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• SNP genotyping data in genes related to trace element homeostasis

  In this study we provide data regarding sample charactheristics and genotypes in 150 human samples of European origin for SNPs located around genes related to metal homeostasis. SNPs were genotyped with the Illumina VeraCode technology (192-plex format). The genotyped SNPs were used to identify quantitative trait loci in the same samples. Data referring to the quantification of 18 micronutrients, the expression levels of 90 genes and the protein abundances of 40 proteins related to metal homeostasis in the same samples are directly available as supplementary material in the publication of this study.

  Study EGAS00001001292

• Genetic Epidemiology of Chronic Lymphocytic Leukemia

  Chronic lymphocytic leukemia (CLL) is a subtype of B-cell lymphoproliferative disorders (LPD), and is the most common form of adult leukemia in Caucasians in the United States. Small lymphocytic lymphoma (SLL) is also a B-cell LPD and is typically considered to be the same disease as CLL, based on pathology. We consider CLL and SLL as the same disease entity, and hereafter refer to both simply as "CLL". Using genealogical databases and cancer records, the familial clustering for CLL is one of the strongest for all cancer sites, strongly implicating germline genetic risk. We ascertained CLL cases and controls for a genomewide association study (GWAS) that was undertaken as part of the International Lymphoma Epidemiology (InterLymph) consortium GWAS. Some CLL cases are also part of extended high-risk CLLpedigrees.

  Study phs001568

• Whole-exome sequencing of breast cancer metastasis and corresponding blood samples

  This study included samples from metastatic breast cancer patients who underwent a biopsy in the context of SAFIR01 (NCT01414933), SAFIR02 (NCT02299999), SHIVA (NCT01771458) and MOSCATO (NCT01566019) prospective trials. These French multicentre trials used high throughput genome analysis on fresh frozen tumor biopsies as a therapeutic decision tool for metastatic cancer patients, with solid cancers (SHIVA, MOSCATO) or specifically with breast cancer (SAFIR01, SAFIR02). All patients gave their informed consent for translational research and genetic analyses of their somatic DNA. Overall, whole-exome sequencing for a total of 216 pairs of metastatic tumor and unmutated DNA derived from corresponding blood samples was performed using Illumina technology. The results of the analysis of the mutational profile of metastatic breast cancer was reported in Lefebvre et al. (PMID:28027327).

  Study EGAS00001001695

• Direct Comparative Analysis of 10X Genomics Chromium and Smart-seq2

  Single cell RNA sequencing (scRNA-seq) is widely used for profiling transcriptomes of individual cells. The droplet-based 10X Genomics Chromium (10X) approach and the plate-based Smart-seq2 full-length method are two frequently-used scRNA-seq platforms, yet there are only a few thorough and systematic comparisons of their advantages and limitations. Here, by directly comparing the scRNA-seq data by the two platforms from the same samples of CD45- cells, we systematically evaluated their features using a wide spectrum of analysis. Smart-seq2 detected more genes in a cell, especially low abundance transcripts as well as alternatively spliced transcripts, but captured higher proportion of mitochondrial genes. The composite of Smart-seq2 data also resembled bulk RNA-seq data better. For 10X-based data, we observed higher noise for mRNA in the low expression level. Despite the poly(A) enrichment, approximately 10-30% of all detected transcripts by both platforms were from non-coding genes, with lncRNA accounting for a higher proportion in 10X. 10X-based data displayed more severe dropout problem, especially for genes with lower expression levels. However, 10X-data can better detect rare cell types given its ability to cover a large number of cells. In addition, each platform detected different sets of differentially expressed genes between cell clusters, indicating the complementary nature of these technologies. Our comprehensive benchmark analysis offers the basis for selecting the optimal scRNA-seq strategy based on the objectives of each study.

  Dataset EGAD00001005448

• Genome-Wide associations of Lung Health Study (LHS)

  The 'Genome-Wide Associations Environmental Interactions in the Lung Health Study' at Johns Hopkins University aims to test for association between lung function decline as a primary outcome associated with chronic obstructive pulmonary disease (COPD) using banked DNA and phenotype data on 4,287 European Americans from the longitudinal, multicenter Lung Health Study (LHS). The broad goals of the LungGO/ESP-GO falls into two general categories: (i) discovery of all variants (i.e., common and rare) in all protein-coding regions of the human genome (i.e., the exome) conferring risk to complex pulmonary diseases including COPD, in a subset of the LHS cohort. The Johns Hopkins University LHS cohort offers a unique opportunity to elucidate genetic variants that cause COPD. The Lung Health Study I was a randomized multicenter clinical trial with 5887 participants carried out from October 1986 to April 1994, designed to test the effectiveness of smoking cessation and bronchodilator administration in smokers aged 35 to 60 with mild lung function impairment. Participants were randomly assigned to one of three groups: usual care, who received no intervention smoking intervention with the inhaled bronchodilator ipratroprium bromide smoking intervention with an inhaled placebo. The effect of intervention was evaluated by the rate of decline of forced expiratory volume in one second (FEV1). For the GWAS, only the subset of European American LHS participants for whom lung function data from three time points or more are available. Thus, the GWAS represents 73% of the 5,887 volunteers who participated in the LHS study. Importantly, LHS subjects included had similar demographics (including age, gender and BMI) and rates of lung function decline (mean annual change in FEV1% predicted: -0.96 %/yr vs. -0.99 %/yr, p=0.57) compared with those not included in the GWAS, reflecting little selection bias for our primary outcome. They were, however, more likely to have quit smoking after 5 years. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to lung function through large-scale genome-wide association studies of smokers enrolled in a multicenter clinical trial. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000335

• NHLBI TOPMed - NHGRI CCDG: Early-onset Atrial Fibrillation in the CATHeterization GENetics (CATHGEN) Cohort

  The CATHeterization GENetics (CATHGEN) biorepository collected biospecimens and clinical data on individuals age ≥18 undergoing cardiac catheterization for concern of ischemic heart disease at a single center (Duke University Medical Center) from 2000-2010; a total of N=9334 individuals were collected. Samples were matched at the individual level to clinical data collected at the time of catheterization and stored in the Duke Databank for Cardiovascular Diseases (DDCD). Clinical data included subject demographics, cardiometabolic risk factors, cardiac history including symptoms, age-of-onset of cardiovascular diseases, coronary anatomy and cardiac function at catheterization, laboratory data, and yearly follow-up for hospitalizations, vital status, medication use and lifestyle factors. AF cases were defined as individuals who had ever had AF based on any ECG available at Duke University or ICD-9 code for AF used for inpatient or outpatient billing.

  Study phs001600

• T2D-GENES Consortium: San Antonio Mexican American Family Studies (SAMAFS)

  The Type 2 Diabetes (T2D) Genetic Exploration by Next-generation sequencing in Ethnic Samples (T2D-GENES) Consortium is a collaborative international effort to identify genes influencing susceptibility to type 2 diabetes in multiple ethnic groups using next generation sequencing. To fulfill this objective, T2D-GENES Consortium undertook two large sequencing studies, called T2D-GENES Projects 1 and 2. Project 1 has carried out whole exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 non-diabetic controls, equally divided among five continental ancestry groups: Europeans, East Asians, South Asians, Hispanic Americans, and African Americans. The goal of Project 1 is to identify all genetic variants in the complete coding regions of the genomes (i.e., whole exome) by sequencing, including rare variants. Project 2 (i.e., SAMAFS substudy 2) is a pedigree-based study designed to identify low frequency or rare variants influencing susceptibility to T2D, using whole genome sequence information from approximately 600 individuals in 20 Mexican American T2D-enriched pedigrees from San Antonio, Texas, augmented with family-based imputation into approximately 440 additional family members. The major objectives of Project 2 are to identify low frequency or rare variants in and around known common variant signals for T2D, as well as to find novel low frequency or rare variants influencing susceptibility to T2D. Both T2D-GENES Projects 1 and 2 involve the San Antonio Mexican American Family Studies (SAMAFS), which are composed of four San Antonio, Texas-based family studies: the San Antonio Family Heart Study (SAFHS), San Antonio Family Diabetes/Gallbladder Study (SAFDGS), Veterans Administration Genetic Epidemiology Study (VAGES), and Family Investigation of Nephropathy and Diabetes - San Antonio (FIND-SA) Component and its extension called the Extended FIND [E-FIND]. The SAFHS and SAFDGS began in 1991 and have followed participants with extensive clinical phenotyping related to T2D for over 20 years. The VAGES was initiated in 1994 and a large battery of T2D-related phenotypic data has been obtained from its participants. The FIND-SA began in 2000, a part of the multicenter FIND study which was designed to identify genetic determinants of diabetic kidney disease; data from its participants related to T2D were used for this project. Non-overlapping subsets of SAMAFS participants are part of the T2D-GENES Projects 1 and 2, henceforth referred to as SAMAFS substudies 1 and 2, respectively. The SAMAFS substudies 1 and 2 are part of one of the five awards funded by NIDDK under a cooperative agreement award mechanism, which is governed by the Steering Committee of the T2D-GENES Consortium. Since Project 1 relies on population based subsets of cases and controls, 491 unrelated participants are drawn from the four SAMAFS as part of the T2D-GENES Project 1 Mexican American sample (i.e., SAMAFS substudy 1). The whole exome sequencing was performed at the Broad Institute. For Project 2, 1048 individuals are drawn from two SAMAFS (SAFHS and SAFDGS), representing 20 large families for substudy 2. The substudy 2 strategy is to sequence approximately 600 individuals at an average of 50x coverage across the entire genome, then impute genome wide genotypes for about 440 additional family members. The 600 sequenced individuals are specifically chosen for their value in imputing sequence information into other family members. By studying large pedigrees, we expect to find multiple individuals carrying each genetic variant, even if this variant is very rare in the population at large. Thus, a pedigree-based approach provides an excellent opportunity for identifying rare novel variants influencing risk of T2D and quantitative variation in T2D-related phenotypes. The whole genome sequencing has been done commercially by Complete Genomics, Inc. (CGI). The available sample of 1,048 includes 5 sequenced individuals who do not belong to any of the 20 large pedigrees. The final family data of 1,043 individuals includes whole genome sequence data for 607 individuals. After quality control, 590 sequenced individuals provide data for family based imputation using Merlin linkage analysis software into approximately 440 additional family members for whom chip based genotypes are available to indicate which parental haplotype is transmitted. The complete SAMAFS data including phenotype, genotype, sequence, other T2D-related trait data utilized for Projects 1 and 2 are available. These data can readily be viewed by clicking on the substudy title shown below or in the box: "Substudies", located on the right hand side of this parent or top study page phs000847.v1.p1, titled T2D-GENES Consortium: San Antonio Mexican American Family Studies (SAMAFS). phs000849 T2D-GENES Project 1: San Antonio Mexican American Family Studies (SAMAFS), Substudy 1: Whole Exome Sequencing phs000462 T2D-GENES Project 2: San Antonio Mexican American Family Studies (SAMAFS), Substudy 2: Whole Genome Sequencing in Pedigrees

