq 2500 and 4000 platforms, installed in the Genomics Core of the Nucleic Acids Research Facilities at VCU. Thus, segments of the 16S rRNA genes are amplified from the complex samples taken from various target sites in and around the vagina of each study participant. These segments are sequenced and subjected to taxonomic classification protocols to identify and quantify the bacterial taxa present in each sample. Additionally, total DNA isolated from these samples are subjected to shotgun sequence analysis to empirically reconstruct the metabolic potential of these microbiomes. Finally, specific bacterial clones are completely sequenced and analyzed to associate the unavoidable strain and isolate diversity with the clinical phenotypes presented.

  Study phs000256

• The Atherosclerosis Risk in Communities (ARIC) Study

  The Atherosclerosis Risk in Communities (ARIC) Study, sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective epidemiologic study conducted in four U.S. communities. The four communities are Forsyth County, NC; Jackson, MS; the northwest suburbs of Minneapolis, MN; and Washington County, MD. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date. ARIC includes two parts: the Cohort Component and the Community Surveillance Component. The Cohort Component began in 1987, and each ARIC field center randomly selected and recruited a cohort sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every three years with the first screen (baseline) occurring in 1987-89, the second in 1990-92, the third in 1993-95, and the fourth and last exam was in 1996-98. Follow-up occurs yearly by telephone to maintain contact with participants and to assess health status of the cohort. In the Community Surveillance Component, currently ongoing, these four communities are investigated to determine the community-wide occurrence of hospitalized myocardial infarction and coronary heart disease deaths in men and women aged 35-84 years. Hospitalized stroke is investigated in cohort participants only. Starting in 2006, the study conducts community surveillance of inpatient (ages 55 years and older) and outpatient heart failure (ages 65 years and older) for heart failure events beginning in 2005. ARIC is currently funded through January 31, 2012. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to atherosclerosis and cardiovascular disease through large-scale genome-wide association studies of well-characterized cohorts of adults in four defined populations. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000090

• HDAC inhibitors in synovial sarcoma cells

  Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-Seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell cycle arrest, neuronal differentiation and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb-group targets were reactivated including tumor suppressor CDKN2A, and pro-apoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and pro-apoptotic factors BIK, BIM and BMF were important to apoptosis induction following HDAC-inhibition in synovial sarcoma

  Study EGAS00001002637

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

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

  Study JGAS000179

• Associations between APOE status and cognitive ability across the lifecourse

  The association between APOE genotype and cognitive function suggests a positive role for the e2 allele and a negative role for the e4 allele. Both alleles have relatively low frequencies in the general population, hence meta-analyses have been based on many small, heterogeneous studies. Here we report the APOE-cognition associations in the largest single analysis to date. APOE status and cognitive ability were measured in 18,337 participants from the Generation Scotland study between 2006 and 2011. The age range was 18-94 years with a mean of 47 (SD 15). Four cognitive domains were assessed: verbal declarative memory (paragraph recall), processing speed (digit symbol substitution), verbal fluency (phonemic verbal fluency), and vocabulary (Mill Hill synonyms). Linear regression was used to assess the associations between APOE genetic status and cognition. Possession of the e4 allele was associated with lower scores on the measures of memory and processing speed in subjects aged >60. Across all age ranges, the e4 allele was linked to better verbal fluency scores. In younger subjects (≤60 years) the e4 allele was linked to higher vocabulary scores. There were no associations between the e2 allele and cognitive ability. As seen in previous meta-analyses, the APOE e4 allele is linked to poorer cognitive performance in the domains of memory and processing speed. By contrast, positive associations were seen between the e4 allele and measures of verbal fluency and vocabulary. All associations were relatively small and, in many cases, nominally significant despite the very large sample size.

  Study EGAS00001001235

• Mutations in SPINK2 induce azoospermia

  Azoospermia, characterized by the absence of spermatozoa in the ejaculate is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility. Further analysis demonstrated that in the absence of Spink2, protease-induced stress initiates Golgi fragmentation and prevents acrosome biogenesis leading to spermatid differentiation arrest. We also observed a deleterious effect of acrosin overexpression in HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 is necessary to neutralize proteases during their cellular transit towards the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes.

