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• Deep intronic homozygous variation in PSMC3 causes a syndromic neurosensory disorder combining deafness and cataract

  The association of congenital deafness and early-onset cataracts inherited as a recessive trait is a rare combination described in only a few syndromes with very few genes identified to date. We propose that the PSMC3 proteasome subunit dysfunction leads to a novel human syndrome that includes early-onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear and lens development.

  Study EGAS00001003942

• BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology)

  The BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) study is an ongoing longitudinal, population-based prospective birth cohort including 4,089 children born between 1994 and 1996 in Stockholm, Sweden. The cohort was initially designed to study risk factors for asthma, allergic diseases and lung function in childhood, and to study factors of importance for prognosis at already established disease.Questionnaires on respiratory symptoms and medication were answered at age of 1, 2, 4, 8 and 16 years. Response rates ranged from 96-82% at each occasion with very minor selection bias over the years. Exposure to air pollutants and other environmental factors has been mapped since birth.At the 8 and 16 year follow-up, spirometry and FeNO measurements were performed and at the latter, impulse oscillometry was measured. Blood samples (including plasma) from around 2,500 children were taken at 4, 8 and 16 years and have been analyzed for different IgE-ab and biomarkers. Genome-wide genetic, global methylation and transcriptomic data exist on a subset of the children.

  Study EGAS00001002746

• Whole Genome Profiling to Detect Schizophrenia Methylation Markers

  Schizophrenia (SCZ) is a devastating psychiatric disorder. The aim of this study was to detect DNA methylation (5meC) profiles in whole blood associated with SCZ. The sample consisted of schizophrenia cases and controls selected from national population registers in Sweden. We employed MBD protein-based enrichment of the methylated DNA fraction, followed by single end sequencing (50 bp reads) on the SOLiD platform. To improve methylome-wide coverage we used an existing protocol variant, which increases the relative number of fragments from CpG poor regions. To analyze the data, we used an analysis pipeline described elsewhere7, that was designed specifically for MBD-seq and included alignment, quality control (QC) of reads and samples, coverage calculations for the 26,752,702 autosomal CpGs in the reference genome using a non-parametric estimate of the fragment size distribution, an in silico experiment to identify CpGs in loci with alignment problems, a 2-stage adaptive algorithm to combine data from correlated adjacent CpG sites in "blocks", principal component analysis (PCA), association testing, bioinformatics annotation and network analysis. After QC, 1459 subjects with on average 32.4 million high quality reads remained. Association testing was performed on 4.3 million high quality blocks after regressing out possible assay related technical artifacts, sex/age, and unmeasured confounders through the PCA components.

  Study phs000608

• Carolina Breast Cancer Study (CBCS)

  The Carolina Breast Cancer Study (CBCS), phase III, is a population-based study aiming to understand the social and molecular correlates of breast cancer outcomes, particularly among Black and young women. CBCS recruited first primary breast cancer cases from 44 North Carolina counties between 2008-2013. All cases were between age 20 and 74 and self-identified as female. Black women and young women were systematically oversampled by randomized recruitment such that the study includes approximately 50% Black women and approximately 50% women diagnosed before age 50. A total of 2,998 participants were enrolled. In the ten years following diagnosis, women completed surveys approximately every 1-2 years and diagnoses of subsequent distant local recurrence and second primary tumors were ascertained via linked medical records. We identified records of women who developed secondary breast tumors (including second primary tumors, contralateral breast cancers, and locoregional recurrences), and these participants were oversampled for targeted DNA sequencing using the UNCseq panel (~1200 genes).CBCS germline pathogenic mutations cannot be investigated because participants were consented between 2008 and 2013 with specific language prohibiting this. However, germline data can be used to call somatic mutations or to standardize somatic genomic data.For sharing of study data not included here, please visit unclineberger.org for instructions on submitting a data use agreement.

  Study phs003725

• Clonal selection and double hit events involving tumor suppressor genes underlie relapse from total therapy

  In order to gain insights into the mechanisms of disease progression in multiple myeloma (MM) patients treated with multi-agent and high-dose chemotherapy we have performed a longitudinal study of 33 patients entered into Total Therapy protocols using gene expression profiling, high resolution copy number analyses and whole exome sequencing. The results of this study show the importance of acquired mutations in MM driver genes, bi-allelic events affecting tumor suppressor genes and increased proliferation rates in driving relapse, which is enhanced by intra-clonal heterogeneity and Darwinian type clonal evolution. Branching was the most frequent evolution pattern, characterized by clonal loss and appearance of new clones. We found a higher number of lost and acquired copy number aberrations and an excess of bi-allelic inactivation of tumor suppressor genes in GEP70 high risk (HiR) cases, consistent with genomic instability being a key feature of HiR MM. In conclusion, our study further stresses the impact of known prognostic markers and driver genes on the fitness level of MM cells to survive multi-agent chemotherapy. The frequent bi-allelic loss of tumor suppressor genes in HiR cases and the potentially resulting failure of treatment with DNA damaging agents highlight the need for new therapies for HiR MM.