  Study phs000847

• WES data for Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood BALL

  Whole exome sequencing data for 425 samples with B-cell acute lymphoblastic leukemia

  Dataset EGAD50000000150

• The Melbourne Urological Research Alliance (MURAL) Collection of Patient-Derived Models of Prostate Cancer

  1. Low-Dose Carboplatin Modifies the Tumor Microenvironment to Augment CAR T Cell Efficacy in Human Prostate Cancer Models.Single-cell RNA sequencing (scRNA-seq) was performed to analyze the transcriptional modifications in the tumor microenvironment of prostate cancer patient-derived xenografts (PDX). The analyzed PDX tumor was PDX-287R from the MURAL collection of PDXs (PMID: 34413304). Mice harboring PDX tumors were treated with the carboplatin chemotherapy, and tumors were harvested 3 weeks later. RNA sequencing (RNA-Seq) was used to define immune and non-immune cell populations and anti-tumor innate immune signaling within the tumor microenvironment.To investigate the response of tumor cells to carboplatin treatment in more detail, RNA-Seq was performed on FACs-isolated tumor cells from PDX-287R at one week post-treatment. Gene set enrichment analysis showed an enrichment for apoptotic pathways, with significantly increased expression of the pro-apoptotic genes FAS, BAX, BBC3, IFI6, and JUN. Previously, carboplatin has been shown to activate the cGAS/STING pathway, and here we also found an increase in STING signaling, with an enrichment for the cytosolic DNA sensing pathway and increased expression of STING1, STAT1 and STAT2. There was also a significant increase in the expression of genes involved in T cell chemotaxis, including CXCL10, CXCL11, and CCL20. Collectively, carboplatin-induced cell death in tumor cells likely initiated a pro-inflammatory phenotype in prostate cancer PDXs.2. Co-Targeting BET, CREBBP, and EP300 Inhibits Neuroendocrine Signaling in Androgen Receptor-Null Prostate Cancer.The landscape of castration-resistant prostate cancer (CRPC) is characterized by a multitude of phenotypes, among which neuroendocrine disease holds a prominent position, each displaying unique responses to therapeutic interventions. The efficacy of inhibitors targeting BET and CREBBP/EP300 in prostate cancer treatment is widely acknowledged, primarily due to their ability to attenuate androgen receptor (AR) signaling. However, the effectiveness of these inhibitors in prostate cancers devoid of AR remains uncertain.This investigation sought to elucidate the role of BRD4, CREBBP, and EP300, which are co-expressed in both AR-positive and AR-null prostate cancer. Our study revealed that a compound targeting all three proteins, NEO2734, exhibited efficacy in suppressing the growth of organoids from both AR-positive and AR-null tumors, as evidenced by alterations in viability, size, and cellular composition. Furthermore, NEO2734 treatment consistently led to transcriptional downregulation of cell cycle pathways across various models. In the context of neuroendocrine prostate cancer (NEPC), NEO2734 demonstrated notable efficacy. Treatment with NEO2734 resulted in decreased expression of ASCL1 and other neuroendocrine markers (including SYP) , accompanied by a reduction in tumor growth in vivo. These findings collectively underscore the potential of epigenome-targeted inhibitors in impeding the growth of neuroendocrine prostate cancer, by disrupting lineage regulators in a phenotype-dependent manner. Consistent with the NEPC organoids and explants, NKX3-1 was upregulated in NEO2734-treated PDXs.In this study, we examined the impact of NEO2734 treatment on 6 organoids (treated for 24 hrs), 3 explants treated with JQ1 (for 48 hrs) and 2 PDXs (at two time points) using bulk RNA sequencing (RNA-Seq). These results are available through this dbGaP submission. The implications of these results warrant further exploration and development of compounds possessing similar activities for clinical applications. The ability of NEO2734 to mitigate the growth of both AR-positive and AR-null prostate cancer underscores its potential as a versatile therapeutic agent. Moreover, its efficacy in targeting neuroendocrine phenotypes offers promising avenues for addressing a subtype of CRPC that poses significant clinical challenges. In conclusion, this study sheds light on the intricate interplay between epigenetic regulators and prostate cancer phenotypes. The observed effects of NEO2734 on growth inhibition and phenotype-specific disruption highlight the importance of continued research into compounds with similar epigenome-targeting mechanisms for advancing precision medicine approaches in the treatment of prostate cancer.3. Defining Focal Neuroendocrine Differentiation as a Transcriptionally Distinct Form of Prostate Cancer Pathology Characterized by the Expression of Androgen ReceptorsThe study aimed to understand the transcriptional differences among different neuroendocrine pathologies of prostate cancer. The study hypothesized that the diverse neuroendocrine pathology observed in prostate might be attributable to differences in transcriptional level that remain hidden in bulk RNA-Seq data. To investigate, we employed scRNA-seq to generate gene expression profiles of 18,632 individual tumor cells from 9 PDX models representing five distinct neuroendocrine pathologies of prostate cancer. Our analysis identified 3-8 transcriptionally distinct sub-populations per PDX. The expression of key oncogenic signaling pathways and master regulator activity varied across in neuroendocrine pathologies, with each type of pathology displaying a unique set of transcriptional sub-populations. We discovered that, like the amphicrine pathology, focal neuroendocrine differentiation (focal NED) cells maintain androgen receptor (AR) signaling. However, the expression profiles of focal NED cells differed from the other pathologies, indicating it should be considered as a distinct type of neuroendocrine pathology in prostate cancer. Analysis of copy number alterations suggested little clonal divergence between focal NED cells and neighboring adenocarcinoma cells, emphasizing the transcriptional distinctiveness of focal NED.Overall, the findings suggest potential differences in treatment approaches for tumors from prostate cancer patients showing neuroendocrine pathology, especially focal NED.4. Reprogramming of Androgen Receptor Activity in Castration-Resistant Prostate Cancer is Shaped by Truncated Variants.Under the influence of treatments that target the androgen receptor (AR) axis, prostate cancer cells undergo various changes to the AR gene. This includes the production of truncated AR variants that lack the ligand binding domain and are constitutively active. However, the exact role of these truncated variants in shaping the AR signaling axis and their importance in therapy resistance is not yet fully understood. By examining the AR cistrome in a group of patient-derived prostate cancer models with different mechanisms of castration resistance, we observed diverse changes in AR activity in metastatic prostate cancer, including castration-resistant models. Specifically, we identified a unique subset of tumors characterized by the expression of ARv567es, a variant resulting from structural rearrangements of the AR gene. Tumors positive for ARv567es showed a distinct AR binding profile and epigenome compared to those without ARv567es, which was linked to an altered transcriptional profile. The presence of ARv567es is associated with poor responses to treatments, such as castration and bipolar androgen therapy (BAT), regardless of the presence of full-length AR. This involves disruption of the autoregulatory loop that controls AR gene transcription and reduced transcriptional responses to treatment. Overall, this study demonstrates that ARv567es can lead to transcriptional reprogramming in advanced prostate cancer and drive therapy resistance. 5. The MURAL Collection of Prostate Cancer Patient-Derived Xenografts Enables Discovery Through Preclinical Models of Uro-Oncology.We created a comprehensive PDX resource for prostate cancer to facilitate the rapid and systematic evaluation of new therapies. This collection includes 59 tumors from 30 patients, gathered between 2012 and 2020, aligning with the availability of abiraterone and enzalutamide in the clinic. The PDXs cover the clinical, pathological, and genomic spectrum of prostate cancer, ranging from treatment-naïve primary tumors to castration-resistant metastases. We characterized heterogeneity in adenocarcinoma and neuroendocrine phenotypes using bulk and single-cell RNA sequencing. Additionally, organoids were cultured from PDXs, enhancing our preclinical study capabilities. Employing a 1x1x1 design, we quickly identified tumors with responses to combination therapies. To manage the distribution of PDXs, we established the Melbourne Urological Research Alliance (MURAL). This PDX collection significantly enhances our ability to test and prioritize effective treatments for future clinical trials in prostate cancer.6. Prostate Cancer Associated Fibroblasts Have Distinct Morpho-Mechanical Features That Are Associated With Patient Outcome.The tumor stroma, including cancer-associated fibroblasts (CAFs), has a crucial role in tumor progression. This study focused on the morphological and mechanical properties of CAFs and normal prostatic fibroblasts. The findings revealed that CAFs had distinct morphological and mechanical characteristics compared to normal fibroblasts, such as differences in nuclear size, shape, F-actin arrangement, cellular volumes, and elasticity. Additionally, the study correlated these biophysical properties with transcriptomic data, identifying pathways and cellular components linked to the observed changes. Overall, high-throughput assessments of biophysical properties in prostate cancer cells and stromal components may serve as predictive tools for patient outcomes and help identify new therapeutic approaches targeting the tumor stroma.

  Study phs003369

• NHLBI TOPMed: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE)

  ECLIPSE was a longitudinal observational study of 2164 COPD subjects and a smaller number of smoking controls (337) and nonsmoking controls (245) followed regularly for three years, with three chest CT scans (at baseline, one year, and three years) (Vestbo et al., 2008, PMID: 18216052). Subjects were enrolled at clinical centers in the US, Canada, Europe, and New Zealand. Inclusion criteria included subjects ages 40-75, at least 10 pack-years of smoking, and spirometry in GOLD grades 2-4 (COPD cases) or normal spirometry with post-bronchodilator FEV1 >85% (predicted) and FEV1/FVC>0.7 (controls). Study visits were performed at enrollment, three months, and every six months thereafter with spirometry, questionnaires, and other clinical evaluations. The ECLIPSE CT scans have been analyzed with the VIDA software for emphysema and airway phenotypes. ECLIPSE has provided key insights into the clinical epidemiology of COPD, including COPD exacerbations (Hurst, et. al., 2010, PMID: 20843247) and lung function decline in COPD (Vestbo, et. al., 2011, PMID: 21991892). ECLIPSE has been used in a number of genetic studies of COPD susceptibility and protein biomarkers (Faner, et. al., 2014, PMID: 24310110). Genome-wide gene expression microarray data are available in 147 induced sputum samples from COPD subjects and 248 peripheral blood samples from COPD and control subjects. Phenotype data for ECLIPSE subjects is available through dbGaP phs001252.