  Study EGAS00001002450

• Out with the Java, in with the Python - new EGA data download client unveiled

  We will shortly be deprecating the Java-based download client also known as API V2. The Java client began its life at the back end of 2014, and during its time has seen many developments that have served our users well. During its tenure, the Java client enabled distribution of over 6.5 million files totalling nearly 15 petabytes of data to researchers around the globe. Recent increases in genomic and phenotypic data file sizes, the number of datasets archived in the EGA, the number of users downloading data, and the diversity of download locations has meant that at times the Java client struggled to distribute data efficiently. In response, our team of developers have built a new download client with more robust features and better functionality and reliability. Enter stage left our shiny new API V3.1! The new API V3.1 will replace both API V2 and API V3. The download client for the new API V3.1 is written in Python, and the code is openly available on Github. This Python client makes https calls to the EGA AAI (https://ega.ebi.ac.uk:8443/) and to the EGA Data API (https://ega.ebi.ac.uk:8052), both of which must be accessible from the client location. In addition to general updates to improve performance, the API V3.1 has three new features enhancing the EGA distributions services. First, requested data are now downloaded over secure https connections rather than http, meaning that data can be delivered unencrypted. Instead of separately requesting, downloading, and decrypting data using the Java client, data can now be requested and downloaded using a single command without the need for decrypting. The API V3.1 also automatically verifies each file’s unencrypted md5 after download to ensure the file has downloaded correctly. Second, the new API supports segmenting and automatic resuming. To enable quicker download speeds, the API breaks files into up to four segments and downloads them in parallel. With the new resume feature, downloads - both segmented and continuous stream - will automatically resume if they encounter any errors or the connection is interrupted. These features result in both a faster and more reliable download experience. Finally, the new API V3.1 implements the GA4GH-compliant htsget protocol for supporting requests over genomic ranges. This exciting new feature means that for data files with accompanying index files (e.g. .crai for CRAM files) users can download specific regions of interest rather than the entire file saving both time and storage space. The new features of the Python-based API V3.1 represent significant improvements in security, speed, reliability, and flexibility that are sure to provide a better data download experience. To take full advantage of these features, users must update to Python 3.X. Considering the changes in the data structures with the new API, the upgrade to a new version of the Python client is also mandatory. Updating the client to the latest version can be achieved by running the following command: pip3 install pyega3 -U We are excited for users to try out the new features and take advantage of the multifariously growing EGA distribution services for human biomedical omics data. If you have any questions or feedback, please email the EGA Helpdesk team. We'd love to hear from you!

  Blog new-ega-data-download-client

• Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer

  Mutations in the TERT promoter are the single most common non-coding mutation in cancer and represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, G228A and G250A, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants in the TERT promoter are unknown. We identified duplications of wildtype sequence within the core promoter region of TERT in 7 different cancer types that have strikingly similar features including size, insertion position, and inclusion of one of the native ETS motifs. Each duplication activates the TERT promoter to a similar level as G228A and G250A and is critically dependent on the insertion site. The GABP tetramer binds to the TERT duplicated promoter sequence by virtue of the native ETS motif and its duplicated version with precise spacing, and it is necessary for the transcriptional activation by all duplications tested. Spatiotemporal analysis in a multifocal glioblastoma shows the duplication is clonal and its activation of TERT is readily detectable at the single cell level and in bulk tumor tissue. We conclude that recurrent TERT promoter duplications of the native ETS sequence are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

  Study EGAS00001006118

• Y chromosome variability in Polish population

  The aim of the present study was to define the Y chromosome variability in Polish male population. For the first time, the study of Polish population was conducted on such a large number of individuals (n=2705) representing administrative units of both levels of local administration in Poland (voivodeships and counties). Furthermore, the clusters were used as an additional form of population subdivision, corresponding to geographic regions of Poland.

  Study EGAS00001004111

• Microbiota and Complications in Kidney Transplant Recipients

  In this study, we investigated the role of the gut microbiota on the development of complications in kidney transplant recipients. We collected serial fecal specimens from 168 kidney transplant recipients within the first 3 months after transplantation. We performed 16S rRNA gene sequencing of the V4-V5 hypervariable region and examined whether the relative gut abundance of pathogenic bacteria was associated with future development of complications like bacteriuria and urinary tract infections. In a subset of samples, we performed metagenomic sequencing of stool and urine supernatant specimens to determine strain level analysis. We collected an additional 5 fecal specimens from 5 kidney transplant recipients to evaluate the gut microbiota's ability to convert inactive mycophenolic acid glucuronide to active mycophenolic acid and fecal specimens from one kidney transplant recipient several years after transplantation.

