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• NIDA Genetic Epidemiology of Opioid Dependence in Bulgaria (GEODB)

  The study was conducted in Bulgaria as a collaboration between the Molecular Medicine Center (Medical University, Sofia), the Bulgarian Addictions Institute (Sofia), the Initiative for Health Foundation (Sofia) and Washington University School of Medicine (Saint Louis, MO, USA). This is a case-population control study. Participants (N=2,499 interviews; N=1,995 with GWAS data) in our study are primarily active heroin users (78%) aged 18 and over, with a median 8.9 years of daily heroin use (minimum of 12 months). Virtually all participants (99.1%) qualified for a lifetime DSM-IV diagnosis of dependence, symptom endorsement probabilities ranging from 77% to 99.3%; and 61% endorsing all symptoms. 85% were heroin injectors and 97% reported using (or having used) heroin daily. Anonymized, population-representative control samples (no phenotypic data, N = 1,062 with GWAS data) were drawn from the MMC repository. Unlike other studies, where samples are clinically ascertained (e.g., from ORT programs), our participants are primarily untreated. PTSD, major depression, suicidality, mania, alcohol, nicotine and substance dependence (separating heroin and opioids) were assessed using the MAGIC (Todd et al., 2003, PMID: 14627881), a broad semi-structured psychiatric assessment tool with good reliability and prospective stability. The onset of (any) illicit drug use in this sample is not particularly remarkable (age~16), but the age of onset of heroin use is much lower than in the USA: 25% by age 16; 50% by age 19, with no differences between ethnicities or gender. This is consistent with findings from other studies in Bulgaria. In contrast, in 2008, SAMHSA estimated an average age of 23.4 for new heroin initiates in the USA. Further, progression from first use to regular use appears to be more rapid, with the majority of participants reporting onset of dependence problems within one year of initiation. Another unique aspect of this study population are the comparatively low levels of polysubstance use (outside of nicotine and alcohol). This early-use, fast-transition and monosubstance heroin pattern stands in sharp contrast to what is reported in many studies in the Western World. In our study, 47% of Ethnic Bulgarians and 66% of Roma used only opioids, even years after the onset of drug use. 15.4% of Ethnic Bulgarians and 66.2% of Roma reported heroin as the very first illicit drug used. Lifetime, 12.5% of Ethnic Bulgarians and 52.8% of Roma report never having used another illicit drug other than heroin more than five times. While both Roma and Ethnic Bulgarians certainly experiment with other drugs, abuse/dependence rates for these drugs are low in Ethnic Bulgarians (from 8.4% for inhalants to 28% for stimulants) and in the Roma population (from 1.3% for hallucinogens to 11.2% for stimulants).

  Study phs001804

• PE-CGS: Optimizing Engagement of Hispanic Colorectal Cancer Patients in Cancer Genomic Characterization Studies

  Colorectal Cancer (CRC) is the second leading cause of cancer death in the US. Hispanic/Latinos (H/L) are the largest and fasting growing ethnic group in the US, and cancer is the leading cause of death among H/L in the US. Therefore, we need to fully understand the full complexity of the molecular etiology of cancer in this ethnic group. For instance, although incidence rates of CRC are lower among Latinos as compared to Whites or African Americans, Hispanics with metastatic disease have shorter overall survival when adjusted for health care setting, demographics, disease characteristics and treatment factors. H/L also tend to be diagnosed at a younger age and with higher stage, and we have previously reported that Mexican H/L in California have the greatest proportion of young (The Cancer Genome Atlas has provided a deep overview of the molecular taxonomy of CRC in 594 cases, however, less than 1% of the cases (n=5) were H/L. Therefore, it is imperative for us to take more detailed assessment of the molecular genomic landscape of CRC in H/L. One of the major issues likely limiting our ability to perform these large genomic initiatives in minority patients is that Patient or Participant Engagement practices may not be investigated to identify best practices for accruing and consenting patients into clinical translational biomedical research studies. This concept of Participant Engagement is critically important for both the patients and the translational cancer research community. Optimizing and improving our approaches for directly engaging patients at initial contact, throughout the course of a translational genomic study, and during the time of return of results is likely to lead to stronger relationships between the medical community and patients, but could also lead to significant improvement in outcomes for patients and for the cancer care community as a whole. As such, we propose the creation of the USC Center for Optimization of Participant Engagement in Cancer Characterization (COPECC) with a focus on optimizing the engagement of Latinos in CRC Genomic Characterization research studies. USC COPECC would serve as a member of the NCI U2C Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Our investigative team includes experts in all relevant areas of research for genomic characterization, participant engagement, and engagement optimization. We have an established platform for consenting patients into cancer genomics studies that will serve as a standard process. The overall goal of USC COPECC is to generate results on participant engagement optimization and CRC genomic research that will be shared with the broader community to distribute best practices for engaging Latinos in hopes of improving overall outcomes for CRC in this underserved population.

  Study phs003985

• NHLBI TOPMed: San Antonio Family Heart Study (SAFHS)

  The San Antonio Family Heart Study (SAFHS) is a complex pedigree-based mixed longitudinal study designed to identify low frequency or rare variants influencing susceptibility to cardiovascular disease, using whole genome sequence (WGS) information from 2,590 individuals in large Mexican American pedigrees from San Antonio, Texas. The major objectives of this study are to identify low frequency or rare variants in and around known common variant signals for CVD, as well as to find novel low frequency or rare variants influencing susceptibility to CVD. WGS of the SAFHS cohort has been obtained through three efforts. Approximately 540 WGS were performed commercially at 50X by Complete Genomics, Inc (CGI) as part of the large T2D-GENES Project. The phenotype and genotype data for this group is available at dbGaP under accession number phs000462. An additional ~900 WGS at 30X were obtained through Illumina as part of the R01HL113322 "Whole Genome Sequencing to Identify Causal Genetic Variants Influencing CVD Risk" project. Finally, ~1,150 WGS at 30X WGS were obtained through Illumina funded by a supplement as part of the NHLBI's TOPMed program. Extensive phenotype data are provided for sequenced individuals primarily obtained from the P01HL45522 "Genetics of Atherosclerosis in Mexican Americans" for adults and R01HD049051 for children in these same families. Phenotype information was collected between 1991 and 2016. For this dataset, the SAFHS appellation represents an amalgamation of the original SAFHS participants and an expansion that reexamined families previously recruited for the San Antonio Family Diabetes Study (R01DK042273) and the San Antonio Family Gall Bladder Study (R01DK053889). Due to this substantial examination history, participants may have information from up to five visits. The clinical variables reported are coordinated with TOPMed and include major adverse cardiac events (MACE), T2D status and age at diagnosis, glycemic traits (fasting glucose and insulin), blood pressure, blood lipids (total cholesterol, HDL cholesterol, calculated LDL cholesterol and triglycerides). Additional phenotype data include the medication status at each visit, classified in four categories as any current use of diabetes, hypertension or lipid-lowering medications, and, for females, current use of female hormones. Anthropometric measurements include age, sex, height, weight, hip circumference, waist circumference and derived ratios. PBMC derived gene expression assays for a subset of ~1,060 individuals obtained using the Illumina Sentrix-6 chip is also available from the baseline examination. The WGS data have been jointly called and are available in the current TOPMed accession (phs001215).