  Study phs001472

• Single cell transcriptomics of hESC-derived midbrain dopaminergic neurons generated by a new human development-based protocol

  Recent advances in stem cell technologies provide new opportunities for regenerative medicine and Parkinson’s disease modelling. However, the precise composition and quality of human embryonic stem cell (hESC)-derived preparations at the single cell level, compared to endogenous brain standards, remains to be determined. In addition, multiple developmental pathways important for midbrain dopaminergic (mDA) neuron development remain to be implemented in hESCs. Here we use mouse developmental knowledge and human single cell RNA-sequencing (scRNA-seq) data to generate a new development-based protocol to differentiate hESCs into mDA neurons. We found that Laminin 511, dual WNT activation with CHIR99021 and WNT5A, together with FGF8b, improved different aspects of midbrain patterning. Moreover, mDA neurogenesis and differentiation were enhanced by activation of liver X receptors and inhibition of fibroblast growth factor signaling. Analysis of hESC-derived midbrain cultures by scRNA-seq revealed multiple hESC-derived clusters, which resembled those in the endogenous human ventral midbrain. Moreover, high quality mDA neurons were detected and found to progressively acquire functionality in vitro. Thus, we hereby provide a hESC differentiation protocol that recapitulates several aspects of endogenous mDA neuron development, and a strategy to determine cell composition and quality of hESC-derived preparations that can be useful for disease modeling and cell therapy.

  Study EGAS00001006313

• DAC for study Hypothalamic transcriptome in Prader-Willi syndrome

  Dac EGAC00001000869

• DAC for study Non-coding RNAs in Breast Cancer

  Dac EGAC00001001090

• Data access Commitee for anti-PD1 in HCC data

  Dac EGAC00001002404

• DAC for RNAseq data in B cell malignancies

  Dac EGAC50000000399

• DAC for GWAS of Phenytoin-Induced SJS/TEN in Thailand

  Dac EGAC00001003602

• Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer's disease and Longitudinal follow-up of Genotype-Phenotype Associations in Alzheimer's disease and Neuroimaging component of Genotype-Phenotype Associations in Alzheimer's disease

  GenADA is a multi-site collaborative study, involving GlaxoSmithKline Inc and nine medical centres in Canada, to develop a dataset containing 1000 Alzheimer's disease patients and 1000 ethnically-matched controls in order to associate DNA sequence (allelic) variations in candidate genes with Alzheimer's disease phenotypes. The study consists of both retrospective and prospective components, that is, patients with an existing diagnosis of Alzheimer's disease as well as newly diagnosed patients were enrolled in the study. Thus, clinical data was retrospectively or prospectively obtained on Day 1 of entry into GenADA. Where possible, biological relatives with Alzheimer's (up to third degree relationship such as cousins) and unaffected siblings of AD cases were also recruited. Note that recruitment numbers for biological relatives were lower than expected and genotypic data has not been submitted to dbGap for these subjects. The purpose of this study is: To identify DNA sequence variations (genotype) in candidate genes that are associated with the clinical symptoms and behavioural features of Alzheimer's disease (phenotype), which differ between study participants with and without the disease. To identify other genotype-phenotype associations in cognitively impaired study participants such as age of onset, family history, rate of cognitive decline, patterns of behavioural/psychiatric non-cognitive symptoms factors, response to treatment co-morbid conditions, and risks/exposure. The final subject recruitment for this study included 875 Alzheimer's disease patients, 850 ethnically-matched controls, and 37 family members. GenADA LONG is a longitudinal assessment to the original GenADA study. Eligible subjects were recruited from five of the nine memory clinics that participated in the GenADA study. Mild to moderate AD participants, a matched subset of controls, and biological related siblings (both affected and unaffected) or other blood relatives affected with AD, were initially examined a minimum of 12 months from recruitment into the original GenADA study, then at two further intervals of 12 and 18 months after time of entry into GenADA LONG. This enables an evaluation of the disease progression in AD patients and a determination of whether controls show evidence of cognitive decline. The overall goal of this extension study is to identify genetic differences and environmental influences that modulate the age of onset of the disease, the course of the disease, and/or biomarkers for neurodegenerative processes. Three of the five memory clinics that participated in the GenADA LONG study recruited eligible patients into GenADA Imaging. A concurrent neuroimaging sub-study was conducted at three of the five memory clinics participating in GenADA LONG. Eligible AD cases with mild to moderate AD, who were recruited into the original GenADA study and participated in the GenADA LONG extension study, were enrolled. Additionally, controls that showed signs of cognitive decline, as part of the assessment in GenADA LONG, were imaged at baseline, 12 and 18 month scanning intervals. The objective of this study is to find genes that: affect changes in AD brain volume measure by magnetic resonance in order to investigate how well change in brain volume predicts other key clinical measures in AD, such as neurodegenerative scales; that correlate changes in brain volume for other genotype-phenotype associations in cognitively impaired study participants; and that correlate with other clinically applicable magnetic resonance measures of pathology that can be conducted at the same time as structural volume measures, and are complementary to the volume measures. The ultimate aim of this research is to obtain a better understanding and definition of Alzheimer's Disease in order to develop new improved medicines.

  Study phs000219

• Kibbutzim Family study

  The Kibbutzim Family Study (KFS) was established in 1992 to investigate the environmental and genetic determinants of cardiometabolic risk factors and their change over time. The participants belong to large families living in close-knit communities, called “Kibbutzim”, in Northern Israel. The Kibbutz has been a communal settlement, which has created a relatively homogeneous environment for its members. Kibbutz members are mostly of Ashkenazi Jewish ancestry, with the remaining members belonging to other Jewish subgroups. Participants were recruited in two phases from six Kibbutzim. In the first recruitment phase of the study (1992–1993) 500 individuals from 80 extended families (range 2 to 43) were examined. During the second phase (1999–2000), all participants from the first phase were invited for repeat examinations (80% response rate) and additional new participants were recruited, giving a total of 922 individuals from 150 extended families (range 2 to 55). Families were invited to participate if they consisted of at least four individuals who (i) lived in the Kibbutz, (ii) spanned at least two generations, and (iii) were at least 15 years old. Families were retained if at least two family members consented to participate in the study. Overall, 1033 participants were recruited; 111 were examined only in the first phase, 533 only in the second phase, and 389 were included in both. 901 individuals were successfully genotyped using Illumina HumanCoreExome BeadChip.

  Study EGAS00001002782

• Therapeutic Genetics and Disease Modeling in LAMA2-CMD

  Merosin-deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder caused by mutations in the LAMA2 gene, resulting in a defective form of the extracellular matrix protein laminin-α2 (LAMA2). Individuals diagnosed with MDC1A exhibit progressive muscle wasting and declining neuromuscular functions. No treatments for this disorder are currently available. This study involves transcriptomic comparison analysis between MDC1A patient fibroblasts and healthy control fibroblasts to reveal changes in gene expression that contribute to LAMA2 congenital muscular dystrophy (LAMA2-CMD).

  Study phs003250

• genetic analysis of carcinogenesis in GAPPS

  Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal dominant syndrome characterized by polyposis localized in the gastric body and fundus with a strong tendency for adenocarcinoma. The genetic mutations that accumulate during the progression from normal mucosa through fundic gland polyps (FGPs) to carcinoma in GAPPS remain unclear.We investigated the evolutionary process from normal mucosa to FGPs and carcinoma in GAPPS. Through comprehensive mutational and transcriptome analyses, we aimed to provide insights into the biology of this disease.

  Study JGAS000843

• Spatial multiomic analyses reveal carcinogenic pathways in end-stage renal disease

  Patients with end-stage renal disease (ESRD) are at increased risk for acquired cystic kidney disease (ACKD) and renal tumours, but the molecular basis of such disorders remains elusive. Here, we performed spatial immunogenomic analyses on specimens from 43 patients with ACKD and associated tumours. In this study, we characterized the genomic and transcriptomic features of renal tumours in ESRD. Second, we elucidated the genetic background and microenvironment of cysts in ACKD via comprehensive spatial transcriptomics.

  Study JGAS000855

• Immune Biomarkers in Metastatic Castration-resistant Prostate Cancer

  Background: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease in which molecular stratification is needed to improve clinical outcomes. The identification of predictive biomarkers can have a major impact on the care of these patients, but the availability of metastatic tissue samples for research in this setting is limited. Objective: To study the prevalence of immune biomarkers of potential clinical utility to immunotherapy in mCRPC by tumour RNA sequencing, and to determine their association with overall survival (OS).

  Study EGAS50000001269

• MYD88/TLR mutations in CLL

  The Chronic Lymphocytic Leukemia (CLL) Genome Project aims to identify genetic alterations involved in the development and progression of the CLL, which are still unknown, with the objective of generating a comprehensive catalogue of genetic alterations in 500 independent tumours. The CLL Genome Project, as a contributing member of the International Cancer Genome Consortium (ICGC), has the purposes of creating diagnostic tools, discovering therapeutic targets and developing new strategies that will allow a customized therapy for CLL in order to make it more precise and effective.

  Study EGAS00001000772

• Paired exome analysis in urothelial carcinoma

  In this study we characterized genomic alterations in two to five metachronous tumors from 29 patients initially diagnosed with early stage disease. Fourteen patients (32 tumors) had non progressive disease (NPD) and 15 patients (34 tumors) had progressive disease (PD). Whole exome sequencing (WES, ~50x mean read depth), Ultra deep targeted sequencing (~6,809x mean read depth) and whole transcriptome RNA-seq was performed for all samples. In addition multiregional WES was performed on 8 adjacent regions from a single tumor.

  Study EGAS00001001686

• Tumour evolvability metrics predict recurrence in advanced localised prostate cancer (normal data)

  There is a need for quantitative measurements of evolutionary metrics in controlled clinical trials with long term follow-up information. This is particularly true in advanced localised prostate cancer, which can recur more than a decade after diagnosis. Here we mapped genomic intra-tumour heterogeneity in 642 tumour samples from 114 patients who took part in the IMRT and DELINEATE clinical trials, for which full clinical information and 12y median follow-up was available. We concomitantly assessed phenotypic (morphological) heterogeneity using Deep Learning in 1,923 histological sections from 250 IMRT patients (fully overlapping with the genetic set). This study shows that combining genomics with AI-aided histopathology in clinical trials leads to novel clinical biomarkers. This EGA repository contains data produced from tumour samples using low coverage whole genome sequencing and a prostate cancer specific gene panel data following compression of unique molecular identifiers.

  Dataset EGAD00001010295

• Tumour evolvability metrics predict recurrence in advanced localised prostate cancer (tumour data)

  There is a need for quantitative measurements of evolutionary metrics in controlled clinical trials with long term follow-up information. This is particularly true in advanced localised prostate cancer, which can recur more than a decade after diagnosis. Here we mapped genomic intra-tumour heterogeneity in 642 tumour samples from 114 patients who took part in the IMRT and DELINEATE clinical trials, for which full clinical information and 12y median follow-up was available. We concomitantly assessed phenotypic (morphological) heterogeneity using Deep Learning in 1,923 histological sections from 250 IMRT patients (fully overlapping with the genetic set). This study shows that combining genomics with AI-aided histopathology in clinical trials leads to novel clinical biomarkers. This EGA repository contains data produced from tumour samples using low coverage whole genome sequencing and a prostate cancer specific gene panel data following compression of unique molecular identifiers.