  Study EGAS00001001810

• T cell landscape definition by multi-omics identifies galectin-9 as novel immunotherapy target in chronic lymphocytic leukemia (CLL)

  Failure of immunotherapy after applying checkpoint inhibitors or CAR-T cells is linked to T cell exhaustion. Here, we explored the T cell landscape in chronic lymphocytic leukemia (CLL) by single-cell omics analyses of blood, bone marrow and lymph node samples of patients and spleen samples of a CLL mouse model. By single-cell RNA- sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we defined the spectrum of phenotypes and transcriptional programs of T cells and and their differentiation state trajectories. We identified disease-specific accumulation of distinct regulatory T cell subsets and T cells harboring an exhausted phenotype exclusively in the CLL lymph node tissue. Integration of TCR data revealed a clonal expansion of CD8+ precursor exhausted T cells, suggesting their reactivity for CLL cells. Interactome analyses identified the TIM3 ligand Galectin-9 as novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3 expressing T cells. Galectin-9 expression correlated with shorter survival of CLL patients. Thus, Galectin-9 contributes to immune escape in CLL and represents a novel target for immunotherapy.

  Study EGAS00001006864

• Preferential infiltration of unique Vγ9Jγ2‐Vδ2 T cells into glioblastoma multiforme

  Glioblastoma multiforme (GBM) is clinically highly aggressive as a result of evolutionary dynamics induced by cross-talk between cancer cells and a heterogeneous group of immune cells in tumor microenvironment. The brain harbors limited numbers of immune cells with few lymphocytes and macrophages; thus, innate‐like lymphocytes, such as γδ T cells, have important roles in antitumor immunity. Here, we characterized GBM‐infiltrating γδ T cells, which may have roles in regulating the GBM tumor microenvironment and cancer cell gene expression. V(D)J repertoires of tumor‐infiltrating and blood‐circulating γδ T cells from four patients were analyzed by next-generation sequencing-based T-cell receptor (TCR) sequencing in addition to mutation and immune profiles in four GBM cases. In all tumor tissues, abundant innate and effector/memory lymphocytes were detected, accompanied by large numbers of tumor‐associated macrophages and closely located tumor‐infiltrating γδ T cells, which appear to have anti-tumor activity. The immune-related gene expression analysis using the TCGA database showed that the signature gene expression extent of γδ T cells were more associated with those of cytotoxic T and Th1 cells and M1 macrophages than those of Th2 cells and M2 macrophages. Although the most abundant γδ T cells were Vγ9Vδ2 T cells in both tumor tissues and blood, the repertoire of intratumoral Vγ9Vδ2 T cells was distinct from that of peripheral blood Vγ9Vδ2 T cells and was dominated by Vγ9Jγ2 sequences, not by canonical Vγ9JγP sequences that are mostly commonly found in blood γδ T cells. Collectively, unique GBM‐specific TCR clonotypes were identified by comparing TCR repertoires of peripheral blood and intra‐tumoral γδ T cells. These findings will be helpful for the elucidation of tumor-specific antigens and development of anticancer immunotherapies using tumor-infiltrating γδ T cells.

  Dataset EGAD00001004862

• Recurrent DNMT3B gene rearrangements are associated with unfavorable outcome in dicentric (9;20)-positive pediatric BCP-ALL

  We provide clinical data sets of Array CGH, targeted RNA-seq, total RNA-seq, whole genome bisulfite (WGBS) and whole genome DNA sequencing (WGS) obtained from bone marrow (BM) or peripheral blood (PB) mononuclear cells of 57 pediatric patients with dicentric chromosome dic(9;20) positive Acute lymphocytic leukemia (ALL), from which in 6 cases DNMT3B gene rearrangement was identified. This data is complemented by total RNA-seq and WGBS of samples from 4 additional ALL patients with a t(12;21) translocation and ETV6-RUNX1 gene fusion. DNA was isolated from BM or PB B-lymphocytes using Qiagen QIAamp DNA Blood Midi Kit to perform i) Array CGH of 58 dic(9;20) positive samples by hybridizing 500ng DNA using a Agilent 400K SurePrint G3 Custom CGH Human Genome Microarray (e-Array design 84704) ii) WGBS of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples using Tecan TrueMethyl oxBS-Seq module for library preparation and Illumina NovaSeq 6000 platform to run 2x151 cycles iii) WGS of DNMT3B rearrangement positive samples using Illumina Lotus DNA Library Prep Kit followed by sequencing running 2x160 cycles on an Illumina NovaSeq 6000 platform. RNA was isolated from PB B-lymphocytes using the PerkinElmer Chemagic 360 instrument, followed by i) targeted RNA-seq of 56 dic(9;20) positive samples prepared using Illumina TruSight RNA Pan-Cancer Panel and sequenced on an Illumina MiSeq platform running 2x75 cycles ii) total RNA-seq of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples utilizing TruSeq Stranded Total RNA Library Prep Gold kit and running 2x100 cycles on an Illumina NovaSeq 6000 platform.

  Dataset EGAD00001011122

• SUM-seq data for spontaneous differentiation of iPSCs upon perturbation of GATA2, NR4A2 or SOX17

  We combined SUM-seq with arrayed CRISPR screening, modulating the expression of key lineage transcription factors (TFs) (GATA2 - mesoderm, SOX17 - endoderm, and NR4A2 - neuroectoderm) in hiPSCs via CRISPR interference (CRISPRi) or activation (CRISPRa) over a time course of spontaneous differentiation (days cultured in vitro: 0, 4, 12, and 18). This totalled to 54 samples (4 day/time points x 3 target TFs x 2-3 gRNAs per target x CRISPRi/a). Single-cell chromatin accessibility and gene expression data is provided as demultiplexed fastq files.