  Study phs001215

• Genome-Wide Association Study of Breast Cancer in the African Diaspora - the ROOT study

  The paucity of data on the genetic epidemiology of breast cancer for racial/ethnic groups other than those of European ancestry hinders the development of innovative interventions to reduce health disparities. Women in the African Diaspora experience a disproportionate burden of pre-menopausal breast cancer in comparison to all other races for reasons that remain unknown and understudied. This higher proportion of early-onset breast cancer might suggest a stronger genetic component in these populations. Genome-wide association studies (GWAS) have revealed several genetic loci that confer risk of breast cancer. Because all GWAS started the discovery stage in women of European ancestry and replicated mainly in women of European ancestry, we propose a novel approach for a GWAS in indigenous African women to identify alleles associated with breast cancer risk which will then be replicated in other populations. This innovative design builds on our current understanding of the etiologic heterogeneity in breast cancer and the distribution of breast cancer molecular subtypes which differ between women of African ancestry and women of European ancestry. The major objective of the proposed studies is to get to the "root" causes of breast cancer by identifying breast cancer risk alleles in a pooled sample of women of African ancestry and to replicate our findings in other populations. To achieve this objective, we conducted a case control study of breast cancer in women of African ancestry, including Africans living in Nigeria, African Americans and African Barbadians. We will genotype ~3800 individuals using the Illumina HumanOmni2.5-Quad platform. We will conduct both standard and novel genetic analyses of the data to map genes associated with breast cancer susceptibility, verify genotyping and carry out fine-mapping studies in genes or regions showing association with breast cancer risk, and replicate in other African American and non-African American populations. By pooling unique resources from studies throughout the African Diaspora, this study has the potential to identify risk alleles in several genes that contribute to increased breast cancer risk and may have implications for early detection, prognosis and treatment of breast cancer in ALL women. This should ultimately lead to improved outcomes for those who suffer a disproportionate burden of early-onset breast cancer.

  Study phs000383

• (Epi)genetic Risk Architectures of Opioid-Dependent Brain

  With nearly 20,000 overdose deaths in 2014 alone, opioid addiction (OA) has emerged as one of the most pressing public health crises in recent US history. One-fifth of individuals who try heroin develop an addiction to opioids. Genetics is a major contributor to OA with an estimated 60% heritability, only somewhat less than schizophrenia (80%) which has recently seen substantial gains in identified underlying genetics. Yet, studies to date have failed to uncover most of the genes that predispose individuals to OA, leaving the overwhelming fraction of OA heritability unexplained. The proposed study takes a novel, integrated "omics-based" strategy to investigate the molecular basis of OA and uncover both genetic and epigenetic factors associated with opioid addiction. The premise for our approach is founded on studies from our labs, and others, implicating regulatory variation in common traits and diseases, including those associated with complex brain phenotypes like addiction. We have collected the largest known cohort of postmortem brains from addicts who overdosed on opioids, along with matched control brains from non-users. From both cases and control specimens, we will isolate cells from 2 regions of the brain closely implicated in the addiction phenotype: the Prefrontal Cortex (PFC) and the Nucleus Accumbens (NAc). In Aim 1, we propose ChIP-seq studies to identify regulatory elements that distinguish cases from controls and define the opioid addiction phenotype. The regulatory differences will be connected to their gene targets through high resolution in situ Hi-C. In Aim 2, we propose QTL-based approaches to identify genetic variants that underlie the regulatory differences (hmQTLs). We also propose eQTL analyses to identify genetic variants that underlie differences in transcript levels between cases and controls. Aim 3 leverages the largest heroin addiction GWAS meta-analysis to date to test the hypothesis that SNPs in regions associated with chromatin and expression differences between cases and controls define novel loci for predisposition to OA. Each Aim has the potential for discovery independent of the others (differential HM, RNAexp, QTLs, and variant-phenotype associations) but their synergy is the most powerful component of the proposed study: identifying regulatory pathways that generate, not only phenotype associations, but hypothesized mechanisms for those associations which can be the focus of new opioid addiction prevention and treatment development.

  Study phs002724

• The genomic complexity of early T-cell progenitor acute lymphoblastic leukemia

  CREST The accurate identification of structural variations using whole-genome DNA sequencing data generated by next-generation sequencing technology is extremely difficult. To address this challenge, we have developed CREST, an algorithm that uses sequencing reads with partial alignments to the reference human genome (so-called soft-clipped reads) to directly map the breakpoints of somatic structural variations. We applied CREST to paired tumor/normal whole genome sequencing data from five cases of T-lineage acute lymphoblastic leukemia (T-ALL). A total of 110 somatic structural variants were identified, >80% of which were validated by genomic PCR and Sanger sequencing. The validated structural variants included 31 inter-chromosomal translocations, 19 intra-chromosomal translocations, one inversion, 22 deletions and 16 insertions. A comparison of the results generated with CREST to those obtained using the traditional paired-end discordant mapping methods demonstrate CREST to have a much higher sensitivity and specificity. In addition, application of CREST to publicly available whole-genome sequencing data from the human melanoma cancer cell line COLO-829 demonstrated the identification of 50 novel structural variations not detected using the standard methods, 20 of which were selected for validation with a 90% success rate. These data demonstrate that direct mapping of soft-clipped reads offers an improved method for detecting structural variants at the nucleotide level of resolution. T-ALL Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

  Study phs000340

• The Effect of the Menstrual Cycle on DNA Expression in the Normal Human Breast Epithelium

  The Susan G. Komen for the Cure® Tissue Bank at the IU Simon Cancer Center [www.komentissuebank.iu.edu] (KTB) was established expressly for the prospective collection of normal, healthy breast tissue from volunteer donors. Blood is also obtained from donors at the time of donation and is processed for serum, plasma and peripheral blood leukocyte DNA. Specimens are annotated and data includes age, race, ethnicity, personal health history, family cancer history, medication usage at the time of donation, and breast cancer risk factors. Premenopausal donors to the KTB were identified by a query of the Bank's database. Hematoxylin and eosin stained sections of the formalin-fixed paraffin-embedded tissue of the identified donors were reviewed and tissue was graded on the basis of the abundance of epithelium within the section. Only tissue containing abundant epithelium was considered for this study. Based on dates, the specimens of nine women in the follicular phase of the menstrual cycle and five in the luteal phase were chosen. Six donors using hormonal contraception at the time of donation were also included. Whole blood obtained from 19 of the 20 donors at the time of tissue donation was available and it was processed for serum. Estradiol, estriol, luteinizing hormone and progesterone concentrations were determined by the Indiana University Health Pathology Laboratory using a Beckman Unicel DxI 800 Immunoassay System. The phase of the menstrual cycle was verified by serum progesterone concentration. The epithelium of these 20 specimens was microdissected from multiple 8 micron frozen tissue sections. Total RNA extracted from the tissue was subsequently depleted of rRNA via locked nucleic acid probes. This enabled profiling of both poly-A and non-poly-A RNA species. Barcoded cDNA libraries from the 20 normal breast epithelia were prepared and sequenced on an Applied Biosystems (AB) SOLiD3 or SOLiD 4 platform. RNA-seq reads for each sample were then mapped to the human genome (hg19) using the LifeScope software version 2.5.1 (Life Technologies, Foster City, CA) and BAM (Binary Alignment/Map) files generated. Read counts for each gene were derived from the output BAM files using the RefSeq database (UCSC Genome Brower) as the gene model.