  Dataset EGAD00001010274

• The landscape of somatic mutation in normal colorectal epithelial cells

  The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic events and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ~1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

  Dataset EGAD00001004193

• NCI COVID-19 in Cancer Patients Study (NCCAPS): A Longitudinal Natural History Study

  NCCAPS is a longitudinal prospective cohort study designed to assess patient, disease and treatment factors associated with short- and long-term outcomes in patients with cancer who develop COVID-19. We also aimed to describe COVID-19 symptoms and treatments, and to describe disruptions in cancer treatment due to COVID-19. The study enrolled patients with cancer on active treatment or with a history of stem cell transplant or CAR-T cell therapy with new, active COVID-19, defined as being within 14 days of their first positive SARS-CoV-2 test. The study found that receipt of chemotherapy and baseline history of stroke, atrial fibrillation or pulmonary embolism were associated with a higher risk of hospitalization for COVID-19. Vaccination for SARS-CoV-2 was associated with a lower risk of hospitalization. Death due to COVID-19 was highest in patients with lymphoma, intermediate in those with acute leukemia and lung cancer, and lowest in those with other solid tumors and other hematologic cancers. Disruptions of cancer treatment were frequent in the first 30 days after SARS-CoV-2 infection.

  Study phs004178

• Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease

  Population level variation and molecular mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized despite ramifications for personalized nutrition. We now define prototypical insulin secretion dynamics in response to the three macronutrients in islets from 140 cadaveric donors, including those diagnosed with type 2 diabetes. We leverage the insulin response heterogeneity and use transcriptomics and proteomics to identify molecular pathways of specific nutrient responsiveness. Surprisingly, we find robust insulin secretion to fatty acid stimulus in ~8% of donors, challenging the idea that fat has negligible effects on insulin release. Distinct islet proteomes with differences in metabolic signalling networks convey this hyper-responsiveness to fat relative to carbohydrate. By comparing human islets to human embryonic stem cell-derived islet clusters, we show that, unlike glucose-responsiveness, fat hyper-responsiveness is equivalent and may be a hallmark of functionally immature cells. Our study represents the first comparison of dynamic responses to nutrients and multi-omics analysis in human insulin secreting cells. Responses of different people’s islets to carbohydrate, protein, and fat lay the groundwork for personalized nutrition.

  Study EGAS00001007241

• Single cell RNA sequencing of synovial B cells in early Rheumatoid Arthritis

  Rheumatoid Arthritis (RA) is a prevalent autoimmune disease characterized by inflammation of the peripheral joints and occurence of autoantibodies, i.e. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA), in circulation. Previous studies have shown that there are memory B cells and autoantibody producing plasma cells present in the joint tissue of patients with long-standing RA. However, it has remained unclear, whether these B cell populations are already present in the joint tissue of patients at the disease onset and whether these are autoreactive. Here, we used a single cell RNA sequencing approach to dissect the B cell repertoire at this early timepoint. We found evidence for B and T cell interaction and presence of memory and plasma cell pools in ACPA- and ACPA+ RA. Our results demonstrated clonal relationships between the memory and plasma cell compartments and autoreactivity within the plasma cell pool. These findings challenge our understanding of the local adaptive immune response in the joints of ACPA- and ACPA+ RA patients with direct implications for B and T cell targeting therapy in both patient subgroups.

  Study EGAS00001005144

• African American Multiple Myeloma GWAS

  The case set is from a case-control study designed to identify common genetic risk factors for multiple myeloma in African Americans, the population with the highest risk for this cancer. We conducted two GWAS and combined each of these with convenience controls consisting of unaffected African American participants in cohorts with existing GWAS data. We then conducted a meta-analysis of the two sets. Cases were persons of African ancestry with smoldering or active multiple myeloma identified at participating oncology clinics or through SEER registries, as part of the African American Multiple Myeloma Study (AAMMS) diagnosed from Jan 1, 1988 through July 31, 2016. The majority of the samples were collected from incident and prevalent cases diagnosed since Jan 1, 2008 (80.9%), with a minority obtained from biobanks from cases diagnosed prior to 2008 (19.1%). Additional samples were obtained from the Multiethnic Cohort (USC and University of Hawaii) (n=40), the University of California at San Francisco Multiple Myeloma Study (n=27), and from the Multiple Myeloma Research Consortium for secondary analysis (samples originally provided to MMRC by 8 additional sites (n=84)). We have identified the phenotype (smoldering myeloma, plasma cell multiple myeloma, or myeloma not otherwise specified (myeloma NOS) when myeloma phenotype was not known), sex and age at diagnosis in this data set. The initial GWAS set consisted of 1308 (1,305 passed QC) cases with DNA samples, with a GWAS performed on the Illumina Human Core. Controls consisted of 7,078 unaffected African American subjects who were participants in the African American Prostate and Breast Consortium, with existing GWAS data from the Illumina1M Duo BeadChip. The second GWAS set consisted of 529 African American multiple myeloma patients with samples (406 from University of Arkansas, results not contained in this dataset because NCI funds were not used for the collection and genotyping) with GWAS data resulting from the Illumina Mega-BeadChip v1.1. Controls were 2,390 unaffected African American participants in the Multiethnic Cohort with existing GWAS data from the same array. After QC and removal of duplicates within sets, sex mismatches, and removal of plasmacytoma cases (ICD-0 code 9731), this deposited data set contains the typed GWAS data for the Illumina Human Core (set 1) (n=1298), and for the MegaBead Chip v1.1 (set 2) (n=123), with the University of Arkansas samples removed, for a total of 1,421 case genotypes. Note that 13 samples that overlap set 1 and set 2 were included.

  Study phs001632

• GoNL raw sequence data in fastq format

  Raw sequencing data for all samples in fastq format.

  Dataset EGAD00001000821

• Semibulk RNA-seq analysis as a convenient method for measuring gene expression statuses in a local cellular environment

  For two cases of breast cancers, semibulk RNA-seq and single cell RNA-seq were performed.

  Study JGAS000387

• Adult-type Granulosa Cell Tumour of the Ovary

  A recurrent mutation in FOXL2 (c.402C>G; p.C134W) is present in over 95% of adult-type granulosa cell tumours (AGCTs). In contrast, various loss-of-function mutations in FOXL2 lead to the development of blepharophimosis, ptosis and epicanthus inversus syndrome (BPES). BPES is characterized by an eyelid malformation often accompanied with primary ovarian insufficiency but not granulosa cell tumours. Two recent studies suggest that FOXL2 C402G is a gain or change-of-function mutation with altered DNA-binding specificity. Another study proposes that FOXL2 C402G is selectively targeted for degradation inducing somatic haploinsufficiency suggesting its role as a tumour suppressor. The latter study relies on data indicative of an FOXL2 allelic imbalance in AGCTs. Here we present RNA-seq data as genetic evidence that no real allelic imbalance is observed at the transcriptomic level in AGCTs. Additionally, there is no loss of protein expression in tumours harboring the mutated allele. These data and other features of this mutation as compared to other oncogenes and tumour suppressor genes argue strongly against FOXL2 being a tumour suppressor in this context. Given the likelihood that FOXL2 C402G is oncogenic, targeting the variant protein or its downstream consequences is the most viable path forward to identifying an effective treatment for this cancer.

  Study EGAS00001005414

• Childhood Cancer Data Initiative (CCDI): Enhancement of Data Sharing in Pediatric, Adolescent and Young Adult Cancers

  NCI's Childhood Cancer Data Initiative (CCDI) is building a community centered around childhood cancer care and research data. Through enhanced data sharing, we can improve our understanding of cancer biology to improve preventive measures, treatment, quality of life, and survivorship, as well as ensure that researchers learn from every child with cancer. While childhood cancers represent the leading cause of death in children over the age of 1, they are collectively rare, comprising approximately 1%‒3% of cancers diagnosed annually in the United States. Information on diagnosis, treatment, and outcomes is often stored at the hospital or institution where a child is treated, making it difficult to answer scientific questions about childhood cancer. Sharing clinical care and research data generated by children's hospitals, clinics, or networks broadly with the community can help us learn faster and, on a scale much larger than any single institution caring for children can learn on its own. To exploit the rapid advances in high-throughput DNA sequencing technologies and realize the goals of precision cancer medicine, the UMICH Cancer Center established the Michigan Oncology Sequencing Center (MI-ONCOSEQ). This UMICH Cancer Center provisions genomic data derived from the Michigan Oncology Sequencing Center (MI-ONCOSEQ) clinical sequencing assay for patients that fall within the inclusion criteria of the CCDI data sharing initiative. An "integrative sequencing approach" carried out in a CLIA-certified laboratory is utilized to provide a comprehensive landscape of the genetic alterations in individual tumor specimens for the purpose of identifying informative and/or actionable mutations. Using a number of computational pipelines that we have developed in-house or have adapted from the public domain, candidate molecular aberrations are nominated and then analyzed by scientists for clinical significance and/or relevance. This approach enables the detection of point mutations, insertions/deletions, gene fusions and rearrangements, amplifications/deletions, and outlier expressed genes. Furthermore, we can identify certain germline alterations that may also be relevant.

  Study phs002431

• Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation

  As part of the study "Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation" we wanted to identiffy the SNVs that are located in STRC and which ones in STRCP1. For this we applied targeted long-read sequencing.

  Dataset EGAD00001011305

• Harnessing transposons for drug resistance gene discovery in cancer

  This study involves a forward genetic screen to identify common insertion sites in drug resistant clones. We will be utilising piggybac transposon systems in order to generate multiple drug resistant clones in a range of human cancer cell lines.