  Dataset EGAD50000001205

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Isolated memory and naïve T cells were activated using anti-CD3, anti-CD28 or both in combination. As a control we cultured cells in the same conditions but without the stimuli. We carried Chipmentation using the H3K27ac antibody on 200,000 cross-linked cells. 1) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/ .

  Dataset EGAD00001006611

• Small‑scale mutations are infrequent as mechanisms of resistance in post‑PARP inhibitor tumour samples in high grade serous ovarian cancer

  These are 28 targeted exome sequencing fastq files (tumour and germline) generated from ovarian cancer samples which had been exposed to PARP inhibitors, for the described project.

  Dataset EGAD50000000206

• scRNA-seq data of BALF and blood cells from COPD and control

  Chronic obstructive pulmonary disease (COPD) is ranked the third leading cause of death worldwide and hence constitutes a significant burden, both medically and financially. To date, the cellular mechanism underlying COPD is poorly understood and thus no effective therapy is currently available. To broaden the current knowledge of the immune landscape in the alveolar space, we performed scRNA-Seq of CD45-enriched bronchoalveolar lavage fluid (BALF) cells and isolated blood leukocytes obtained from COPD patients and healthy controls using both the Seq-Well and the Chromium (10x Genomics) technology.

  Study EGAS00001004369

• Whole-Genome Sequencing Analysis of Extrachromosomal DNA with Amplicon Architect

  The study is related to our manuscript entitled "Single-cell genetic heterogeneity linked to immune infiltration in glioblastoma". Using multiplexed FISH analysis of 3-4 tumor cores from 17 glioblastoma formalin-fixed paraffin-embedded (FFPE) tumors, we identified two classes of tumors based on single cell co-occurrence of EGFR and CDK4 amplification. Tumors with a low odds ratio for finding EGFR and CDK4 amplified in the same cell (ORlow tumors) had higher EGFR copy number and higher diversity of copy number in cells harboring EGFR amplification. This suggested that in ORlow tumors EGFR is likely present on extrachromosomal DNA. To test this hypothesis, we performed whole genome sequencing on DNA extracted from FFPE slides from 3 ORlow samples and 3 ORhigh samples and used AmpliconArchitect to investigate the structure of the EGFR amplicon. We found multiple breakpoints and high complexity structure in the 3 tested ORlow samples, but not in the ORhigh samples, supporting the possibility of an extrachromosomal nature of EGFR amplification in the first group.

  Study phs003100

• High MAPK Activity Leading to Reduced WNT Signaling Drives Metastasis in Colorectal Cancer

  Colorectal cancer, a leading cause of cancer-related mortality due to distant metastases, is driven by activating mutations in the Wnt and MAPK pathways. Understanding the interplay between these crucial pathways during metastatic progression is essential for developing effective treatments. Here we developed an immunocompetent mouse model of metastatic colorectal cancer using in vivo orthotopic passaging. We demonstrate that highly metastatic tumor cells exhibit chromosomal amplifications in MAPK pathway genes, leading to increased MAPK activity, which in turn suppresses Wnt-associated transcriptional programs, including stem cell-associated genes. Inhibiting mutant KrasG12D effectively reversed this metastatic transcriptional state, reducing MAPK-driven gene expression and restoring Wnt activity. Notably, this treatment significantly curtailed lung metastases and reduced liver metastases during early seeding stages. Analysis of CRC patient data revealed that high MAPK activity and the associated metastatic gene signature correlated with poorer survival outcomes. These findings underscore that the plasticity of metastasis-initiating cells in CRC arises from the opposing roles of MAPK and Wnt signaling, despite their synergistic importance in colon tumor initiation.

  Study EGAS50000001231

• Multimodal single-cell and bulk glioma analyses

  Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We show that local DNA methylation disorder associates with cell-to-cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption, and is altered in environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identifies an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.

  Study EGAS00001005300

• Exome sequencing identifies mutation of the ribosome in T-cell acute lymphoblastic leukemia

  Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and responds well to therapy in children, but not in adults. We used exome sequencing of 67 T-cell ALL (T- ALL) samples to gain insight in the mutational spectrum and age related differences of these leukemias. We detected protein-altering mutations in 508 genes, with an average of 8.2 mutations in pediatric and 21.0 in adult T-ALL. Based on stringent filtering, we predict 15 of these genes to be drivers, including 7 genes that were not previously implicated in T-ALL. We identify CNOT3 as a new tumor suppressor, as it is mutated in 12.2 % of adult T-ALLs and its knock-down causes de novo tumors in a sensitized drosophila eye tumor model. In addition, we identify mutations in RPL5 and RPL10, proteins of the 60S ribosomal complex2, in 18.2 % of pediatric T-ALLs. Mutation of arginine 98 in the X-linked RPL10 gene was most frequent. Yeast cells expressing the Rpl10 R98S mutant showed a clear ribosome biogenesis defect, excluding that this mutation is a passenger mutation. Our data provide insights in the mutational landscape of pediatric and adult T-ALL and identify the ribosome as a potential oncogenic factor in cancer.