  Study phs000644

• Potential Modulatory Role of Osteoprotegerin in Bone Metabolism of Patients with 21-Hydroxylase Deficiency

  21-hydroxylase deficiency (21-OHD) is an inherited disorder that results from a mutation on the CYP21A2 gene. It affects the adrenal glands and is the most common cause of congenital adrenal hyperplasia (CAH). 21-OHD CAH causes the body to produce an insufficient amount of cortisol and an excess of androgen, the type of hormone that produces male characteristics. The primary treatment for 21-OHD CAH, glucocorticoid replacement therapy, has been shown to cause bone loss. However, the elevated hormone levels caused by 21-OHD CAH may increase production of the protein osteoprotegerin (OPG), which in turn may protect against bone loss. This study will compare bone density and OPG levels in women who have 21-OHD CAH and have undergone a lifetime of glucocorticoid replacement therapy to that in women who have neither of these criteria. In doing so, the study will aim to determine the relationship between OPG and bone loss. Because of the excess of androgen caused by 21-OHD CAH, women with CAH may exhibit some male-like characteristics. Glucocorticoids are a member of a class of drugs called corticosteroids, which are used in hormone replacement therapy. In order to counteract the effects of 21-OHD CAH, women with the disease are given hormone replacement therapy with glucocorticoids beginning at infancy. Glucocorticoids are known to cause bone loss. Despite many years of treatment with glucocorticoids, however, young women with 21-OHD CAH seem to be protected against bone loss. Researchers believe that the increased androgen levels in these women lead to increased estrogen levels, which in turn increase OPG production. The increase in OPG levels may protect women against bone loss. This study will evaluate bone density and OPG levels in women with and without 21-OHD CAH to determine the relationship between OPG and bone loss. Participants in this observational study will attend only one study visit. At this visit, they will undergo a blood draw; a scan of their lower spine, hip, and forearm; height and weight measurements; and a body fat analysis test. This last test will entail a weak and painless electrical signal being sent from foot to foot. Participants will not attend any follow-up visits for this study.

  Study phs001314

• Proteomic Biomarkers of Progressive Fibrosing Interstitial Lung Disease: a Multicentre Cohort Analysis (PF-ILD Proteomics-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: To identify novel plasma biomarkers of progressive fibrosing interstitial lung disease and develop a proteomic signature to predict this phenotype. Background: Progressive fibrosing interstitial lung disease (ILD) is a devastating condition characterized by parenchymal scar formation, leading to deteriorating lung function and early death. Whereas almost all patients with idiopathic pulmonary fibrosis (IPF) progress, a variable proportion of patients with other common ILDs, including connective tissue disease associated ILD, chronic hypersensitivity pneumonitis, and unclassifiable ILD, develop progressive fibrosing ILD. There are criteria that effectively identify those experiencing ILD progression. However, the criteria do not allow patients who are at risk to be identified before progression occurs. Several blood-based biomarkers have been linked to differential progression in patients with IPF and other fibrosing ILDs. Inflammatory signaling also appears to have a prominent role in fibrotic-predominant ILDs. As such, cytokines, interleukins, and other immune mediators might serve as useful biomarkers of progressive fibrosing ILD. The PF-ILD Proteomics study was a targeted investigation of inflammation-related proteins to identify and validate novel biomarkers of progressive fibrosing ILD in patients with fibrotic connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, and unclassifiable ILD. Participants: There were 589 participants. The discovery cohort comprised 385 participants and the validation cohort comprised 204 participants. Design: PF-ILD Proteomics was a multicenter cohort analysis study. Peripheral blood was collected from consenting patients and plasma was isolated according to center-specific protocols. Relative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative, targeted proteomic platform. Patients from UC Davis and UCSF comprised the discovery cohort and those from UTSW comprised the validation cohort. Participants who were alive with less than 10% relative decline in forced vital capacity (FVC) at 12 months-after blood draw were considered to have non-progressive ILD. Participants who died of any cause, underwent lung transplant, or experienced 10% or greater relative FVC decline within 12 months of blood draw were deemed to have progressive fibrosing ILD. Conclusions: 17 plasma biomarkers of progressive fibrosing interstitial lung disease were identified and showed consistent associations across ILD subtypes.

  Study phs003954

• CRCbiome: Gut metagenome of Norwegian screening participants using FIT sampling

  The study aims to characterize the gut metagenome of Norwegian screening participants and assess the ability of the gut metagenome to identify those at need for colonoscopy. Background: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions. Methods: The CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50–74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period. Discussion: The CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome-based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high.

  Study EGAS50000000170

• UK10K RARE COLOBOMA

  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. Ocular coloboma is the most common significant developmental eye defect with an incidence of ~1 in 5,000 live births. It results from failure of optic fissure closure during embryogenesis. The position and extent of the fusion failure dictates the clinical appearance and functional effect. ~30% of coloboma cases are associated with other systemic malformations. These UK10K samples will mostly comprise isolated coloboma cases without systemic involvement (aka non-syndromal coloboma). There is strong evidence from family studies that coloboma has a major genetic component with autosomal dominance being the most common pattern of inheritance. However, many cases are isolated or show complex patterns of familial clustering. The genes responsible for isolated coloboma are largely unknown, but in a small number of families mutations in SHH, CHX10, and PAX6 have been identified indicating marked genetic heterogeneity. Thus in addition to the clinical benefits of achieving a molecular diagnosis there are also major scientific advantages to identifying coloboma genes, as these are likely to provide insights into the complex process of optic fissure closure, that is critical to normal eye development. In the longer term, understanding the molecular basis of the disease may provide clues to therapeutic strategies.For further information with regard to this cohort please contact David Fitzpatrick (david.fitzpatrick@ed.ac.uk).

  Study EGAS00001000127

• Multi-omics data of 1000 Inflammatory Bowel Disease patients

  Portal available at https://1000ibd.org Inflammatory bowel disease (IBD) is a chronic complex disease of the gastrointestinal (GI) tract. Patients with IBD can experience a wide range of symptoms, but the pathophysiological mechanisms that cause these individual differences in clinical presentation remain largely unknown. In consequence, IBD is currently classified into subtypes using clinical characteristics. If we are to develop a more targeted treatment approach, molecular subtypes of IBD need to be discovered that can be used as new drug targets. To achieve this, we need multiple layers of molecular data are generated from the same IBD patients.We initiated the 1000IBD project to prospectively follow more than 1000 IBD patients from the Northern provinces of the Netherlands. For these patients, we have collected a uniquely large number of phenotypes and generated multi-omics profiles. To date, 1,215 participants have been enrolled in the project and enrolment is on-going, with 609 patients being present in the first data release. Phenotype data collected for these participants includes information on dietary and environmental factors, drug responses, and adverse drug events. Genome information has been generated using genotyping (ImmunoChip, Global Screening Array and HumanExomeChip) and sequencing (whole exome sequencing and targeted resequencing of IBD susceptibility loci), transcriptome information generated using RNA-sequencing of intestinal biopsies and microbiome information generated using both sequencing of the 16S rRNA gene and whole genome shotgun metagenomic sequencing.All molecular data generated within the 1000IBD project will be shared in multiple data on the European Genome-Phenome Archive (www.ega-archive.org). The first data release, will contain basic phenotypes for 609 participants, genotypes of 314 participants, gut microbiome data generated by tag sequencing the 16S gene of feces from 315 participants and intestinal biopsies from 107 participants, and gut microbiome metagenomic sequencing of feces of 355 participants . Future releases will comprise many more additional phenotypes and -omics data layers. 1000IBD data can be used by other researchers as a replication cohort, a dataset to test new software tools, or a dataset for applying new statistical models.