  Dataset EGAD00001000980

• Bone Microarchitecture

  Osteoporosis affects more than 28 million people in the United States and the lifetime risk for osteoporosis-related morbidity is higher than a woman's combined risk for breast cancer, endometrial cancer and ovarian cancer. Health care expenditures for osteoporotic patients in this country are currently nearly 13 billion dollars per annum and are predicted to increase markedly in the next decades due the aging of the population; therefore, it is important to understand the factors that contribute to bone strength and fracture risk. With the advent of skeletal imaging modalities such as high resolution peripheral quantitative computed tomography (HR-pQCT), it is now possible to study the genetics of more highly refined peripheral skeletal microarchitecture phenotypes. Because these refined phenotypes have not been measured in many cohort studies, this project was a collaborative effort to include almost all the existing data on HR-pQCT of the radius and tibia, and genetics from around the world. Cohorts involved in the discovery included: 1) Framingham Osteoporosis Study, 2) Mayo Clinic cohort; 3) Geneva Retirees cohort; 4) OFELY cohort from Lyon France; 5) STRAMBO cohort from Lyon France; 6) Swedish Male cohorts. Replication cohorts undergoing de novo genotyping include: 1) QUALYOR cohort from Lyon France; 2) CaMOS cohort from Canada. Other than the Framingham cohort and the Swedish male cohorts, all discovery cohorts underwent genome wide genotyping with the Affymetrix Axiom Biobank array that had common variants along with exome content based on the early findings from the Exome Sequencing Project. All genotype data from the discovery cohorts were then imputed using the Haplotype Reference Consortium reference panel. Variants for replication genotyping using the Kasp technology were selected based on novelty compared with previously identified loci using DXA phenotypes, minor allele frequency, underlying LD structure within a locus, and likelihood of a variant being functional as assessed using various algorithms for coding and non-coding variants.    

  Study phs002102

• Separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution

  Chronic myeloid leukemia (CML) is a clonal disease, initiated and sustained by a subpopulation of CML stem cells (CML-SC) containing the BCR::ABL1 oncogene. Genetic markers that enrich for CML-SC have been identified, including CD26 being most specific. Genome sequencing analysis remain yet to be performed at single cell level in order to determine differences and heterogeneity in the genetic profile of CML-SC versus normal hematopoietic stem cells (HSC). Here we show that CD26 and CD33 separate CML-SC from normal HSC in freshly isolated bone marrow samples from newly diagnosed CML patients. DNA sequencing confirms that single CML-SC derived colonies are positive for BCR::ABL1 and harbor a recurrent set of patient-specific clonal somatic mutations across different CML-SC derived colonies. In contrast, marker-negative (CD26-CD33-) HSC from the same patients are negative for the BCR::ABL1 oncogene and do not carry recurrent, clonal mutation across different colonies. These results support the concept that CD26/CD33 expression separates genetically defined, clonal mutant CML-SC from normal HSC that carry individual sets of random mutations in CML patients. We provide whole exome DNA sequencing data for 23 clinical samples of CML-SC plus two buccal swipes derived normal samples. CML samples are comprised of 4 to 8 replicates from two patients, at diagnosis and after treatment. Single CML stem cells before treatment and single non-transformed HSC at remission were selected from bone marrow samples by FACS, according to genetic markers CD33+CD26+ at diagnosis and CD33+CD26-/CD33-CD26- at remission. WES libraries of colony forming assays derived CML-SC and HSC populations were prepared using Agilent SureSelect Human All Exon V6 kit and sequenced running 150 cycles (2x 75bp paired-end) on an Illumina NextSeq 500 platform. Following GATK best practices for somatic mutation calling, novel CML variants and random mutation events during remission phase were obtained.

  Study EGAS00001006904

• Analyzing Somatic Mutagenesis in Systemic Sclerosis

  The study was undertaken with the aim of estimating differences in the mutational burden in lung tissues from healthy vs systemic sclerosis (SSc) patients. SSc is an auto-immune disease, with patients often developing cancer. However, the etiology of this phenomenon is poorly understood. As such we sought to uncover potential molecular mechanisms prevalent within SSc tissues that might be potentiating cancer. Samples were randomly collected from individuals from two broad ethnic groups, European (EA) and African American (AA). In total, samples were obtained from 7 individuals belonging to the EA group and 4 individuals from the AA group. For this study, ethnicity was not included as a confounding variable, given that the data set has roughly comparable number of individuals from both ethnicities for the healthy and SSc cohorts. Study participants ranged in age from 37-63 years old. Median age (52 years old) of healthy individuals was comparable to the SSc cohort (~48 years old). Participants were self-described as current/former smokers or non-smokers. Lung tissues were obtained under a protocol approved by the University of Pittsburgh Institutional Review Board. Written informed consent statements were provided to the University of Pittsburgh IRB by the study participants/patients. Sample sizes were determined by the ability of bulk lung fibroblast tissues to stably propagate in culture until single cell clones could be obtained. Samples for which sufficient cell density could not be achieved for downstream high-depth sequencing analysis were excluded from the study and are not reported. Five or greater than 5 samples are collected from each cohort including healthy and SSc patients. Subjects were allocated to two basic cohorts based on diagnosis at the time of explant. Participants with no reported lung anomalies were allocated to the "healthy" cohort, whereas individuals with reported lung abnormalities, primarily SSc with pulmonary fibrosis and/or hypertension were allocated to the "SSc" cohort. All tissue samples were cultured, propagated and processed in identical fashion without requiring individual-specific protocols. Additionally, equivalent amounts of DNA were used for preparing sequencing libraries from both cohorts, and all samples were sequenced using Illumina whole genome sequencing (WGS) and analyzed using identical computational pipelines. Our study primarily discovered that there is a significantly higher burden of somatic mutations in SSc samples, compared to healthy samples. We observed an overall increase in a range of mutations in genomes of SSc patients, including single base substitutions, indels, structural variants and copy number alterations. Additionally, we uncovered a novel mutation signature associated with SSc samples, hinting at the activity of POLH in these samples, and highlighting the potential nexus between inflammation, DNA damage, and cancer.

  Study phs003700

• Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) Center for Environmental Health Disparities

  MADRES is a prospective pregnancy cohort based in urban Los Angeles, recruiting predominantly low income Hispanic mothers-to-be as part of a children's health study, funded by Environmental Influences on Child Health Outcomes (ECHO). Participants were measured for a number of chemical exposures and biomarkers. Two epigenetic markers will be available through dbGaP: miRNA expression in pregnancy (measured via Nanostring human assay, v3) and DNA methylation from pregnancy and children's cord blood (measured via EPIC array). Principal findings of this research described differences in miRNA expression profiles between early and late pregnancy, as well as miRNA expression affected by psychosocial stress.

  Study phs003194

• Genome-wide DNA methylation profiles of NSCLC xenograft and primary lung tissues for the identification of epigenetic predictive biomarkers.

  Non-small cell lung cancers (NSCLC) are the most common cause of cancer-related deaths worldwide and primarily treated with platinum-based drugs like cisplatin and carboplatin, radiation and surgery. The major challenge in the management of NSCLC are intrinsic or acquired resistance mechanisms with only few published molecular markers which can predict the outcome of the patients. On the other side, changes in DNA methylation are observed in nearly all cancer types making them suitable as biomarker. Here genome-wide methylation profiles from MeDIP-Seq and gene expression profiling data of 22 primary NSCLC, adjacent normal tissue and PDX samples are provided. For each PDX tumor growth rates were measured in absence or presence of chemotherapy.

  Study EGAS00001002479

• Recording physiological history of cells with chemical labeling.

  Recordings of the physiological history of cells provide insights into biological processes, yet obtaining such recordings is a challenge. To address this, we introduce a method to record transient cellular events for later analysis. We designed proteins that become labeled in the presence of both a specific cellular activity and a fluorescent substrate. The recording period is set by the presence of the substrate, whereas the cellular activity controls the degree of the labeling. The use of distinguishable substrates enabled the recording of successive periods of activity. We recorded protein-protein interactions, G-protein-coupled receptor activation and elevations in intracellular calcium. Recordings of elevated calcium levels allowed selections of cells from heterogenous populations for transcriptomic analysis and tracking of neuronal activities in flies and zebrafish.

  Study EGAS50000000056

• High Glucose Macrophage Exosomes Enhance Atherosclerosis by Driving Cellular Proliferation and Hematopoiesis

  In this study, we aimed to explore whether hyperglycemia alters inflammatory properties and microRNA levels in immune cells as well as their extracellular vesicles (EVs) as a mode of intercellular communication in cardiovascular disease. To this end, we isolated EVs from the plasma of diabetic mice as well as from human subjects that included 7 healthy individuals (control), 5 individuals with diagnosed peripheral arterial disease but no diabetes, 9 diabetic individuals with no vascular disease and 5 diabetic subjects with established vascular disease. The human plasma EVs were examined for the content of microRNA and their capacity to communicate signaling when incubated with cultured human THP1 macrophages. Subsequently, the plasma EV-exposed macrophages were examined for total RNA sequencing to identify inflammatory and molecular pathways targeted by the human EVs. 

  Study phs002401

• NHLBI TOPMed - NHGRI CCDG: Intermountain INSPIRE Registry

  The INtermountain Healthcare Biological Samples Collection Project and Investigational REgistry for the On-going Study of Disease Origin, Progression and Treatment (Intermountain INSPIRE Registry) purpose is to collect biological samples, clinical information and laboratory data from Intermountain Healthcare patients. The registry originally collected samples in patients undergoing a coronary angiography as part of the Intermountain Heart Collaborative Study. It has been expanded to collect samples in patients diagnosed with all types of medical conditions, and patients from the general population including those who have not been diagnosed with health related issues. Just over 25,000 individuals have provided samples as part of this registry. The registry enables researchers to develop a comprehensive collection of information that may help in disease management, including determining best medical practices for predicting, preventing and treating medical conditions.

  Study phs001545

• EGA synthetic data

  Synthetic Data One of the limitations in genomics research is that human genomics data is not openly available; access must be controlled according to participant consent agreements and data protection regulations such as GDPR. Obtaining authorization to access such data can sometimes take a long time, resulting in delays to important research work. In this context, synthetic genomic and phenotype data can be useful resources for researchers to avoid these delays. Synthetic data are artificially generated datasets, often created with algorithms, which can be used without the need for authorization to test new products and tools, build technical demonstrators, validate data models, and train AI models. The EGA provides access to synthetic cohort datasets augmented with rich synthetic metadata that overcomes these real data usage restrictions. Whilst synthetic datasets are not included in the general EGA mandate and services, we can consider such submissions and evaluate their acceptance on the basis of their unique use cases not already covered by existing synthetic datasets. Access to synthetic data studies is managed by the EGA Helpdesk Data Access Committee. Study ID Title Located in EGAS00001002472 CINECA synthetic cohort EUROPE UK1 referencing fake samples Central EGA EGAS00001005591 Synthetic data - Genome in a Bottle Central EGA EGAS00001005042 Test Study for EGA using data from 1000 Genomes Project - Phase 3 Central EGA EGAS00001005702 Human genomic and phenotypic synthetic data for the study of rare diseases Central EGA EGAS50000000190 EOSC4Cancer Synthetic Colorectal Cancer Genomic data Central EGA EGAS50000000086 Synthetic - FEGA Sweden Heilsa synthetic dataset December 2023 Federated EGA Sweden EGAS50000000678 Synthetic - GDI synthetic data Federated EGA Spain

  Documentation synthetic-data

• UCSF Pediatric Bithalamic Glioma Genome Project

  Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. We performed targeted next-generation sequencing of approximately 500 cancer-associated genes on a cohort of 13 pediatric bithalamic diffuse gliomas, a lethal brain tumor of childhood for which the genetic basis is largely unknown. We identified that bithalamic diffuse gliomas harbor frequent mutations in the EGFR oncogene in the absence of accompanying gene amplification and only rare histone H3 mutation. These EGFR mutations were either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain). Accompanying alterations included frequent TP53 mutation, CDK6 amplification or CDKN2C mutation, and BCOR and BCORL1 mutation or deletion.