  Study EGAS00001000296

• Reasons for Geographic and Racial Differences in Stroke Cardiorenal GWAS

  REGARDS is a national, population-based, longitudinal study of incident stroke and associated risk factors including over 30,000 Black and White adults aged 45 years or older from all 48 contiguous U.S. states and the District of Columbia. The study was designed to investigate reasons underlying the higher rate of stroke mortality among Black participants compared to White participants and among residents of the Southeastern U.S. compared to other U.S. regions. By design, Black adults and residents of the deep south were oversampled. Between 2003 and 2007 (baseline visit) participants completed a computer-assisted telephone interview to collect demographic information and medication adherence, and an in-home visit for blood pressure measurements and collection of blood and urine samples. Following the baseline visit, participants have been contacted by phone at six-month intervals to obtain information on incident stroke or secondary outcomes. Additionally, samples and data were collected on about 50% of the original cohort during a second study visit an average of 10 years after the baseline visit. Genotyping was performed as part of an ancillary study on 10,788 (84% Black) participants using Illumina MEGA arrays.

  Study phs002719

• Genomics of Substance Use Disorders in Latin American Populations

  This is a subsample of the National Survey of Drug, Alcohol, and Tobacco Use, administered in 2016 between August and October to participants aged 12-65 in urban and rural Mexican households, named Mexican Genomic Database for Addiction Research (MxGDAR). The objective of the survey was to evaluate the patterns of use of different psychoactive substances and mental health problems in Mexico. The sample universe was made up of primary sampling units (PSUs) that were the sum of basic statistical geographic areas, stratified by state and urban-rural communities. An adult aged 18-65 was chosen randomly from each household, and an adolescent aged 12-17 was also chosen randomly from the household which has at least one member under 18. The second administration of the survey included a subsample of 13,130 respondents who agreed to give a saliva sample for DNA analysis, to be used in analyzing the relationship of mental health, addiction, and genetics. This sample was weighted according to selection probability to be representative on the national level. Mental health symptomatology for these individuals was evaluated using the Diagnostic Interview for Psychosis and Affective Disorders (DI-PAD) using the operational criteria for psychotic disorders (OPCRIT v.4.0), administered by interviewers trained in its use. It includes the evaluation of symptomatology of psychosis, depression, anxiety, obsession/compulsion, mania/hypomania, and post-traumatic stress. The study seeks to replicate genetic associations with substance use (LINC01622), psychiatric disorders (PTPRM), or comorbidity between both (MGMT) reported in following paper: https://pubmed.ncbi.nlm.nih.gov/33762635/. Funding for genotyping was provided by the National Institute on Drug Abuse (NIDA), one of the National Institutes of Health (NIH).

  Study phs003558

• Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians

  In a genome-wide genetic study of early progression to active tuberculosis (TB), we genotyped 4,002 active TB cases and their household contacts in Lima, Peru. We first established TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases (h2g=0.212). We identified a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 x 10-8). With in silico and in vitro analyses we identified genetic variant rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.

  Study phs002025

• Whole Exome Sequencing of controls performed at the Broad Institute on a cohort from Bristol, UK

  These data were generated as part of a collaboration between University of Bristol, UK and the Stanley Center at the Broad Institute. This project sequenced and analysed the whole exomes of 2969 samples from the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC is a population-based pregnancy cohort with participants acting as ‘controls’ for this project. Genomic DNA from each sample was sequenced to a mean depth of 20x. The exome used Twist capture and samples were sequenced on Illumina NovaSeq 6000 machines producing CRAM files. ALSPAC recruited pregnant women in the Avon County of south-west England between 1991 and 1992. Of the 15,447 pregnancies, 14,901 children were alive at 1 year of age.  DNA was extracted from child blood samples taken between ages 7 and 24.

  Dataset EGAD50000000716

• An MTOR mutation hitchhikes through renal embryogenesis, driving multifocal, multiphenotypic tumours - WGS

  Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the seeding of cells predisposed to disease within mature organs, creating a field effect. We characterise an embryonic cancer mutation that drives multifocal, multiphenotypic renal tumours in a 14-year-old girl. Their shared MTOR mutation, absent from normal tissues, increases protein flexibility which enables a FAT domain hinge to dramatically increase mTORC1 activity. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

  Dataset EGAD00001011645

• An MTOR mutation hitchhikes through renal embryogenesis, driving multifocal, multiphenotypic tumours - RNA

  Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the seeding of cells predisposed to disease within mature organs, creating a field effect. We characterise an embryonic cancer mutation that drives multifocal, multiphenotypic renal tumours in a 14-year-old girl. Their shared MTOR mutation, absent from normal tissues, increases protein flexibility which enables a FAT domain hinge to dramatically increase mTORC1 activity. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

  Dataset EGAD00001011646

• An MTOR mutation hitchhikes through renal embryogenesis, driving multifocal, multiphenotypic tumours - scRNA

  Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the seeding of cells predisposed to disease within mature organs, creating a field effect. We characterise an embryonic cancer mutation that drives multifocal, multiphenotypic renal tumours in a 14-year-old girl. Their shared MTOR mutation, absent from normal tissues, increases protein flexibility which enables a FAT domain hinge to dramatically increase mTORC1 activity. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

  Dataset EGAD00001011647

• Frequent mutation of the major cartilage collagen gene, COL2A1, in chondrosarcoma

  Chondrosarcoma (CHS) is a heterogeneous collection of malignant bone tumours and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1/2 in nearly half of central CHS. However, there has been little systematic genomic analysis of this tumour type and thus the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 cases of CHS. We identified hypermutability of the major cartilage collagen COL2A1 with insertions, deletions and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition we identified mutations in IDH1/2 (59%), TP53 (20%), the RB1 pathway (27%) and hedgehog signaling (22%).