  Study phs001879

• Mechanism of Action of Vitamin E in NAFLD

  We conducted a single-center prospective mechanistic randomized trial (clinicaltrials.gov NCT01792115). Adult patients with NAFLD were enrolled between May 2013 and November 2016. All patients underwent a 12 weeks run-in period of lifestyle intervention. Following the run-in phase, patients underwent a baseline evaluation including blood tests, glucose tolerance testing, measurement of liver fat content by 1H-magnetic resonance spectroscopy (MRS) and a percutaneous liver biopsy. Patients with no evidence of NAFLD on the entry liver biopsy ended their participation in the study at that point. Patients with histological confirmation of NAFLD (either NAFL or NASH) on the baseline biopsy were randomized at a 1:1:1 ratio to receive one of 3 doses of natural vitamin E (RRR-alpha-tocopherol, Pharmavite), 200, 400 or 800 IU/d, for 24 weeks, and were followed at a 1-8 week intervals in a parallel assigned design. While on vitamin E treatment, patients were encouraged to continue and adhere to the lifestyle and dietary guidelines of the run-in phase. On week 4 of vitamin E treatment, a repeat MRS and liver biopsy were performed. On week 24, a final MRS was performed to assess treatment response. The primary endpoint was the reduction of liver fat content by MRS from baseline (immediately prior to starting vitamin E) to week 24 of treatment, and a response was defined as a relative reduction of ≥25% in liver fat content by MRS between baseline and week 24. Early changes in the hepatic transcriptome were investigated at week 4 comparing non-responders to responder in a nested design.

  Study phs001930

• CARE idiopathic subglottic stenosis bulk transcriptomics.

  Idiopathic subglottic stenosis (iSGS) is a severe chronic orphan disease characterised by recurrent scarring of the subglottis, predominantly affecting Caucasian females in their fourth to sixth decade of life. Due to its rarity, understanding the clinical trajectory and molecular factors involved in iSGS disease development and prognosis has been challenging. In this study, we prospectively enrolled patients with iSGS, trauma-induced subglottic stenosis, and controls to investigate the clinical, transcriptional, and genetic features that may be associated with disease pathogenesis and treatment outcomes.

  Study EGAS50000000879

• Germline variant analysis in childhood AML

  Analysis of rare germline variants in childhood AML in a large panel of cancer predisposition genes (n=216) compiled from literature review, and including genes involved in familial hematological malignancies (HM) and bone marrow failure (BMF) syndromes. The prevalence of extremely rare variants in the combined childhood AML cohort (n=72) was compared to that in the Medical Genome Reference Bank (MGRB; n=2570) comprising individuals aged at least 70 years with no history of cardiovascular disease, dementia or cancer. This showed a significant increase of rare alleles in childhood AML for 100% of subset comparisons. Next additional stringent filtering was applied to determine predicted damaging germline predisposition variants. Overall, 21% of the Australian cohort and 25% of the TARGET cohort presented germline variants predicted to be damaging predisposition variants.

  Study EGAS00001006276

• Whole_genome_sequence_of__third_generation_family_member__SFHS_

  Previously we performed deep WGS on 6 parents and 13 children from 3 large families from the Scottish Family Health Study to identify de novo mutations. This prelim is cover the additional sequencing of one grandchild from one of these three families. The inclusion of a third generation individual will provide additional experimental validation for the de novo mutations found in the initial trio. As in the previous study, the DNA will be WGS to a depth of approximately 25X to achieve this purpose.

  Study EGAS00001000429

• SCANDARE MACARON

  Among gynecological cancers, high-grade serous ovarian cancer has the highest prevalence and more than 75% of patients have advanced stage at diagnosis with a 5-year survival of 40%. When the initial complete surgical removal is not possible (60% of patients), an interval surgery can be considered after three to four cycles of neoadjuvant chemotherapy to reduce the tumor mass. However, in approximately 50% of cases the tumor has little or no response to neoadjuvant chemotherapy. Therefore, identification of potential drug targets, biomarkers and/or pathways whose modulation can help in the prevention, interception, or curing of the disease is essential to address the unmet need. Therefore, MACARON project aims to address these issues through the identification of shared neoantigens arising out of somatic alterations and aberrant transcriptional programs in ovarian cancer DNA/RNA datasets.