  Study EGAS00001002702

• Mutational dynamics of triple negative breast cancer over neoadjuvant chemotherapy treatment reveal frequent whole genome duplication events

  Background Triple-negative breast cancer (TNBC) is associated with poor survival rate and high genomic instability, generating complex tumour genomes. However, the processes generating this complexity are poorly studied over time. Here, we study the temporal dynamics of TNBC somatic mutations, revealing major transitions in tumour genome evolution, from diagnostic biopsies, through treatment, to cancer remission or recurrence. Methods Deep whole exome sequencing and CUTseq, a reduced representation whole genome sequencing approach, were performed in parallel, to comprehensively identify short nucleotide variants (SNVs), copy number alterations (CNAs) and aneuploidies genome-wide. We profiled (N=74) tumour samples from 22 patients across the course of disease, including spatially diverse samples from many tumours, allowing us to observe the gain and loss of candidate driver variants over time. Results As expected, tumour infiltrating lymphocyte (TIL) levels and residual cancer burden (RCB) score were negatively correlated, with good responses to neoadjuvant chemotherapy (NACT) seen in pre-treatment samples with high infiltration. In general, SNV mutational burden remained stable across disease progression and RCB classes. Recurrent SNVs across the cohort implicated several known TNBC driver genes in disease progression and response to treatment, with TP53, MICA, CYP2D6, BRCA1 and BRCA2 frequently altered. However, the presence of candidate driver SNVs in these genes often varied throughout a patient’s treatment, including the loss of those seen in a given driver gene in pre-treatment samples, but gain of novel variants in the same gene at later time points. Dramatic structural dynamics were seen in all tumours, including abundant CNA including chromosome arm aneuploidies seen in pre-treatment samples, followed by frequent loss of these alterations post-treatment, and their re-emergence at recurrence. Whole genome duplication (WGD) events appear to drive these dynamics, with a higher frequency of pre-treatment WGD seen in patients with the best response to NACT. Conclusions Comprehensive longitudinal profiling demonstrates the complex interplay of SNVs and copy number alterations during TNBC progression, leading to diverse evolutionary trajectories and patient outcomes. Complex mutational patterns emerge as important features during progression, with WGD events emerging as potential candidate biomarkers of response at both tumour establishment and recurrence.

  Study EGAS00001008261

• Precision Medicine for ABCA4 Disease: Modifier Alleles

  Genetic variation affecting the structure and function of the ABCA4 protein gives rise to a broad collection of genetically and clinically heterogeneous diseases, collectively known as ABCA4 disease, which are characterized by both phenotypic overlap and variable penetrance and expressivity. These include autosomal recessive Stargardt disease, cone-rod dystrophy, occult maculopathy, bull's eye macular dystrophy, retinitis pigmentosa-like retinal dystrophy, etc. Some phenotypic variation can be attributed to variability of highly penetrant ABCA4 mutations; however, much of the heterogeneity cannot be explained by ABCA4 mutations alone. The concept of Precision Medicine requires, by definition, identification of all genetic variation contributing to specific disease phenotypes. The main goal of this study is to identify all genetic variation resulting in phenotypes compatible with ABCA4 disease, which, in addition to biallelic disease-causing variants in the ABCA4 locus, include cis- and trans-acting modifiers and mutations in genes other than ABCA4.The study was carried out by performing whole exome sequencing (WES) of affected individuals to identify causal and modifying genetic variation for patients with macular dystrophies compatible with ABCA4 disease. All samples were sequenced with the IDT's Exome Research Panel Version 1 with SeqCap EZ Exome v2 and SeqCap EZ Exome v3 capture kits. Samples were sequenced on Illumina next-generation sequencing machines (San Diego, CA, USA) using DRAGEN Bio-IT Platform v. 2.5.1 (Illumina) to align reads to the Genome Reference Consortium Human Build 37, calling variants in accordance with the Genome Analysis Tool Kit (GATK, v.4.0.2.1) Best Practices Workflow, using ATAV (v.7.0.16) variant-calling pipeline. Variants for analysis were restricted to the consensus coding sequencing public transcripts (CCDS release 20) plus 2 base pair (bp) intronic extensions. Variants were annotated using ClinEff (DnaMiner) with Ensembl-HGRCh37.73 annotations.This set of WES data from unrelated patients of different racial and ethnic backgrounds can be stored and shared through dbGaP. These data provide information on frequencies of disease-causing variants in genes other than ABCA4 in patients with macular dystrophies. These also provide frequencies of selected pathogenic and none-pathogenic variants in different ethnicities.

  Study phs002393

• Metagenomics-Guided Pathogen Discovery in Travelers' Diarrhea

  Traveler's diarrhea (TD) is caused by enterotoxigenic Escherichia coli (ETEC), other pathogenic gram-negative pathogens, norovirus and some parasites. Nevertheless, standard diagnostic methods fail to identify pathogens in more than 30% of TD patients, so it is predicted that new pathogens or groups of pathogens may be causative agents of disease. A comprehensive metagenomic study of the fecal microbiomes from 23 TD patients and seven healthy travelers was performed, all of which tested negative for the known etiologic agents of TD in standard tests. Metagenomic reads were assembled and the resulting contigs were subjected to semi-manual binning to assemble independent genomes from metagenomic pools. Taxonomic and functional annotations were conducted to assist identification of putative pathogens. We extracted 560 draft genomes, 320 of which were complete enough to be enough characterized as cellular genomes and 160 of which were bacteriophage genomes. We made predictions of the etiology of disease in individual subjects based on the properties and features of the recovered cellular genomes. Three subtypes of samples were observed. First were four patients with low diversity metagenomes that were predominated by one or more pathogenic E. coli strains. Annotation allowed prediction of pathogenic type in most cases. Second, five patients were co-infected with E. coli and other members of the Enterobacteriaceae, including antibiotic resistant Enterobacter, Klebsiella, and Citrobacter. Finally, several samples contained genomes that represented dark matter. In one of these samples we identified a TM7 genome that phylogenetically clustered with a strain isolated from wastewater and carries genes encoding potential virulence factors. We also observed a very high proportion of bacteriophage reads in some samples. The relative abundance of phage was significantly higher in healthy travelers when compared to TD patients. Our results highlight that assembly-based analysis revealed that diarrhea is often polymicrobial and includes members of the Enterobacteriaceae not normally associated with TD and have implicated a new member of the TM7 phylum as a potential player in diarrheal disease.