  Dataset EGAD00001000358

• Genetic variability in exon 1 of the glucocorticoid receptor gene NR3C1 is associated with postoperative complications

  Patients having major surgery experience inflammation post-operatively, which may contribute to post-operative morbidity. Endogenous glucocorticoids (GCs) are an essential part of the stress response, but this response varies between individuals, which may in turn affect clinical outcome in general, and post-operative inflammation, specifically. Exon 1 of the NR3C1 gene, encoding the glucocorticoid receptor, contains an established region of differential regulation. DNA methylation patterns in this region have been found to differ between individuals. We investigated the methylation status and genotype in the Cytosine-phosphate-Guanine (CpG) island in exon 1 of NR3C1 in 24 patients who underwent major abdominal surgery and correlated it with post-operative complications. DNA was extracted from peripheral blood leukocytes and underwent targeted bisulfite sequencing of the CpG island. Complications were graded according to the Clavien-Dindo classification and 14 out of 24 had post-operative complications. Multifactorial and partial least square methods were used to analyse the data. A homogenous demethylated pattern was observed in all patients and no single CpG methylation was associated with post-operative complications. Four single nucleotide polymorphisms (SNPs) were significantly correlated with higher Clavien-Dindo scores. Genetic variability in the chr5:143,402,505-143,405,805 region of exon 1 of the glucocorticoid receptor gene NR3C1, but not DNA methylation, was associated with more severe post-operative complications in patients having major abdominal surgery. This indicates that the response to GCs may be of clinical importance for inflammatory conditions.

  Study EGAS00001005737

• Grey_Platelet_Syndrome__GPS_

  As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such pedigree, Grey Platelet Syndrome (GPS) is a rare congenital bleeding disorder caused by a reduction or absence of alpha granules in platelets. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.

  Study EGAS00001000091

• Research in Adaptive Interests, Skills, and Environment

  The Research on Adaptive Interest, Skills, and Environments (RAISE) project is a coordinated set of pilot studies funded and otherwise supported by the Center for the Study of Adolescent Risk and Resilience (C-StARR) at Duke University. The initial data collection effort (Adolescent T1; 2015; NAHDAP 100737) was conducted by telephone and focused on self-regulation and related skills during early adolescence and their role in early instances of health risk behavior. The survey was comprised of brief measures of constructs in six areas of interest to C-StARR investigators: (1) background and home environment; (2) self-regulation and personality; (3) physical and mental health; (4) problem behaviors; (5) academics and school; and (6) technology use. The representative sample of 2104 adolescents was drawn from the population of fifth through eighth graders enrolled in North Carolina public schools during the 2014-2015 school year.In 2016, a subsample of 395 participants from the Adolescent T1 survey (selected on the basis of having resided within 100 miles of study personnel hubs in Durham, North Carolina and Sylva, North Carolina) participated in an additional home visit study that involved the collection of biological data and measures of cognitive ability and executive functioning. The molecular data made available to dbGaP were obtained from saliva samples that were collected (a) in person from 377 of 395 home visit study participants and (b) by mail from 60 participants who had participated in the Adolescent T1 survey but had not participated in the home visit study. The resulting data file was imputed to a 1000G phase 3 panel and is comprised of N = 437 individuals and 7,193,135 markers after filtering. Data were filtered with MAF ≥ 0.01, HWE p-value > 10-6, and genotype rate > 95%.

  Study phs003982

• Indonesian Genome Diversity Project

  Indonesia, the world’s fourth largest country by population, comprises an archipelago of about 900 permanently inhabited islands in tropical Asia, and hosts an astonishing array of human diversity that remains largely underrepresented in modern biological surveys. The region is unique for its key role in both the early and recent evolution of Homo outside of Africa. It has one of the first traces of anatomically modern humans in Eurasia, and was the focus of extensive interaction between archaic hominins and humans – both in the likely co-existence of H. floresiensis with modern humans, and in the introgression of Denisovans into the ancestors of its present inhabitants. More recently, Indonesia was a center of the spread of Neolithic culture by Austronesian speakers. Advancing maritime technologies allowed farming populations to treat this region as a springboard to reach oceanic islands as remote as Madagascar, Hawaii, Easter Island and New Zealand. Here we present complete human genomes from healthy individuals from multiple key islands in Indonesia and Papua. The genomes were sequenced to high depth (30x). The purpose of this dataset is to address different questions of human evolution in Island Southeast Asia and beyond, including early settlement of the area by anatomically modern humans, population structure, genetic admixture and adaptation, and contacts with archaic hominins. We employed a sampling strategy to capture a broad range of diversity across the region incorporating an average of 12 samples from each of 14 islands spanning Indonesia and Papua, from Sumatra in the west to New Britain in the east. Genomes from this dataset form part of an ongoing project to describe and understand human evolutionary history in Island Southeast Asia and Eurasia in general.