  Study EGAS50000000145

• Early Family Prevention of Adolescent Alcohol, Drug Use, and Psychopathology

  The Early Steps Multisite Study is comprised of researchers from the University of Virginia, the University of Pittsburgh, Arizona State University, and Oregon Research Institute. This longitudinal study has been funded by the National Institute on Drug Abuse at the National Institutes of Health since 2002. The Early Steps Multisite Study conducted a randomized control trial to examine the effects of an intervention program called the Family Check-Up (FCU) offered in early to middle childhood. Outcomes include problem behaviors including substance use. Primary caregivers (PC) and their children (TC) were recruited from Women, Infant, and Children's (WIC) Nutritional Supplement centers in and around Pittsburgh, PA, Eugene, OR and Charlottesville, VA when target participating children were age 2. Participants were screened in three key areas of risk for later child conduct problems: (1) sociodemographic risk (e.g., poverty, teen parent status), (2) family risk (e.g. maternal stress, depressive symptoms), and (3) child conduct problems. Randomization to the intervention condition was balanced on gender to assure an equal number of males and females in the control and intervention groups. Data submitted to dbGaP are from the 515 subjects who were consented to provide a saliva sample.

  Study phs003442

• NHLBI GO-ESP: Family Studies (Familial Interstitial Pneumonia)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The Familial Interstitial Pneumonia (FIP) project seeks to identify genetic variants in coding regions of the human genome that are linked to FIP by examining the coding regions among relatives with FIP. These data will be used in conjunction with our other genetic studies to help us better understand how and why some individuals develop pulmonary fibrosis.

  Study phs000582

• Fragmentation signatures in cancer patients are similar to those in patients with vascular and autoimmune diseases

  The analysis of fragmentation patterns in plasma cell-free DNA (cfDNA) has been shown to distinguish individuals with cancer from healthy controls in multiple case-controlled studies. However, there have been few studies that investigate various types cfDNA fragmentomics patterns in individuals with other diseases. For this purpose, we developed a comprehensive metric, called fragmentation signatures, that integrated the distributions of fragment positioning, fragment length, and fragment end-motifs. Using this metric, we found that individuals with venous thromboembolism, systemic lupus erythematosus, dermatomyositis, or scleroderma had cfDNA fragmentation signatures that closely mimicked those found in individuals with advanced cancers. Furthermore, these signatures were highly correlated with increases in inflammatory markers in the blood. Though these data put substantial limitations on the specificity of fragmentomics-based tests for cancer diagnostics, they also offer ways to improve the interpretability of such tests. Moreover, they should lead to a better understanding of the cells – most likely inflammatory cells - from which plasma cfDNA is derived.

  Study EGAS00001008004

• Integration of Clinical and Molecular Biomarkers for Melanoma Survival (Berwick)