  Study phs001352

• A Single Cell Atlas of Gene Regulatory Elements in the Human Heart

  Background: Cis-regulatory elements such as enhancers and promoters are crucial for directing gene expression in the human heart. Dysregulation of these elements can result in many cardiovascular diseases that are major leading causes of morbidity and mortality worldwide. In addition, genetic variants associated with cardiovascular disease risk are enriched within cis-regulatory elements. However, the location and activity of these cis-regulatory elements in individual cardiac cell types remains to be fully defined. Methods: We performed single nucleus ATAC-seq and single nucleus RNA-seq to define a comprehensive catalogue of candidate cis-regulatory elements (cCREs) and gene expression patterns for the distinct cell types comprising each chamber of four non-failing human hearts. We used this catalogue to computationally deconvolute dynamic enhancers in failing hearts and to assign cardiovascular disease risk variants to cCREs in individual cardiac cell types. Finally, we applied reporter assays, genome editing, and electrophysiogical measurements in in vitro differentiated human cardiomyocytes to validate the molecular mechanisms of cardiovascular disease risk variants. Results: We defined >287,000 candidate cis-regulatory elements (cCREs) in human hearts at single-cell resolution, which notably revealed gene regulatory programs controlling specific cell types in a cardiac region/structure-dependent manner and during heart failure. We further report enrichment of cardiovascular disease risk variants in cCREs of distinct cardiac cell types, including a strong enrichment of atrial fibrillation variants in cardiomyocyte cCREs, and reveal 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Two such risk variants residing within a cardiomyocyte-specific cCRE at the KCNH2/HERG locus resulted in reduced enhancer activity compared to the non-risk allele. Finally, we found that deletion of the cCRE containing these variants decreased KCNH2 expression and prolonged action potential repolarization in an enhancer dosage-dependent manner. Conclusion: This comprehensive atlas of human cardiac cCREs provides the foundation for not only illuminating cell type-specific gene regulatory programs controlling human hearts during health and disease, but also interpreting genetic risk loci for a wide spectrum of cardiovascular diseases.

  Study phs002204

• NIDDK IBD Genetics Consortium Crohn's Disease Genome-Wide Association Study

  This dataset contains data from a genome-wide association study performed with 968 Inflammatory Bowel Disease (IBD) affected cases and 995 unrelated controls using the Illumina HumanHap300 Genotyping BeadChip. Cases were selected to have Crohn's disease with ileal involvement, and controls were matched to cases based on sex and year of birth. Subjects were drawn from two cohorts: (1) persons with non-Jewish, European ancestry (561 cases and 563 controls), and (2) persons with Jewish ancestry (407 cases and 432 controls). Genotyping was performed at the Feinstein Institute for Medical Research. Seven-hundred fifty-four of the samples (468 cases and 286 controls) were taken from the NIDDK IBD Genetics Consortium cell line repository. These samples are identified in the IBD_Sample file. The subject IDs for these individuals may be used to request corresponding samples for follow-up research through the repository. In addition, complete phenotype data for these individuals are available, together with the Consortium's phenotyping manual and the forms used to collect the data. The remaining 1,209 samples were obtained from pre-existing collections ascertained through Cedars-Sinai Medical Center, Johns Hopkins University, University of Chicago, University of Montreal, University of Pittsburgh, University of Toronto, and the New York Health project (controls only). For these samples, only sex, cohort (Jewish vs. non-Jewish), and age at diagnosis (cases only) are available. Two-hundred three individuals from among the pre-existing samples did not provide consent to release their genotype data (designated as consent group 2 in the file IBD_Subject). Thus, individual genotype data are only provided for 1,760 samples. To compensate for this, we have provided summary results for each SNP. These are based on a stratified analysis testing case/control association. Fifty-one samples had a call rate less than 93% and were therefore excluded from this analysis, leaving an overall sample size of 1,963 - 51 = 1,912. X Chromosome Heterozygosity Nine samples have X chromosome heterozygosity that is neither consistent nor inconsistent with their phenotypic sex. One of these samples was found to have Turner Syndrome. The remaining 8 samples have heterozygosity ranging from 35-76%.

  Study phs000130

• Type 1 Diabetes Genetics Consortium (T1DGC): ImmunoChip Study

  The Type 1 Diabetes Genetics Consortium (T1DGC) was formed to address issues of limited sample size and consistency of phenotyping that had limited genetic investigations on risk of type 1 diabetes (T1D). The T1DGC first collected affected sib pair (ASP) families from four geographic networks (Asia-Pacific, Europe, North America, United Kingdom). In addition, T1D cases and controls were ascertained from existing and de novo collections. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, T1D cases from the UK Genetic Resource Investigating Diabetes (UKGRID, N=6,670), and controls from the British 1958 Birth Cohort (B58BC, N=6,523), the UK National Blood Services collection (NBS, N=2,893) and the NIHR Cambridge Biomedical Research Centre BioResource (CBR, N=2,846). All samples included in this series have reported or self-declared European ancestry. All DNA samples were collected after approval from relevant institutional research ethics committees. Genotyping was performed using a custom Illumina Infinium high-density genotyping array, ImmunoChip (Illumina, Inc; CA) according to manufacturer's protocols. The ImmunoChip was designed to densely genotype, using 1000 Genomes and any other available disease specific resequencing data, immune-mediated disease loci identified by common variant GWAS. The ImmunoChip Consortium selected 186 distinct loci containing markers meeting genome wide significance criteria (P<5x10-8) from twelve such diseases (autoimmune thyroid disease, ankylosing spondylitis, Crohn's disease, celiac disease, IgA deficiency, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, T1D and ulcerative colitis). All 1000 Genomes Project pilot phase CEU population variants (Sept 2009 release) within 0.1cM (HapMap3 CEU) recombination blocks around each GWAS region lead marker were submitted for array design. No filtering on correlated variants (linkage disequilibrium) was applied. Additional content included regional resequencing data (submitted by several groups) as well as a small proportion of investigator-specific undisclosed content including intermediate GWAS results. After data cleaning and quality control, a total of 154,939 single nucleotide polymorphisms (SNPs) from 186 loci on ImmunoChip were scored. Case-control and family data were analyzed independently and combined by meta-analysis.

  Study phs000911

• 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

• A Genome-Wide Association Study of Sporadic ALS in an Irish Population (SIALS) and Sequencing and Analysis of an Irish Human Genome

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons. Epidemiological studies indicate that 2-5% of cases are familial, usually with an autosomal dominant pattern of inheritance. For a portion of these, causative genes have been identified. The remaining 95% of ALS cases are described as sporadic, and believed to result from a combination of genetic and environmental factors. This study utilized samples from Irish patients with sporadic ALS and Irish control individuals. The aim of the study was to identify susceptibility alleles for ALS in the Irish population. Genome-wide, single-nucleotide polymorphism (SNP) genotyping was undertaken using Illumina 550K version 3 chips. Genotyping data are available on 221 SALS patients and 211 controls. Future work will aim to examine ALS genetic risk at individual sequence level. As an initial step, as of September 2010 we have made available the human genome sequence from a single anonymous male control individual from the SIALS collection. Recent studies generating complete human sequences from Asian, African and European subgroupings have revealed population specific variation and illuminated disease susceptibility loci. The Irish population is of interest because of its location at the periphery of Europe and also the impact its emigrants have had on the genetics of populations in a number of other countries. We have identified sequence variants that may be specific to this population and have identified potentially novel disease associated variants. We describe a novel method for improving SNP calling accuracy at low genome coverage using haplotype information. Overall we demonstrate utility in generating whole genome sequences to test general principles and reveal specific instances of human biology. With increasing access to low cost sequencing we would predict that similar studies will emerge.