  Study EGAS00001003054

• Integrative genome profiling in AML

  AML emerges as a consequence of accumulating independent genetic aberrations that direct regulation and/or dysfunction of genes resulting in aberrant activation of signalling pathways, resistance to apoptosis and uncontrolled proliferation. Given the significant heterogeneity of AML genomes, AML patients demonstrate a highly variable response rate and poor median survival in response to current chemotherapy regimens. For the past 4 years we have conducted gene expression profiling on purified bone marrow populations equating to normal haematopoietic stem and progenitor cells from healthy subjects and patients with de novo AML in order to identify AML signatures of aberrantly expressed genes in cancer versus normal. We are now applying a series of bioinformatic methodologies combined with clinical and conventional diagnostic data to establish novel genomics strategies for improved prognostication of AML. Additionally, we use our AML signatures to unravel oncogenic signalling pathway activities in AML patients and test inhibitory drugs for these pathways inn preclinical therapeutic programmes. We consider that superimposing GEP and clinical data for our AML patient cohort with additional data on their mutational status will significantly improve the prognostic power of the study as well as unravel yet unknown mutations associated with aberrant signalling activities of oncogenic pathways.

  Dataset EGAD00001001873

• Cohort B tumor exome sequencing

  Cohort B includes IDH-wild type, EGFR amplified, surgically derived glioblastoma tissue samples from male and female individuals. Tumor DNA was isolated from FFPE tissue. Both tumor and germline DNA are present for each sample in the overall dataset.

  Study EGAS50000000955

• ChIP-seq for 10 samples

  This dataset contains ChIP-seq data generated from two patient-derived xenograft (PDX) models. For each model, sequencing data are provided from input control (n=1), IgG control (n=2), and FOXF1 immunoprecipitation (n=2). All the 10 samples are in bam file type.

  Dataset EGAD50000001786

• GWAS data (Illumina 2.5 M SNPs) in Cuban cohorts of dengue disease

  We will have 274 individuals typed for the Illumina Human Omni 2.5 chip. The individuals are from two locations in Cuba (Havana and Guantanamo) and from four phenotype classes (asymptomatic, control dengue fever and dengue hemorrhagic fever).

  Study EGAS00001002276

• Distinct genomic profile and specific targeted drug responses in adult cerebellar glioblastoma

  This dataset includes genomic information of 19 adult cerebellar glioblastomas (C-GBMs). Whole-exome sequencing data are available for 9 C-GBMs and their 8 corresponding matched blood samples, and glioma-specific targeted-DNA sequencing (GliomaSCAN) data from additional 10 C-GBMs are also available. Among them, Whole-transcriptome sequencing data were conducted for 6 C-GBM tumors.

  Dataset EGAD00001003417

• Exome_sequencing_of_UK_Birth_Cohorts___Avon_Longitudinal_Study_of_Parents_and_Children

  We propose to exome sequence birth cohorts with near complete population coverage (thus addressing the ascertainment biases of previous studies), which have detailed longitudinal cognitive and educational data on parents and children, and for which genotyping chip data are readily available.

  Study EGAS00001005273

• Exome_sequencing_of_UK_Birth_Cohorts___Born_in_Bradford

  We propose to exome sequence birth cohorts with near complete population coverage (thus addressing the ascertainment biases of previous studies), which have detailed longitudinal cognitive and educational data on parents and children, and for which genotyping chip data are readily available.

  Study EGAS00001006978

• Exome_sequencing_of_UK_Birth_Cohorts___Millennium_Cohort_Study

  We propose to exome sequence birth cohorts with near complete population coverage (thus addressing the ascertainment biases of previous studies), which have detailed longitudinal cognitive and educational data on parents and children, and for which genotyping chip data are readily available.

  Study EGAS00001007789

• Liver CD14+CD8+ T cells scRNAseq dataset

  Sorted single CD8+T cells expressing CD14 from human liver for SMARTSeq2. Livers processed: Kucykowicz et al STAR Prot 2022:pubmed.ncbi.nlm.nih.gov/35516846/ Published: Pallett et al Nature 2022 Tissue CD14+CD8+T-cells are reprogrammed by myeloid cells and modulated by LPS A modified SMART-seq2 protocol was performed on the single flow cytometry sorted-cells as previously described58. After cDNA generation, libraries were prepared (384 cells per library) using the Illumina Nextera XT kit (Illumina). Each library was sequenced to achieve a minimum depth of 1-2 million raw reads per cell using an Illumina HiSeq 4000 using v. 4 SBS chemistry to generate 75-bp paired-end reads.

  Dataset EGAD00001009831

• Sequencing_Acute_Myeloid_Leukaemia_

  This project will aim at sequencing and analysing three samples from a patient with acute myeloid leukaemia (AML) with t(15;17) translocation (acute promyelocytic leukaemia). The patient was treated with standard chemotherapy and samples (blood and bone marrow) taken for minimal residual disease measured during and after chemotherapy. 2-3years later the patient presented a second AML containing inv (16).In this project we will sequence both AML and normal genomes to find associated mutations This will allow unprecedented insights into the dynamics of appearance of secondary AML, since we will be able to use the MRD samples to track the emergence of the inv(16) leukaemia. We will also be able to distinguish whether the 2 leukaemias are clonally related or not. This project will entail sequencing and analysis of three samples (whole genome 30x coverage) using Hi-Seq. The funds from this grant will cover the cost of sequencing 9 lanes from the AML t(15;17) sample, 9 lanes from AML inv(16) sample and 8 lanes from the normal genome.