  Study EGAS00001004033

• Pediatric Low-Grade Glioma RNA and Targeted Sequencing

  Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS/MAPK pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. 84% of cases harbored a driver alteration, while those without an identified alteration also often exhibited up-regulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared to SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

  Study EGAS00001004242

• (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

• Region-specific Transcriptome Analysis of the Human Retina and Retinal Pigment Epithelium (RPE)/Choroid

  Proper spatial differentiation of retinal cell types is necessary for normal human vision. Many retinal diseases, such as Best disease and male germ cell associated kinase (MAK)-associated retinitis pigmentosa, preferentially affect distinct topographic regions of the retina. While much is known about the distribution of cell types in the retina, the distribution of molecular components across the posterior pole of the eye has not been well-studied. To investigate regional difference in molecular composition of ocular tissues, we assessed differential gene expression across the temporal, macular, and nasal retina and retinal pigment epithelium (RPE)/choroid of human eyes using RNA-Seq. RNA from temporal, macular, and nasal retina and RPE/choroid from four human donor eyes was extracted, poly-A selected, fragmented, and sequenced as 100 bp read pairs. Digital read files were mapped to the human genome and analyzed for differential expression using the Tuxedo software suite. Retina and RPE/choroid samples were clearly distinguishable at the transcriptome level. Numerous transcription factors were differentially expressed between regions of the retina and RPE/choroid. Photoreceptor-specific genes were enriched in the peripheral samples, while ganglion cell and amacrine cell genes were enriched in the macula. Within the RPE/choroid, RPE-specific genes were upregulated at the periphery while endothelium associated genes were upregulated in the macula. Consistent with previous studies, BEST1 expression was lower in macular than extramacular regions. The MAK gene was expressed at lower levels in macula than in extramacular regions, but did not exhibit a significant difference between nasal and temporal retina. The regional molecular distinction is greatest between macula and periphery and decreases between different peripheral regions within a tissue. Datasets such as these can be used to prioritize candidate genes for possible involvement in retinal diseases with regional phenotypes. Reprinted from Whitmore, S.S., Wagner, A.H., DeLuca, A.P., Drack, A.V., Stone, E.M., Tucker, B.A., Zeng, S., Braun, T.A., Mullins, R.F., Scheetz, T.E., 2014. Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq. Experimental Eye Research. Used under Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported license. Additional RNA sequencing was performed on temporal, macular, nasal, inferior, and superior retina from a fifth subject and is included in this dataset. See original publication for details.

  Study phs001151

• Genome_Diversity_in_Africa_Project__Benin

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

  Study EGAS00001001688

• HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans

  Based on the prior knowledge of involvement of the human leukocyte antigen locus in Han Chinese patients with carbamazepine-induced Stevens-Johnson syndrome, we imputed the HLA types for each case and control subject from the array of SNPs in the Human610-Quad GWAS platform (NCBI Build 36.1). We then performed a genome-wide association test which included the imputed HLA alleles as markers.

  Study EGAS00000000036

• Identification of Recurrent SMO and BRAF Mutations in Ameloblastomas

  RNA-seq data from two cases of ameloblastoma was analyzed for candidate gene fusions and point mutations. Recurrent point mutations identified in the RNA-seq data, as well as mutations identified with limited panel targeted deep sequencing, were validated as somatic. Expanding to a larger cohort of 28, one of two activating mutations was found in 80% of cases. No recurrent gene fusions events were identified.

  Study phs000739

• RNASeq from PPGL-derived PC12 cell lines cultivated in normoxia and hypoxia conditions.

  PC12 cells derived from rat PPGL were then either continued cultivated in the same normoxia condition (37˚C, 5% CO2 and 21% O2 balanced with N2) or were placed in a hypoxic incubator, that maintained a constant hypoxic environment (37˚C, 5% CO2 and 1% O2 balanced with N2), for different short (12h, 24h, and 48h) or prolonged time (36 days, approximately 860h).

  Study EGAS50000000814

• Summary statistics of meta-analysis using two genome-wide association study of inflammatory bowel disease in Koreans.

  Inflammatory bowel disease (IBD), a chronic inflammatory disorder of the gastrointestinal tract, is thought to develop due to dysregulated mucosal immune responses to gut flora in genetically susceptible individuals. Crohn’s disease (CD) and ulcerative colitis (UC) are the two major subtypes of IBD. To identify additional susceptibility loci for IBD in Asians, we performed meta-analyses using two genome-wide association studies.

  Study EGAS00001005026

• Y chromosome variability in Polish population

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

  Study EGAS00001004111

• Saliva microbiota in Finnish children

  The human intestinal microbiota may play a role in the development of overweight and obesity. However, associations between saliva microbiota and body mass index (BMI) have been sparsely studied, although the oral cavity is the major gateway for microbes into the body. The aim of this study was to identify associations between the saliva microbiota and BMI categories in Finnish children aged 9-14 years.

  Study EGAS00001003039

• The Landscape of Genetic Alterations in Hepatocellular Carcinoma, 88 matched HCC tumour/normal pairs WGS belongs to ICGC LICA-CN project

  Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Genomic analysis is conducted to identify genetic alterations in driver genes which are all druggable targets for cancer therapy. Whole genome shotgun sequencing (WGS) and the landscaple of somatic mutations in 88 paired samples from HCC patients including tumors and matched adjacent normal tissues using Illumina HiSeq 2000 platform were performed.

  Study EGAS00001002218

• A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

  We identified a gradated transcriptional program of coordinately regulated inflammation-suppressive genes in psoriatic resident memory T cells. This dataset includes bulk RNA-seq for CRISPR-based deactivation of two core components of this inflammation-suppressive program, ZFP36L2 and ZFP36, in human PBMCs. It also includes scRNA-seq of cutaneous immune cells from psoriasis patients before and during therapeutic IL-23 blockade.

  Study EGAS00001006716

• Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Uzbeks (DNA samples from the Institute of Immunology, Uzbek Academy of Sciences, Tashkent, Uzbekistan; Republic Specialized Scientific Practical Medical Centre of Obstetrics and Gynecology, Tashkent, Uzbekistan)

  Whole genome sequencing of 100 unrelated Uzbeks in order to impute genotypes into PE cases and controls from Uzbekistan and to provide genetic data and infrastructure for future genetic studies in Uzbekistan and Central Asia more generally and to fill a gap in worldwide information as Central Asia is not adequately represented in available genomic data. This dataset is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators in Tashkent, Uzbekistan at the Institute of Immunology, Uzbek Academy of Sciences and at the Republic Specialized Scientific Practical Medical Centre of Obstetrics and Gynecology.

  Dataset EGAD00001005466

• Pilot experiment on functional genomics in osteoarthritis_RNA

  The aim of this work is to apply an integrated systems approach to understand the biological underpinnings of large joint (hip and knee) osteoarthritis which culminates in the need for total joint replacement (TJR). In this pilot we will assess the feasibility of the approach in the relevant tissue. We will obtain diseased and non-diseased tissue (cartilage and endochondral bone) following TJR, coupled with a blood sample, from 12 patients. We will characterise the 12 pairs of diseased and non-diseased tissue samples in terms of transcription (RNASeq) The pilot will help assess the feasibility of isolating sufficient levels of starting material for the different approaches, and will instigate the development of analytical approaches to synthesising the resulting data.

  Dataset EGAD00001001331

• Characterizing Individual Cells Obtained from Bone Marrow Biopsies of MPN Patients

  We profiled the transcriptomes of individual cells obtained from bone marrow aspirates of 7 treatment-naïve newly diagnosed JAK2-mutant myeloproliferative neoplasm (MPN) patients (3 polycythemia vera and 4 essential thrombocythemia patients), and 2 healthy controls. The submitted data corresponds to sequencing reads mapped to the human reference genome GhRC38 build using CellRanger for a total of 9 samples (one per patient). In addition, to reconstruct the lineage histories of single cells in MPN patients, we performed whole-genome sequencing of single-cell-derived colonies of hematopoietic stem and progenitor cells from 2 essential thrombocythemia (ET) patients: 22 JAK2-mutant colonies and 20 WT colonies for patient ET 1; and 13 JAK2-mutant colonies and 21 WT colonies for patient ET 2. The submitted data consists of sequencing reads aligned to the human reference genome GhRC38 build using bwa-mem. Each file corresponds to the whole-genome sequencing data for one colony.

  Study phs002308

• ALLELE Consortium Glioblastoma Project

  Glioblastoma patient samples were sequenced for this project. The purposes of this project are: (1) to establish an umbrella protocol as a mechanism for identifying patients (in the USA and international sites) who agree to the collection, storage, and broad usage of their specimens and ongoing collection, and review of their medical information for the purposes of minimal-risk research and use of such data in clinical trials on which the patient may enroll; (2) to develop operations that facilitate investigator access to the data and/or tissue to conduct research, while minimizing risks to participants and promoting responsible conduct; and (3) to provide the infrastructure for the sharing of de-identified, coded samples, clinical data, and genomic data between participating investigators and institutions. Eligible patients include patients with known or suspected nervous system tumors or other neurologic diseases. Whole exome sequencing from the stated project will be released under this submission.

  Study phs003000

• NHLBI TOPMed: Genomic Summary Results for the Trans-Omics for Precision Medicine Program

  The NHLBI Trans-Omics for Precision Medicine (TOPMed) program aims to identify the genetic basis of variation in biomedical phenotypes, with emphasis on those related to heart, lung, blood and sleep disorders, as part of a broader Precision Medicine Initiative. The TOPMed program has provided whole genome sequencing (WGS) to over 80 different studies that had previously recruited participants and collected extensive phenotype data. Many TOPMed investigators affiliated with these studies have organized their activities into phenotype-focused Working Groups and have developed genotype-phenotype association projects. These analyses have resulted in valuable cross-study Genomic Summary Results (GSR) that include whole genome association test results of both common and rare variants. Most of the analyses include data from multiple studies, some of which are based on sensitive populations, precluding public sharing of GSR. This dbGaP accession provides a mechanism for sharing sensitive GSR, using the controlled-access mechanisms of dbGaP to provide protections for sensitive populations.