  Study phs000127

• Molecular Etiology of Early-Onset Dystonia

  Primary torsin dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign (except for tremor) and there is no evidence of neuronal degeneration or an acquired cause. Eleven genes have been mapped for primary dystonia including DYT1 (TOR1A), DYT2, DYT4 (TUBB4A), DYT6 (THAP1), DYT7, DYT13,, DYT17, DYT21, CIZ1, DYT24 (ANO3), and DYT25 (GNAL); however, only 3 genes (TOR1A, THAP1, and GNAL) have mutations in early onset dystonia patients. Each is inherited as an autosomal dominant trait but with reduced penetrance, meaning that individuals can carry the mutation but do not show clinical symptoms. The most common form of PTD is adult onset focal accounting for about 90% of all cases of dystonia with a prevalence estimated at 30/100,000 in the general population. A small percentage of focal cases are due to mutations in CIZ1, ANO3, THAP1, TUBB4A, and GNAL, but the vast majority is unaccounted for and is most likely multigenic or multifactorial. In this grant, focusing on early onset PTD, we will uncover genes that influence the penetrance of DYT1 (TOR1A) dystonia through GWAS and exome sequencing studies. We will identify other genes for early onset PTD using exome sequencing and determine whether variants within the identified early onset PTD genes or the pathways associated with these genes contribute to susceptibility in the most prevalent form of PTD, focal dystonia, using a case:control association study. The proposed research will identify novel PTD risk factors and genes, which in turn should reveal shared and intersecting pathways leading to a better understanding of the molecular basis of PTD and provide the underpinnings for developing new treatments. Additionally, insight into the factors that modulate disease penetrance would be a first step in determine whether these could be modified leading to a reduced incidence of the disease.

  Study phs001733

• Gene expression signatures associated with chronic endometritis revealed by RNA sequencing

  Chronic endometritis (CE) is a persistent inflammatory condition of the endometrium characterized by the infiltration of plasma cells. CD138 immunohistochemistry is considered to improve the CE diagnosis rate. Using the number of CD138-positive cells equal or greater than five as a diagnostic criterion for CE, we identified 24 CE and 33 non-CE cases among women with infertility. We conducted RNA-sequencing analysis for these 57 cases in total as an attempt to elucidate the molecular pathogenesis of CE and to search for new biomarkers for CE. By comparing CE and non-CE groups, we identified 20 genes upregulated in the endometria of CE patients, including 12 immunoglobulin-related genes and eight non-immunoglobulin genes as differentially expressed genes. The eight genes were MUC5AC, LTF, CAPN9, MESP1, ACSM1, TVP23A, ALOX15, and MZB1. By analyzing samples in the proliferative and secretory phases of the menstrual cycle separately, we also identified four additional non-immunoglobulin genes upregulated in CE endometria: CCDC13 by comparing the samples in the proliferative phase, and OVGP1, MTUS2, and CLIC6 by comparing the samples in the secretory phase. Although the genes upregulated in CE may serve as novel diagnostic markers of CE, many of them were upregulated only in a limited number of CE cases showing an extremely high number of CD138-positive cells near or over one hundred. Exceptionally, TVP23A was upregulated in the majority of CE cases regardless of the number of CD138-positive cells. The upregulation of TVP23A in the endometria of CE cases may reflect the pathophysiology of a cell-type or cell-types intrinsic to the endometrium rather than the accumulation of plasma cells. Our data, consisting of clinical and transcriptomic information for CE and non-CE cases, helped us identify gene expression signatures associated with CE.

  Study JGAS000621

• Highlights from 2025: Our top 10 requested studies

  In 2025, as in previous years, EGA has facilitated the reuse of numerous datasets spanning a broad range of research and healthcare topics. To reflect on this activity, we would like to highlight the top 10 studies behind the most requested datasets of last year. Notably, the vast majority of these highly requested datasets are cancer-focused, particularly involving the study of immune checkpoint inhibitor therapies. Immune checkpoint inhibitors (ICIs) have become one of the most transformative advances in modern cancer therapy. These monoclonal antibodies enhance antitumor immune responses by targeting inhibitory immune checkpoint molecules. While ICIs have led to remarkably favorable and durable responses in some patients, treatment outcomes vary widely. This variability has fueled intense research efforts aimed at understanding resistance mechanisms, exploring combination therapies, and discovering predictive biomarkers to better stratify patients and guide treatment decisions. Study Title Disease 1 EGAS00001005503 Integrated genomic analyses reveal molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma Liver Cancer 2 EGAS00001005013 Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer Lung Cancer 3 EGAS00001004809 BIOKEY: A single-cell catalogue of the dynamic changes underlying Checkpoint Immunotherapy response in Early Breast Cancer Breast Cancer 4 EGAS50000000138 BIOKEY: Immune heterogeneity in small cell lung cancer and vulnerability to immune checkpoint blockade Lung Cancer 5 EGAS50000000497 Bladder cancer subtyping study across 4 atezo clinical trials Bladder Cancer 6 EGAS50000000689 MOSAIC - Multi-Omics Spatial Atlas In Cancer Cancer Atlas 7 EGAS00000000083 METABRIC (Breast cancer - genome and transcriptome) Breast Cancer 8 EGAS00001005702 Human genomic and phenotypic synthetic data for the study of rare diseases Synthetic data 9 EGAS00001002556 TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells Bladder Cancer 10 EGAS00001004353 Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade Renal Cancer The most requested dataset of the year was EGAD00001008128. It belongs to a study that analyzed 358 liver cancer patients enrolled in clinical trials and treated with the combination of atezolizumab (anti–PD-L1) and bevacizumab (anti-VEGF), atezolizumab alone, or sorafenib. The study highlights how bevacizumab enhances anti-PD-L1 effect and identifies candidate biomarkers to predict treatment response. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related death worldwide [1]. Because symptoms often appear late, many patients are diagnosed at advanced stages, when curative options are no longer viable. For many years, sorafenib—a multikinase inhibitor approved in 2007—was the only systemic treatment available. Although numerous clinical trials followed, it was not until a decade later that additional therapies showed meaningful clinical benefit. Among these advances, immunotherapy emerged as a promising first-line option [2]. In particular, the combination of atezolizumab and bevacizumab demonstrated improved survival in patients with advanced HCC, reshaping the treatment landscape. However, treatment efficacy remains limited by the complex and diverse hepatic microenvironments that influence immune responses, as well as by high intratumoral heterogeneity. Identifying robust predictors of treatment response is critical to enable effective patient stratification and maximize the benefits of these therapies [2]. The continued demand for these datasets highlights the interest and critical role of data reuse in deepening our understanding of cancer, accelerating the development of more effective therapies, and improving patient outcomes. By providing secure access to high-quality genomic and clinical data, EGA acts as a catalyst for biomedical progress. References Sung, Hyuna, et al. "Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries."CA: a cancer journal for clinicians 71.3 (2021): 209-249. Ladd, Alexandra D, et al.“Mechanisms of drug resistance in HCC.” Hepatology 79(4) (2024): 926-940

  Blog top-10-studies-2025

• Exome Sequencing to Define the Landscape of Plasma Cells in Systemic Light chain Amyloidosis