  Study EGAS00001000035

• Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis

  Mutation accumulation during human life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. Somatic mutations in blood progenitors can provide insight into the rate and processes underlying this accumulation, as well as the developmental lineage tree and stem cell division numbers. Here, we catalogue somatic mutations in the genomes of human bone marrow-derived and cord blood-derived hematopoietic stem and multipotent progenitor cells (HSPCs) and find that base substitutions accumulate with approximately 17 base substitutions per year in both populations, while insertions and deletions occur sporadically and at low numbers. The majority of mutations in adult HSPCs were acquired after birth and could be explained by the constant activity of various endogenous processes, which also explains the mutation load in acute myeloid leukemia (AML). We construct a developmental lineage tree revealing a polyclonal architecture of the hematopoietic progenitor compartment and providing evidence that developmental clones exhibit multipotency, though lineage biases can be detected. Our approach highlights novel features of human native hematopoiesis and its implications for leukemogenesis.

  Study EGAS00001003068

• Multiple Myeloma follow-up sequencing study

  A total of 40 Multiple Myeloma (MM) patients at clinical relapse who progressed during Proteasome Inhibitors (PIs) or Immunomodulating Drugs (IMiDs)-based therapies and who are assigned to antiCD38-based salvage treatments, will be enrolled. We will collect bone marrow (BM) and peripheral blood (PB) samples from patients at specific timepoints: baseline (BM, PB and buccal swab) every 3 month (PB) achievement of response (≥ Very Good Partial Response (VGPR)) (BM and PB) relapse or refractory status to antiCD38-based treatments (BM and PB) Samples will be processed and stored in the "Hematological Laboratory" located in the University of Turin (Italy) for various proposed analyses: at specific time-points CD138+ (Plasma Cells-PCs) awill be immunomagnetically enriched from the BM mononuclear cells and frozen as viable cells in dimethyl sulfoxide (DMSO); PB mononuclear cells (PBMCs) will be isolated from whole blood by density-gradient centrifugation, and frozen as above; plasma fraction from PB and BM will be obtained by centrifugation and stored frozen; Neutrophils will be obtained at the time of enrollment as a source of control germline DNA and stored frozen.

  Study EGAS00001007092

• Singapore Adult Metabolism Study - Phase 2 (SAMS2)

  Singapore Adult Metabolism Study - Phase 2 (SAMS2) was an interventional study where hundreds of donors aged 21-45 were recruited to participate in a 16-week weight loss program. Study individuals selected (see below for more detailed selection standards) were sedentary (exercise 1 or fewer times a week), obese or overweight with a body fat mass greater than 24% and a BMI between 23-35 kg/m2. For this study, we adjusted BMI definition for Asian population, based on the WHO Consultation 2002, and the BMI cut-off is 23 kg/m2 for overweight and 27.5 kg/m2 for obese. The weight loss program included a combination of dietary interventions, structured exercise sessions, and additional physical activity performed in participants' own time. Energy and protein requirements were calculated based on each participant's weight, height, and physical activity level, with the goal of achieving a 40% calorie deficit. Participants' calorie intake was tracked using food recalls and questionnaires. Additionally, subjects attended structured exercise sessions at least three times per week, supervised by a coach. Each session consisted of 90 minutes of aerobic and strength training exercises, designed to burn approximately 500 kcal per session. To monitor daily physical activity, participants wore pedometers throughout the study. In total, the exercise sessions (500 kcal per session) and daily physical activity (targeting an additional 500 kcal) were aimed at achieving a total caloric expenditure of 2000 kcal per week. We collected clinical data and skeletal muscle biopsies from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention, which resulted in an average ~10% weight loss, accompanied by a ~30% increase in insulin-stimulated glucose uptake. Improvements were observed in 118 of 252 clinical traits and six blood lipids. Transcriptomic analysis of paired skeletal muscle biopsies identified 505 differentially expressed genes enriched in mitochondrial function and insulin sensitivity. Thousands of muscle-specific e/sQTLs were detected pre- and post- intervention, including hundreds of lifestyle-responsive e/sQTLs. Notably, approximately 4.2% of eQTLs and 7.3% of sQTLs showed Asian specificity. Joint analysis with GWAS identified 16 putative metabolic risk genes. Our study reveals gene-by-lifestyle interactions and how lifestyle modulates gene regulation in skeletal muscle.

  Study phs004078

• Poly(A) RNA sequencing of hepatocellular carcinoma tumors and their matched noncancerous liver tissues

  Background & Aims: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy Methods: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patientswith multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to con-trast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).Results: The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.Conclusions: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.

  Study EGAS00001002337

• Pan Cancer Investigation of Human Leukocyte Antigen Loss of Heterozygosity

  Cancer cells can escape immune recognition through human leukocyte antigen (HLA) loss of heterozygosity (LOH) which results in deletion of HLA alleles, causing a reduction in presentation of tumor neoantigens. Despite its influence on immunotherapy response, few methods exist to detect HLA LOH, and accuracy of the approaches is poorly defined. Here, we present DASH (Deletion of Allele-Specific HLAs), a machine learning-based algorithm developed to detect HLA LOH from paired tumor-normal sequencing data. Using DASH to characterize HLA LOH in 610 patients across 15 cancer types, we found that 18% of patients had loss of heterozygosity in at least one HLA allele, suggesting the HLA LOH is a widespread, and potentially key immune resistance strategy in multiple cancers.