  Study phs001974

• INCLUDE: Down Syndrome Early Post-Natal Brain Multiome

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

  Study phs004098

• Resequencing_candidate_genes_for_male_spermatogenic_impairment

  This study aims to identify novel candidate variants from human Y-chromosomal genes DAZ, BPY2 and CDY1 by resequencing the coding regions of these genes from male patients with spermatogenic impairment. The coding regions of the genes have been amplified by standard PCR, amplicon lengths range from 244 to 486 bp. A total of 61 amplicons were amplified for each of the 96 patients, totalling to approx. 25 kb per sample. Amplicons were quantified by gel electrophoresis and pooled in approx. equimolar concentrations per patient. For each of the 96 submitted samples, approx. 1 microgram of amplified DNA pool is provided in a total volume of 120 microlitres. The samples need to be indexed and libraries prepared for a PE250bp Illumina MiSeq run. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002157

• Spatial Transcriptomics on prostate cancer heterogeneity

  Intratumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.

  Study EGAS00001003001

• Roifman DAC

  This Data Access Committee will oversee all requests for data submitted by Dr. Chaim Roifman at the Hospital for Sick Children in Toronto, Canada. Requests should be directed by email to chaim.roifman@sickkids.ca.

  Dac EGAC50000000396

• RNASeq files for Mullighan_GL_reALL RNASEQ1

  RNASeq files for Mullighan_GL_reALL RNASEQ1 paper titled "Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia"

  Dataset EGAD00001005511

• RNASeq files for Mullighan ECOG2993 data

  RNASeq files for paper titled "Molecular classification improves risk assessment in adult B-lineage ALL: Patients on the international UKALLXII-ECOG2993 trial."

  Dataset EGAD00001006380

• RNAseq files for Mullighan_GL_reALL RNASEQ2

  RNAseq files for Mullighan_GL_reALL RNASEQ2 paper titled "Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia"

  Dataset EGAD00001005510

• RNASeq files for Newman MAP3K8 melanoma

  RNASeq files for MAP3K8 melanoma paper titled "Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas"

  Dataset EGAD00001004567

• RNASeq files for CIC paper data

  RNASeq files for CIC paper titled "Malignant progression of an ancestral bone marrow clone harboring a CIC-NUTM2A fusion in isolated myeloid sarcoma"

  Dataset EGAD00001009788

• M116 Proteome Extracellular Vesicle Profiling

  For extracellular vesicles (ECV) extraction from plasma, 1M ammonium acetate was added to precipitate ECVs on ice for 45 min. Then, 100 mM ammonium acetate was added to the mixture, and ECVs were precipitated by centrifugation at 20,000g for 30 min. ECVs were washed with 50 mM ammonium bicarbonate (Sigma-Aldrich, Cat. 1066-33-7). Then, 600 µl of 1% ammonium deoxycholate (Sigma Aldrich, Cat. K2755-1MG) were added. The concentration of protein in each sample was measured using a bicinchoninic acid assay (BCA assay). Ammonium bicarbonate was used to dilute 500 µg of protein into a final volume of 500 µl. Next, dithiothreitol (Sigma-Aldrich, Cat. D9779) was added to obtain a final concentration of 20 mM, followed by iodoacetamide (Sigma-Aldrich, Cat. I6125) to a final concentration of 40 mM. Next, trypsin (Roche, Cat. RTRYP-RO) was added to the sample in a 1:25 protein ratio and incubated at 37°C overnight. Next day, formic acid (ThermoFisher Scientific, Cat. 28905) in a final concentration of 0.1% was added and extraction of proteins was done using Empore™ Solid Phase Extraction Cartridges (3M), following manufacturer’s instructions. The eluted samples were then centrifuged for 90 min. using a speed vacuum centrifuge (Thermo, RC1010), followed by snap freezing in liquid nitrogen. Then, the samples were kept in a freeze dryer (LyoDry Compact Benchtop, MechaTech) overnight. Next, the samples were reconstituted in 30 µl of 0.1% formic acid (FA) and an o-Phthaladehyde (Oparil) assay was performed to determine the concentration of each sample. After that, the sample was prepared in a concentration of 0.5 µg/µl using 0.1% FA and alcohol dehydrogenase (ADH). The samples were prepared in glass mass spectrometry vials for proteomic analysis using a Waters Synapt G2Si High-Definition Mass Spectrometry (Waters Corporation) operated by the MassLynx 4.1., 110 min. running time with 2 µl of an injection containing 1 µg of peptide. Quality controls were also run along with samples to guarantee consistency. Pooled quality controls were made from all samples, in which the samples were run at the beginning, middle and end of the mass spectrometry run. Samples were randomized before running the experiment. The proteomic data was then imported into Progenesis software 4.2 (Nonlinear Dynamic, UK) to identify and quantify peptides and proteins.

  Dataset EGAD50000001679

• Volasertib preclinical activity in high-risk hepatoblastoma

  Relapsed and metastatic hepatoblastoma represents an unmet clinical need with limited chemotherapy treatment options. In a chemical screen, we identified volasertib as an agent with in vitro activity, inhibiting hepatoblastoma cell growth while sparing normal hepatocytes. Volasertib targets PLK1 and prevents the progression of mitosis, resulting in eventual cell death. PLK1 is overexpressed in hepatoblastoma biopsies relative to normal liver tissue. As a potential therapeutic strategy, we tested the combination of volasertib and the relapse-related hepatoblastoma chemotherapeutic irinotecan. We found both in vitro and in vivo efficacy of this combination, which may merit further preclinical investigation and exploration for a clinical trial concept.

  Study EGAS00001004827

• Center for Common Disease Genomics (CCDG) Neuropsychiatric: Homozygosity Mapping Consortium for Autism (HMCA)

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

  Study phs001894

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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/

  Study EGAS00001003138

• A Collaborative Search for New Genes for Non-Syndromic Deafness

  We seek to identify the DNA variants underlying sensorineural hearing loss. We obtain the DNA sequence of affected individuals and their family members. DNA variants are filtered to determine their segregation in affected families.

  Study phs003701

• A_study_of_the_molecular_pathogenesis_of_Splenic_Marginal_Zone_and_Diffuse_Large_B_Cell_Lymphoma

  We will perform exome sequencing on selected cases of splenic marginal zone lymphoma (SMZL) and diffuse large B-cell lymphoma (DLBCL) in order to characterise their genetic makeup and identify biomarkers for prognosis and prediction of treatment response.

  Study EGAS00001000335

• Whole-exome analysis of corticotropin-independent Cushing's syndrome

  We performed WES for 8 cases with corticotropin-independent Cushing’s syndrome, in whom paired tumor and normal DNA was obtained from fresh frozen adenomas and either normal adrenal tissues or peripheral blood, respectively.

  Study EGAS00001000661

• Whole genome sequencing of adult glioblastoma nuclei

  Three primary adult glioblastoma specimens were dissociated and nuclei were extracted. A portion of the nuclei was used for single-cell ATAC seq and the remainder were submitted for whole genome sequencing, to provide orthogonal validation of copy number variations in the samples compared to single-cell ATAC seq. Samples were sequenced on the Illumina NovaSeq 6000 in paired-end mode.

  Dataset EGAD00001007651

• Transcriptomic Data for Manuscript with title: Comprehensive genomic profiling in esophageal adenocarcinoma unmasks potential precision therapies

  Transcriptomic Data for Manuscript with title: Comprehensive genomic profiling in esophageal adenocarcinoma unmasks potential precision therapies

  Dataset EGAD00001015476

• Colorectal cancer WES/WGS analysis in Dr. Liu’s group in Sun Yat-sen University Cancer Center

  The samples include paired tumor and normal tissues from 205 patients (201 for normal and primary tumor tissues; 4 for normal, primary tumor and liver metastatic tissues). High-coverage WES sequencing or whole genome sequencing of DNA samples were performed on the Illumina HiSeq 2000 system

  Dataset EGAD00001003452

• Functional Significance of Prostate Cancer Risk-SNPs

  Prostate Cancer (PrCa), the most frequently diagnosed solid tumor in men in the U.S., results in ~192,000 new cases and ~27,000 deaths per year. Although the variation of PrCa incidence is likely to be the result of several factors, there is a large body of literature that strongly implicates a genetic etiology. Genome-wide association studies (GWAS) have emerged as the most widely used contemporary approach to identify genetic variants (in particular SNPs) that are associated with increased risk of human disease. For PrCa, at least five GWAS have now been performed yielding a substantial number of well-validated SNPs that are associated with an increased risk of PrCa, and that number continues to grow. A significant problem for many of the PrCa risk-SNPs identified so far, however, is that they do not lie within or near a known gene and they have no obvious functional properties. These findings suggest that many (if not most) of these risk-SNPs will be located in regulatory regions that control gene expression rather than in coding regions that may directly affect protein function. Therefore, in order to define the functional role of currently known risk-SNPs, the target genes must first be identified. A promising strategy to address this problem involves the use of expression quantitative trait loci (eQTL) analysis. Unfortunately, most of the publically available SNP-Transcript eQTL datasets utilize lymphoblastoid cells with only a handful using tissue from target organs. Although useful, these datasets alone are unlikely to be sufficient. Recent studies have demonstrated that gene expression and gene regulation occur in both a tissue-specific and tissue independent fashion and suggest that a complete repertoire of regulatory SNPs can only be uncovered in the context of cell type specificity. To date, such a tissue-specific dataset for normal prostate tissue does not exist. In this study, we have constructed a normal prostate tissue specific eQTL data set.

  Study phs000985

• Genome_Diversity_in_Africa_Project__Uganda

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

  Study EGAS00001002523

• The University of Hong Kong Colon Cancer GCV Study

  Background: Ganciclovir (GCV) is widely used in solid organ and hematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. Methods: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. Results: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig¬¬ were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV¬sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. Conclusions: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.

  Study EGAS00001006707

• The Dynamic Immune Behavior of Primary and Metastatic Ovarian Carcinoma

  Patients with high-grade serous ovarian carcinoma are usually diagnosed at an advanced stage and often develop resistance to conventional therapy. Epithelial ovarian tumors have been shown to be rich in CD8+ lymphocytes, which infiltrate both primary and omental sites. In recent years, several prominent studies have highlighted a positive association between the presence of these immune cells and a good prognosis; however, clinical trials of immune checkpoint inhibitors have so far shown unsatisfactory results in ovarian cancer. In this study, we used an innovative combination of single-cell sequencing and spatial transcriptomics to identify the molecular mechanisms that lead to immunosuppression in primary and metastatic HGSC. Primary tumors consistently showed a more active immune microenvironment than did omental tumors. In addition, while several immune cell subtypes were present in all samples, their relative abundance differed between primary and omental tumors. Finally, we found that primary tumors were mostly populated by dysfunctional CD4 and CD8 T cells in later stages of differentiation, while omental tumors were mostly populated by naïve immune cells; this, in turn, was correlated with expression changes in the interferon α and γ pathways in epithelial cells, showing that cross-communication between the epithelial and immune compartments is important for immune suppression in ovarian cancer. These findings can impact the timing and choice of immune-modulating drugs and should be considered when planning treatment for patients with high-grade serous ovarian carcinoma.