  The long-term goal of the InterMEL Program Project: Integration of Clinical and Molecular Biomarkers for Melanoma Survival is to identify molecular and clinical factors that predict survival of melanoma patients. Our overarching hypothesis is that we can identify factors in the primary melanoma tumor that will lead to more aggressive disease. Melanoma patients diagnosed at American Joint Committee on Cancer (AJCC) tumor, lymph nodes, and metastases (TNM) stages IIA/IIB/IIC/IIIA/IIIB/IIIC/IIID display highly variable clinical outcomes and responses to therapy. We wish to identify robust and reproducible biomarkers or sets of classifiers that distinguish patients likely to have poor prognosis. These biomarkers will help establish targets for adjuvant therapies for this set of patients before the tumors metastasize. Aim 1. Classify actionable somatic mutations, and copy number variations (CNVs) in relationship to melanoma survival. In Project 1, Targeted Sequencing and Clinicopathology to Evaluate Primary Melanoma Molecular Subtypes and Outcomes, we will profile 468 genes using the MSKIMPACT ™ assay and identify somatic mutations and CNVs associated with melanoma-specific survival, as well as their co-occurrence with other mutations, in 1,000 tumors from patients at AJCC TNM stages IIA-IIID: approximately 500 from patients who died with melanoma within five years and approximately 500 from individuals who have lived at least five years. We will also evaluate the joint effects of somatic mutations, CNVs and pathologic characteristics associated with good and poor outcomes. Aim 2. Identify primary melanoma DNA methylation profiles to evaluate subtypes and survival. Although it has been established that melanomas frequently have aberrant DNA methylation, it is unknown if DNA methylation in primary melanomas predicts outcome. In Project 2, Primary Melanoma DNA Methylation Profiling for Evaluating Subtypes and Survival, we will profile the same primary melanomas as in Project 1 with Illumina Infinium 850K methylation arrays. We expect to: identify and characterize DNA methylation-based melanoma subclasses; train, test and validate a CpG signature prognostic for survival from melanoma; determine whether this profile adds information to outcome prediction beyond AJCC TNM staging. This project is based on the hypothesis that DNA methylation in primary melanoma will define subgroups (including a poor-prognosis CIMP – ‘CpG island methylator phenotype' subtype) and that a CpG signature will be prognostic for melanoma survival. Aim 3. Define microRNA expression changes in relation to melanoma survival. MicroRNAs have been associated with poor prognosis in melanoma, as well as in other cancers. In Project 3, Prognostic and Functional Role of a Gene Expression Signature in Melanoma Patients, we hypothesize that altered miRNA expression, captured at the time of diagnosis, may contribute to the aggressive behavior of a subset of early stage primary melanomas. We will profile the same primary melanomas as in Projects 1 and 2 with a Nanostring assay. This project will define and validate a tissue-based microRNA signature in conducted to determine whether the prognostic miRNA signature, as well as other candidate genes emerging from other projects, contribute to melanoma survival. Aim 4. Integrate data from multiple platforms to identify melanoma subtypes and survival. Despite substantial literature on gene tumor mutation-, methylation- and gene expression-based prognostic and predictive signatures for melanoma, few such signatures are used in clinical practice. Project 4, Multiplatform Analysis of Melanoma Molecular Subtypes and Patient Survival Outcome, will use novel integrative clustering methods to identify molecular subtypes of melanoma jointly defined across these platforms.

  Study phs003099

• UK10K_OBESITY_GS

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The GS samples are part of the Obesity group and will undergo exome sequencing.

  Study EGAS00001000242

• Defined Lifestyle and Germline Factors Predispose Asian Populations to Gastric Cancer

  Gastric cancer (GC) is one of the leading causes of cancer mortality throughout the world, with the highest incidence in east-Asia. Although the somatic genetics of GC has extensively been characterized by recent advances in cancer genome sequencing, the germline and environmental effects on GC and their ethnic differences have poorly been understood. Here, we performed genomic scale trans-ethnic analysis of 531 GC cases (319 Asian and 212 non-Asians), by integrating east-Asian and public GC datasets. There is one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, and almost all the cases in the subclass are attributable to alcohol intake behavior, smoking habit, and Asian-specific ALDH2 defective allele. Alcohol-related GCs have low mutation burden and a characteristic immune profile of increased B-cell infiltration into the tumor area in relation to cancer cell-intrinsic CXCL13 chemokine expression. In addition to germline variants of genes involved in BRCA pathways, we found frequent (7.4%) germline CDH1 variants among Japanese GCs. Most of them were attributed to a few recurrent SNVs shared by both Japanese and Koreans, suggesting the existence of common ancestral events and widespread distributions of these pathogenic variants among east-Asian populations. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective-ALDH2 allele or to germline CDH1 variants. These results revealed uncharacterized impacts of germline variants and their interplays with lifestyles in the high incidence areas.

  Study JGAS000229

• Defined Lifestyle and Germline Factors Predispose Asian Populations to Gastric Cancer

  Gastric cancer (GC) is one of the leading causes of cancer mortality throughout the world, with the highest incidence in east-Asia. Although the somatic genetics of GC has extensively been characterized by recent advances in cancer genome sequencing, the germline and environmental effects on GC and their ethnic differences have poorly been understood. Here, we performed genomic scale trans-ethnic analysis of 531 GC cases (319 Asian and 212 non-Asians), by integrating east-Asian and public GC datasets. There is one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, and almost all the cases in the subclass are attributable to alcohol intake behavior, smoking habit, and Asian-specific ALDH2 defective allele. Alcohol-related GCs have low mutation burden and a characteristic immune profile of increased B-cell infiltration into the tumor area in relation to cancer cell-intrinsic CXCL13 chemokine expression. In addition to germline variants of genes involved in BRCA pathways, we found frequent (7.4%) germline CDH1 variants among Japanese GCs. Most of them were attributed to a few recurrent SNVs shared by both Japanese and Koreans, suggesting the existence of common ancestral events and widespread distributions of these pathogenic variants among east-Asian populations. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective-ALDH2 allele or to germline CDH1 variants. These results revealed uncharacterized impacts of germline variants and their interplays with lifestyles in the high incidence areas.