  Systemic light chain amyloidosis (AL) is characterized by the deposition of immunoglobulin light chains as amyloid fibrils in different organs, where they form toxic protein aggregates. The underlying disease is a plasma cell disorder, but limited whole exome data are available. We report the findings of an exome sequencing study in AL to define a plasma cell signature and compare this to monoclonal gammopathy of undefined significance (MGUS) and myeloma (MM). Twenty-four samples from unselected newly diagnosed untreated AL patients were analysed. CD138+ cells were isolated from bone marrow cells using MACSorting (Miltenyi Biotech, Bisley, UK). Cells were lysed in RLT+ buffer and DNA/RNA extracted using the AllPrep kit (Qiagen, Manchester, UK). Peripheral blood was isolated from patients, white blood cells purified by Ficoll-Pacque and DNA extracted using the QIAamp DNA mini kit (Qiagen). There were a median of 47 acquired nonsynonymous variants (range 4-253) per patient. Thirty percent of patients yielded a mutation in a myeloma driver gene. These mutations were either clonal or sub-clonal. There was evidence of MAPK activation with NRAS mutations, NF-κB activation and DNA repair pathway alterations. Exome data were used to determine the cytogenetic groups of AL samples and identified hyperdiploidy in 33% of cases and t(11;14) in 33% of cases. All translocations were generated via class switch recombination and breakpoints on chromosome 11 fell into the expected regions. A novel translocation, unlikely to be driving disease progression was identified involving RCC1. Finally, further analysis of the APCS gene encoding for the SAP protein did not show any biased genotype in the AL population in comparison to the general population. We conclude that exome sequencing identifies a genetic make-up of AL that is similar to other plasma cell disorders such as MM and MGUS. This not only includes copy number abnormalities and translocations but also nonsynonymous mutations.

  Study EGAS00001001418

• UK10K_NEURO_ASD_FI

  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.These samples are a subset of a nationwide collection of Finnish autism spectrum disorder (ASD) samples. The samples have been collected from Central Hospitals across Finland in collaboration with the University of Helsinki. The samples consist of 93 individuals with a diagnosis of autistic disorder or Asperger syndrome from 36 families with at least two affected individuals. Of these individuals, 16 can be genealogically connected to form two large pedigrees originating from Central Finland, suggesting possible genetic risk factors shared identical by descent within the pedigrees. All diagnoses are based on ICD-10 and DSM-IV diagnostic criteria for ASDs. Additional phenotypic data is available for a subset of the individuals.For further information with regard to this cohort please contact Aarno Palotie (Aarno.palotie@helsinki.fi).

  Study EGAS00001000110

• Liver biopsy derived induced pluripotent stem cells provide an unlimited supply for the generation of patient-specific hepatocyte-like cells

  Background: Hepatocyte-like cells (HLCs) differentiated from induced pluripotent stem cells (iPSCs) have emerged as a promising cell culture model to study metabolism, biotransformation, viral infections and genetic liver diseases. However the derivation of iPSCs is restricted by ethical and procedural constraints. Furthermore, incomplete HLC differentiation remains a major challenge. iPSC may carry-on a tissue of origin dependent expression memory influencing iPSC differentiation into different cell types. If liver derived iPSCs (Li-iPSCs) maintain a liver specific gene expression profile is not known. It is also not known, if Li-iPSCs would allow the generation of more fully differentiated HLCs.Methods: Primary liver cells (PLCs) were expanded from liver needle biopsies and reprogrammed into Li-iPSCs using a non-integrative Sendai virus-based system. Li-iPSCs were differentiated into HLCs using established differentiation protocols. The HLC phenotype was characterized at the protein, functional and transcriptional level. RNA sequencing data were generated from the originating liver biopsies, the Li-iPSCs, fibroblast derived iPSCs, and differentiated HLCs, and used to characterize and compare their transcriptome profiles.Results: PLCs were obtained from small pieces of liver biopsies and could be reprogrammed into Li-iPSCs. Li-iPSCs indeed retain a liver specific transcriptional footprint. Li-iPSCs can be propagated to provide an unlimited supply of cells for differentiation into Li-HLCs. Similar to HLCs derived from fibroblasts, Li-HLCs could not be fully differentiated into hepatocytes. Relative to the originating liver, Li-HLCs showed lower expression of liver specific transcription factors and increased expression of genes involved in the differentiation of other tissues.Conclusions: PLCs and Li-iPSCs obtained from small pieces of human needle liver biopsies constitute a novel unlimited source for the production of HLCs. Despite the preservation of a liver specific gene expression footprint in Li-iPSCs, the generation of fully differentiated hepatocytes cannot be achieved with the current differentiation protocols.

  Study EGAS00001002676

• Immune induction strategies to enhance the sensitivity to PD-1 blockade in metastatic triple negative breast cancer: the TONIC-trial

  The response rate in metastatic triple negative breast cancer (TNBC) to PD-1 blockade is low, highlighting an urgent clinical need for strategies that render the TNBC tumor microenvironment (TME) more sensitive to PD-1 blockade. Immunomodulatory mechanisms have been proposed for both chemotherapy and irradiation, but it has not been established whether these therapies may improve efficacy of PD-1 blockade by favorably changing the TME. In the first stage of this adaptive, non-comparative phase II trial (TONIC-trial; NCT02499367), 67 patients with metastatic TNBC were randomized to nivolumab without induction or to one of four induction treatments, consisting of irradiation of one metastatic lesion (3x8 Gy) or a two- week low-dose regimen of cyclophosphamide, cisplatin or doxorubicin, all followed by nivolumab. In the overall cohort of 66 evaluable patients, the objective response rate (ORR; iRECIST16) was 20% (95% CI: 11%-31%), with two complete responses and 11 partial responses. The majority of clinical responses were observed on nivolumab in the cisplatin (ORR 23%; 3/13) and doxorubicin (ORR 35%; 6/17) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes, involved in PD-1/PD-L1, and T-cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNFα-signaling after doxorubicin. In addition, we observed a trend towards increased T-cell infiltration, measured using T-cell receptor (TCR) sequencing, after doxorubicin. Together, the clinical and translational data of this study testing different immune induction strategies prior to nivolumab suggest that short-term doxorubicin and cisplatin may induce a more favorable TME and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant further confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

  Study EGAS00001003535

• Genetic Etiology of Heterotaxy

  To understand the genetic etiology of heterotaxy, patients with heterotaxy were consented and recruited, with blood drawn for DNA extraction and exome sequencing. Using the exome sequencing dataset obtained, rare coding sequence variants were identified.

  Study phs001691

• Data Access Committee for Genomics of bone marrow failure (BMF) and myelodysplastic syndromes (MDS)

  The Data Access Committee for the genomics of bone marrow failure and myelodysplastic syndrome project is responsible for reviewing applications for access to controlled human genomic and phenotypic datasets generated as part of this project. The DAC ensures that data sharing with qualified researchers is conducted in accordance with participant consent, institutional ethical approvals, and all applicable data protection regulations. 

  Dac EGAC50000000754

• Lymphoma_primary_patient_drug_perturbed_RNASeq_samples

  3'-end low-depth RNA sequencing data from 108 patients with chronic lymphocytic leukemia and 8 patients with lymphoma. Each primary patient sample was treated in vitro with DMSO as a control and with up to ten small-molecule inhibitors (ibrutinib, duvelisib, everolimus, trametinib, nutlin-3a, I-BET-762, MK2206, selinexor, compound 26, and a combination of ibrutinib and compound 26). Sequencing was performed on the Illumina HiSeq4000. The dataset contains FASTQ files.