  Study EGAS50000000038

• DNA hypermethylation and differential gene expression associated with Klinefelter syndrome

  The molecular basis for the phenotypic traits and morbidity in Klinefelter syndrome (KS) are not clarified. As DNA methylation affect gene expression and thereby play a role in disease susceptibility, we performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards many new candidate genes (AKAP17A, AMOT, APOB, DACT1, DDX58, DOCK7, EIF2S3, FIGNL1, G3BP1, HENMT1, HERC5, IFI44, IFI44L, IFIT1, IFIT3, ISG15, KANK1, LGALS1, NSD1, PEX10, PLSCR1, RSAD2, SHROOM2, SLC25A6, SPEG, SPON2, TXLNG), which may be implicated in the phenotype and further point towards non-coding genes (RP13-216E22.4, RP13-36G14.4, G087825, G088512), which may be involved in X chromosome inactivation in KS and in the regulation of escape genes.

  Study EGAS00001002797

• Bone marrow breakout lesions act as key sites for tumor-immune cell diversification and exhaustion in multiple myeloma

  Multiple myeloma is a disease characterized by the expansion of cancerous plasma cells in the bone marrow. The bone marrow microenvironment plays a pivotal role in supporting myeloma growth and modulating tumor immunity. As the disease progresses, myeloma cells may become independent of the bone marrow environment, leading to extramedullary disease associated with poor prognosis. However, the early processes associated with bone marrow independence and its implications for disease and immune control remain poorly understood. Here, we employed comprehensive single-cell and spatial mapping to identify the disruption of the cortical bone and subsequent expansion of myeloma cells in breakout lesions as a key event in multiple myeloma pathogenesis and tumor immunity. Breakout lesions harbor an adapted niche and a unique immune microenvironment conferred by sustained immune-tumor interactions. In particular, tumor-reactive T cells with a highly exhausted phenotype, alongside unique NK cell and macrophage subtypes, specifically expanded in breakout lesions. Spatially-resolved genomic, transcriptomic and cellular analyses uncovered extensive intra-lesion heterogeneity, suggesting a divergent co-evolution of genomic variation and locally confined T cell responses in distinct subregions. Ultra-high plex imaging revealed that tumor-reactive T cells, together with other immune-regulatory cells and dendritic cells, co-expand and exhaust upon sustained tumor interactions in locally confined immune islands. In contrast, immune-regulatory macrophage and NK cell subsets operate spatially separated within myeloma cell deserts. Jointly, our analyses uncover bone marrow breakout lesions as a hotspot for tumor-immune cell interactions, diversification and exhaustion, representing a key event in myeloma pathogenesis with significant therapeutic implications.

  Study EGAS50000000304

• Longread sequencing of selected 12q-amplified osteosarcomas

  Longread sequencing of selected 12q-amplified osteosarcomas for verification of SV data. This was carried out in order to verify findings from mate-pair sequencing regarding the structure of the chromosome 12q-amplicons and whether material from other chromosomes is also intertwined and amplified in a bid to further characterise these tumours beyond CDK4 and MDM2 amplification.

  Study EGAS50000000495

• singel cell RNAseq dataset for the study "Composition and functional status of T and NK cells in Extramedullary myeloma tumor microenvironment""

  Dataset contains all newly generated single cell RNAseq data generated for the study. It includes 5 EMM soft tissue samples, 5 EMM bone marrow samples (EMM_BM) and 6 RRMM BM samples without EMM (RRMM_BM). Samples that are sequenced twice are marked by _1 or _2 in the sample name. The sample name mentioned corresponds to the sample name used in the publication. The rest of the EMM single cell RNAseq samples mentioned int the publication, EMM_03_1, EMM_11, EMM_14_1, EMM_14_2, EMM_16, and EMM_15_1 are already uploaded in EGA archive – dataset id EGAD50000000053.

  Dataset EGAD50000001511

• Microarray genotyping of idiopathic hypersomnia patients (11 orexin mutation-positive patients, 85 orexin mutation-negative patients)

  We performed a principal component analysis (PCA) to determine whether population stratification or differences in the genetic background are present between the orexin mutation-positive and -negative idiopathic hypersomnia groups. Genome-wide single nucleotide polymorphism (SNP) data in patients with idiopathic hypersomnia (orexin mutation-positive patients and orexin mutation-negative patients) were utilized for the PCA.

  Study JGAS000508

• Transcriptome sequencing of myelodysplasia

  Transcriptome sequencing was performed on 214 patients with myelodysplasia in this study. RNA was obtained from bone marrow CD34+ cells (n=100) and/or bone marrow mononuclear cells (n=165). Transcriptome sequencing was performed for both cell fractions in 51 patients. We also studied bone marrow CD34+ cells and bone marrow mononuclear cells obtained from three healthy adults each.

  Study EGAS00001002346

• Multiple esclerosis and mixed microbial infections

  This Project deals with the sequencing of ITS1 region, which is highly variable both in length and in nucleotide sequence for different yeast using yeast-specific primers ITS1 and ITS2. A total of 19 samples involving different brain regions from patients with different conditions were analysed. Of these, 10 are controls-healthy patients and 9 multiple sclerosis (MS) patients.

  Study EGAS00001002957

• RNA-sequencing of ex vivo exhausted human antigen-specific T cells

  Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. To explore new pathways for reinvigoration of anti-tumor immune functions, we developed a human ex vivo exhaustion model by repetitive antigenic stimulation of primary CD8 T cells. This results in T cells that resemble patient-derived T cells in tumors on a phenotypic and transcriptional level.

  Study EGAS00001006794

• Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Kazakhs (DNA samples from the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan; Gulnara Svyatova, Principal Investigator

  Whole genome sequencing of 100 unrelated Kazakhs in order to impute genotypes into PE cases and controls from Kazakhstan and to provide genetic data and infrastructure for future genetic studies in Kazakhstan and Central Asia more generally and to fill a gap in worldwide information as Central Asia is not adequately represented in available genomic data. This dataset is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator)

  Dataset EGAD00001005467

• Identification of drug resistance genes in melanoma

  Our aim is to analyze the genome of human melanoma cell lines and short term culture from human melanoma samples in order to identify genes that confer drug resistance to clinically relevant targeted therapies. We will perform whole-exome sequencing, copy number variation analysis and methylome analysis in a collection of human melanoma cell lines and short term culture that will be then screened for drug sensitivity/resistance through a library of clinically relevant drugs and drug combinations. By the combined analysis of the genomic lesion and the drug sensitivity/resistance profile of different cell lines, we will look for genes whose mutation is associated to the sensitivity or resistance to a specific drug in different samples.

  Dataset EGAD00001001124

• Three-dimensional patient-derived models of glioblastoma retain intra-tumoral heterogeneity

  The intra- and inter- tumoral heterogeneity of glioblastoma represents a significant therapeutic challenge, as well as difficulty in generating reliable models for in vitro studies. Here, we quantify the tumor cell composition from matched patient-derived neurospheres (PDN) and organoids (PDO) established from the same primary tumor using a series of multi-omic interrogations, relative to primary tissue

  Study EGAS00001008023

• Deep single-cell RNA sequencing data for 12346 T cells from tumour, adjacent normal tissue and peripheral blood of treatment-naive NSCLC patients

  Cancer immunotherapies have shown sustained clinical responses in treating non-small cell lung cancer (NSCLC), but efficacy varies between patients and is believed to depend in part on the amount and properties of tumor infiltrating lymphocytes (TILs). To comprehensively depict and dissect the baseline landscape of the composition, lineage and functional states of TILs in lung cancer, here we generated deep single-cell RNA sequencing data for 12,346 T cells from the primary tumour, adjacent normal tissues and peripheral blood of 14 treatment-naive NSCLC patients. Combined expression and TCR-based lineage tracking revealed a significant proportion of effector T cells with common origins and similar functional states across peripheral blood and tumours pointing towards a highly migratory nature of these T cells. We also observed tumour-infiltrating CD8+ T cells undergoing extensive clonal expansion and exhaustion, with two clusters of cells exhibiting states preceding exhaustion. Survival analysis on independent datasets suggested that high ratio of pre-exhausted to exhausted T cells is associated with better prognosis of lung adenocarcinoma (LUAD). In addition, we observed further heterogeneity within the tumour regulatory T cells (Tregs), characterized by the bimodal distribution of TNFRSF9, an activation marker for antigen-specific Tregs. The gene signature of this group of activated tumour Tregs, which included IL1R2, correlated with poor prognosis in LUAD. The T cell clusters revealed by our single cell analyses provide a new approach for patient stratification, and the accompanying compendium of data will help the research community to gain further insight into the functional states and dynamics of T cell responses in lung cancer.

  Study EGAS00001002430

• A genome scan for genes underlying adult body size differences between Central African hunter-gatherers and farmers.

  The evolutionary and biological bases of the Central African pygmy phenotype, a characteristic of rainforest huntergatherers defined by reduced body size compared with neighboring farmers, remain largely unknown. Here, we perform a joint investigation in Central African hunter-gatherers and farmers of adult standing height, sitting height, leg length, and body mass index (BMI), considering 358 hunter-gatherers and 169 farmers with genotypes for 153,798 SNPs. In addition to reduced standing heights, hunter-gatherers have shorter sitting heights and leg lengths and higher sitting/standing height ratios than farmers and lower BMI for males. Standing height, sitting height, and leg length are strongly correlated with inferred levels of farmer genetic ancestry, whereas BMI is only weakly correlated, perhaps reflecting greater contributions of non-genetic factors to body weight than to height. Single- and multi-marker association tests identify one region and eight genes associated with hunter-gatherer/farmer status, and 24 genes associated with the height-related traits. Many of these genes have putative functions consistent with roles in determining their associated traits and the pygmy phenotype, and they include three associated with standing height in non-Africans (PRKG1, DSCAM, MAGI2). We find evidence that European height-associated SNPs or variants in linkage disequilibrium with them contribute to standing- and sitting-height determination in Central Africans, but not to the differential status of hunter-gatherers and farmers. These findings provide new insights into the biological basis of the pygmy phenotype, and they highlight the potential of cross-population studies for exploring the genetic basis of phenotypes that vary naturally across populations. Pemberton et al. Human Genetics 2018 https://doi.org/10.1007/s00439-018-1902-3

  Study EGAS00001002975