  Study JGAS000228

• Cellular and Molecular Investigations of Human Hearts

  We aim to discover gene regulatory networks that govern heart morphogenesis in the early fetal heart. To this end, we have performed single-nucleus ATAC-seq on cells derived from 2 human hearts at 15 weeks post conception to define the chromatin profiles and genomic regulatory networks for these in vivo specific cardiomyocyte lineages during development, from which the FASTQ files are available through dbGAP. This information will help us understand the process of heart morphogenesis early in development and may further our understanding of how congenital heart disease impacts development.

  Study phs003473

• Gene-Environment Interactions in COCCaINE Use Disorder: Collaborative Case-Control Initiative in Cocaine Addiction

  Drug addiction is a phenotype that has high heritability estimates. In recent years, association studies of candidate genes and some genome-wide association studies (GWAS) have identified a large number of SNPs associated with substance use, abuse or dependence, particularly in phenotypes related to alcohol and nicotine use. Regarding snorted or smoked cocaine dependency, only one GWAS has been conducted so far. In addition, genetic association studies that specifically evaluated smoked cocaine dependence (e.g. crack) are rare, because of characteristics related to the route of administration and duration of the effect of the drug. Thus, the main aim of this GWAS was to identify genetic variations that modulate the risk for the cocaine dependence.

  Study phs001810

• RODAM cohort

  The RODAM study assesses the health and wellbeing of Ghanaian residents in Ghana and Europe and follows them up over time. With this unique approach the RODAM study attempts to unravel the causes of cardiovascular disease and its risk factors among African migrants in Europe and non-migrants sub-Saharan Africa. Fecal samples from RODAM participants in rural, urban Ghana and Amsterdam, the Netherlands were sequenced using 16S rRNA sequencing to assess gut microbiome differences between research sites.

  Study EGAS50000000805

• Biased allelic expression in human primary fibroblast single cells.

  The study of gene expression in mammalian single cells using genomic technologies now provides the possibility to investigate the patterns of allelic gene expression. We have used single-cell RNA sequencing to detect the allele-specific mRNA level in 203 single human primary fibroblast cells over 133,633 unique heterozygous single nucleotide variants (hetSNVs). We have observed that at the snapshot of analyses each cell contains mostly transcripts from one allele from the majority of genes; indeed 76.4% of the hetSNVs display stochastic monoallelic expression in single cells. Remarkably, adjacent hetSNVs exhibit haplotype consistent allelic ratio; in contrast distant sites located in two different genes are independent of the haplotype structure. Moreover, the allele-specific expression in single cells correlated with the abundance of the cellular transcript. We observed that genes expressing both alleles in majority of the single cells at a given time point are rare and enriched in highly expressed genes. The relative abundance of each allele in a cell is controlled by some regulatory mechanisms since we observed related single-cell allelic profiles according to genes. Overall, these results have direct implications in cellular phenotypic variability.

  Study EGAS00001001009

• Multi-omic characterisation of PBMCs in IBD

  We generated 10X, droplet-based Multiome (paired RNA+ATAC) data of PBMCs in 38 IBD patients. Patients are either UC or CD patients. To test the responsiveness of the cells to bacterial stimuli, we stimulated samples with either RPMI, LPS or S. Salmonella (total: 80 samples). Single-nuclei libraries are multiplexed across donors. Genotypes are provided in this dataset to perform genetic demultiplexing, phenotypes providing mapping information to retrace donors / pools / stimulations.

  Study EGAS50000000140

• Genomics of Circulating Tumor Cells

  Comprehensive analyses of cancer genomes in clinical settings promise to inform prognoses and guide the deployment of precise cancer treatments. A major barrier, however, is the inaccessibility of adequate metastatic tissue for accurate genomic analysis in prostate and other cancers. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming multiple technical hurdles. Here, we report an integrated process to isolate, qualify, and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of over 99.995% of the territory accessible in bulk exome sequencing is possible in CTCs. We validated our sequencing process in two prostate cancer patients including one for whom we compared CTC-derived mutations to mutations found in a lymph node metastasis and nine cores of the primary tumor. 51 of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early trunk mutations and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

  Study phs000717