  Study phs002783

• Exome sequencing of autosomal recessive progressive external ophthalmoplegia (arPEO)

  Progressive external ophthalmoplegia (PEO) is an inherited mitochondrial disease that follows either autosomal dominant or recessive forms of inheritance (adPEO or arPEO). AdPEO is a genetically heterogeneous disease and several genes including POLG1 and C10orf2/Twinkle have been identified as responsible genes. On the other hand, POLG1 was the only established gene causing arPEO with mitochondrial DNA deletions. We previously reported a case of PEO with unidentified genetic etiology. The patient was born of a first-cousin marriage. Therefore, the recessive form of inheritance was suspected. To identify the disease causing variant in this patient, we subjected the patient's DNA to whole-exome sequencing and narrowed down the candidate variants using public data and runs of homozygosity analysis.

  Study phs000392

• Longitudinal analysis of bone marrow heterogeneity reveals the co-evolution of malignant B cells and their T-cell niche supporting follicular lymphoma persistence

  Follicular Lymphoma (FL) is an indolent lymphoid malignancy characterized by cycles of remission and relapse, reflecting the inability of current therapies to fully eradicate tumor cells. Our hypothesis is that rare cancer precursor/persister cells (CPCs) evade treatment by homing to a protective tumor microenvironment, particularly within the bone marrow (BM), and/or by adopting specific cellular states, and form a rare reservoir of residual cells seeding lymphoma recurrence. To adress this, we collected paired BM samples at diagnosis and one year post-therapy from a clinical trial (FLIRT trial, NCT02303119) and applied multi-modal single-cell analysis to dissect the transcriptomics determinants of rare drug-tolerant persister cells and their surrounding T-cell niche.

  Study EGAS50000001295

• Comprehensive analyses of clinicopathological features and genomic mutations of combined hepatocellular-cholangiocarcinoma

  Combined hepatocellular and cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer. We performed whole exome sequencing to clarify the relationship between genetic mutations and clinicopathological features in cHCC-CCA.

  Study JGAS000599

• The epigenetic landscape controlled by p63 in epidermal development

  Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Heterozygous mutations of TP63 encoding p63 cause a spectrum of developmental disorders. EEC syndrome is caused by point mutations in the p63 DNA-binding domain, and manifests ectodermal dysplasia with defects in the epidermis and epidermal related appendages, limb malformation and cleft lip/palate. Five hotspot mutations affecting amino acids, R204, R227, R279, R280 and R304, have been found in approximately 90% of the EEC population. Although the role of p63 in normal epidermal development and differentiation has been demonstrated, the molecular mechanism by which p63 mutations cause the epidermal phenotype in diseases is not yet understood. In the two related studies, we characterize p63 mutant keratinocytes (R204W, R279H and R304W) and p63 mutant iPSCs (R204W and R304W) and the molecular mechanisms underlying their differentiation defects.

  Study phs001737

• Spatiotemporal immune atlas of the first clinical-grade gene-edited pig-to-human kidney xenotransplant

  Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. We transplanted a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and studied the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells were uncommon in the porcine kidney cortex early after xenotransplantation and consisted of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages expressed genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft was detected. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression is sufficient to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

  Study EGAS50000000244

• Stand Up To Cancer East Coast Prostate Cancer Research Group

  Most prostate cancer deaths are caused by metastatic, castration resistant disease (mCRPC). To develop a precision medicine framework for mCRPC, we established a multi-institutional, international clinical sequencing infrastructure to enroll and carry out prospective whole exome and transcriptome sequencing of tumors from a cohort of mCRPC patients. We obtained high quality DNA and RNA sequence data from 150 bone or soft tissue biopsies. Central pathology revealed high-grade adenocarcinoma with only four cases (3.6%) showing neuroendocrine differentiation. Aberrations of AR, ETS genes, TP53 and PTEN were frequent (40-60% of cases), with TP53 and AR alterations being the most enriched in mCRPC compared to primary prostate cancer. We identified novel genomic alterations in PIK3CA/B (fusions and mutations); R-spondin, BRAF and RAF1 (fusions); APC (inactivating mutations); delta-catenin (missense mutations); and ZBTB16/PLZF (homozygous deletions). Aberrations of BRCA2, BRCA1 and ATM were observed at substantially higher frequencies (19.3% overall) than seen in primary prostate cancers, with 56% of these being exclusively somatic. Putative driver gene alterations were identified in nearly all patients, and over half also harbored driver gene fusions, homozygous deletions and/or amplifications. Moreover, 89% of patients harbored a clinically actionable aberration including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. Overall, integrative clinical sequencing analysis can be safely and efficiently performed in mCRPC, yields findings that may be actionable for enrolling patients in clinical trials of targeted therapies, and may inform the basis of individual clinical responses.

  Study phs000915

• UK10K NEURO ASD SKUSE

  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. This sample set of UK origin consists of clinically identified subjects with Autism Spectrum Disorders, mostly without intellectual disability (ie. Verbal IQs >70). The subjects represent children and adults with Autism, Asperger syndrome or Atypical Autism, identified according to standardized research criteria (ADI-algorithm, ADOS). A minority has identified comorbid neurodevelopmental disorders (e.g. ADHD). Family histories are available, with measures of broader phenotype in first-degree relatives.For further information on this cohort please contact David Skuse (d.skuse@ucl.ac.uk).

  Study EGAS00001000114