  Dac EGAC50000000578

• Chlamydia trachomatis exploits sphingolipid metabolic pathways during infection of phagocytes

  This study looks at the response of M2 macrophages stimulated with GM-CSF and IL4 for 7 days and 2 days respectively to C. trachomatis infection on an Illumina platform.

  Study EGAS50000000960

• DNA Dataset

  The DNA dataset includes 5 samples sequenced using the Oncomine Comprehensive Assay (OCA) panel. Libraries were prepared following the manufacturer’s protocol and sequenced on the Ion Torrent S5 System. The dataset contains FASTQ files and includes information on single nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs). (non so se hanno sequenziato su ION Torrent)

  Dataset EGAD50000002501

• ScRNA-seq of kidney organoids expressing different APOL1 variants and treated with IFN-γ

  This dataset includes scRNA-seq fastq files and Seurat counts and metadata for 3 samples of hiPSC-derived kidney organoid cells cultured in vitro in presence of IFN-γ. Samples were obtained from kidney organoids with APOL1 G1G1 variant, APOL1 G2G2 variant and an isogenic control.

  Dataset EGAD50000001743

• Fragmentomics profiling and quantification of plasma Epstein-Barr virus DNA enhance prediction of future nasopharyngeal carcinoma.

  This dataset included human plasma EBV DNA target-capture sequencing data. The capture probes were designed to cover the entire EBV genome and selected human autosomal regions. After enrichment, the products were sequenced on the NextSeq500 System (Illumina) and aligned to the EBV genome (AJ507799.2) and the human genome (hg19) in BAM format.

  Dataset EGAD50000000580

• Effect of ETS2 modulation on chromatin accessibility and enhancer activity in primary human macrophages

  3 datasets included: - H3K27ac ChIP in ETS2-edited and unedited TPP macrophages from 3 biological replicates - H3K27ac ChIP in ETS2-overexpressing and control M0 (resting) macrophages from 3 biological replicates - ATAC-seq (deep sequencing) in ETS2-edited and unedited TPP macrophages from 3 biological replicates

  Dataset EGAD50000000154

• Whole_Exome_sequencing_in_a_large_IBD_pedigree

  We perform whole exome sequencing on samples from a large IBD pedigree. The selected samples are from more distantly related family members (healthy and with IBD) and a set of matched population (Ashkenazy Jewish ancestry) samples.

  Study EGAS00001000240

• Single-cell RNA sequencing of chemotherapy-resistant muscle-invasive urothelial bladder cancer

  All single-cell mRNA sequencing data were acquired from a single patient (BC159-T#3) and patient-derived xenografts (BC159-T#3-PDX-vehicle and BC159-T#3-PDX-tipifarnib).

  Study EGAS00001004233

• Rare_renal_tumours_RNA_

  Rare renal tumours are by hard to classify and there is very little available information regarding prognosis and sensitivity to treatment. Here we endevour to understand their genomic properties in order to better understand their biology.

  Study EGAS00001004323

• Rare_renal_tumours_WGS_

  Rare renal tumours are by hard to classify and there is very little available information regarding prognosis and sensitivity to treatment. Here we endevour to understand their genomic properties in order to better understand their biology.

  Study EGAS00001004322

• SPATC1L variants associated with age-related and hereditary hearing loss.

  The dataset contains three BAM files that include SPATC1L variants identified in Italian patients affected by hearing loss (both hereditary and age-related hearing loss). Data have been produced by whole exome sequencing and targeted re-sequencing, using Ion Proton and Ion Torrent PGM platforms respectively.

  Dataset EGAD00001004147

• Fibromyalgia versus small fiber neuropathy: Diverse keratinocyte transcriptome signature

  We provide a diverse keratinocyte transcriptome signature between SFN and FMS patients, which may hint towards distinct pathomechanisms of small fiber sensitization and lay the basis for advanced diagnostics in both entities

  Study EGAS00001005004

• Gut microbiome sequencing in patients receiving combination immune checkpoint blockade

  This dataset contains 16S and WMS data for gut (fecal) microbiome samples taken from patients treated with combined anti-CTLA-4 and anti-PD-1 checkpoint blockade for advanced melanoma.

  Study EGAS00001004885

• AT2 COPD Methylomics

  We generated genome-wide DNA methylation maps at single CpG resolution of primary human lung AT2 cells isolated from distal parenchyma of ex-smoker controls and COPD patients, with both mild and severe disease

  Study EGAS00001007386

• Sequencing data for personalized therapy design and endotype identification

  Whole exome sequencing of 15 DNA samples, and whole genome sequencing of 2 matched DNA samples. Whole exome sequencing is of RMS samples (both alveolar and embryonal) and from cell lines as well as patient samples. Patient samples are of pediatric RMS patients.

  Dataset EGAD00001005458

• Circulating tumor DNA in urine and plasma of glioma patients - sequencing data

  Dataset consisting of sequence data from 36 glioma patients. Data includes; -Whole exome sequencing of tumour tissue and matched germline -Shallow whole genome sequencing of urine cell-free DNA -Targeted capture sequencing of plasma and CSF cell-free DNA Additional sequencing data are provided from non-glioma and healthy controls

  Dataset EGAD00001006156

• scRNA-seq of first and second trimester human gonads - HUGODECA dataset

  Comprehensive map of first- and second-trimester gonadal development in humans using a combination of single-cell and spatial transcriptomics, chromatin accessibility assays, and imaging. ArrayExpress Accession: E-MTAB-10551

  Dataset EGAD00001009386

• RNA sequencing data from children with febrile illness and multisystem inflammatory syndrome in children (MIS-C)

  RNA sequencing data from children with febrile illness and multisystem inflammatory syndrome in children (MIS-C). Samples used were Whole Blood. Febrile illness controls include children with bacterial and viral infections and healthy controls. This dataset contains samples from patients recruited into the DIAMONDS study.

  Dataset EGAD00001011134

• Advanced iPSC-CMs maturation by integrating maturation medium, nanopatterning, and electrical stimulation

  RNA seq of iPSC-derived cardiomyocytes cultured in lipid-enriched maturation medium (MM), in MM on nanopattern-surfaces (NP) and under the influence of MM, NP and electrical Stimulation (ES, 2Hz, 14 days). 9 Samples from 3 Independent batches/differentiations of cardiomyocytes from 2 different iPSC-lines (iWTD2.1 and isWT7.22).

  Dataset EGAD00001011289

• Single-cell T-cell receptor sequencing of intraepithelial CD8+ αβ T-cells in celiac disease

  Single-cell paired TCR sequencing of intraepithelial CD8+ αβ T-cells in gluten-free diet treated and untreated celiac disease patients and in controls. (Paired end, amplicon sequencing).

  Study EGAS00001004989

• OMKar: optical map based automated karyotyping of genomes to identify constitutional disorders

  This dataset contains optical genome mapping (OGM) data from 56 samples, processed for structural variation and copy number analysis. The data includes .xmap, .cmap, and .smap files representing high-resolution genome maps and structural variant calls. These samples were used to identify complex rearrangements and reconstruct genome karyotypes.

  Dataset EGAD00001015674