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• Asthma in the Lives of Families Today (ALOFT)

  Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here we investigated the effect of psychosocial experiences on gene expression in peripheral blood immune cells of 251 children with asthma in Metro Detroit. Participants were included from an ongoing longitudinal study Asthma in the Lives of Families Today (ALOFT; recruited from November 2010-July 2018. The ALOFT project was established to identify the behavioral and biological pathways through which family social environments impact youth with asthma.In version 1 we used RNA-sequencing and a new machine learning approach to identify transcriptional signatures of 19 variables including psychosocial factors, blood cell composition and asthma symptoms. Using longitudinal data collected from a subset of the participants we showed that transcriptional signatures track the longitudinal changes in measured phenotypes. Importantly, we found 169 genes associated with asthma that are regulated by psychosocial factors, and 344 significant gene-environment interactions for gene expression levels. These results demonstrate that immune gene expression mediates the link between negative psychosocial experiences and asthma risk.In version 2, we focused on pubertal development. We identified substantial gene expression changes associated with age and pubertal development. We showed that genetic effects on gene expression change dynamically during pubertal development. Gene expression changes during puberty are correlated with gene expression changes associated with asthma and may explain sex differences in prevalence. Our results show that molecular data used to study the genetics of early onset diseases should consider pubertal development as an important factor that modifies the transcriptome.Version 3 uses single cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated Peripheral Blood Mononuclear Cells from 96 African American children. We employed novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we demonstrated that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and demonstrated widespread genetic regulation of the transcriptional dynamics of the gene expression response.Version 4 adds scATAC-seq in activated peripheral blood mononuclear cells (PBMC) from 16 children with asthma with phytohemagglutinin (PHA) or lipopolysaccharide (LPS), and treated with dexamethasone (DEX), an anti-inflammatory glucocorticoid. We analyzed changes in chromatin accessibility, measured transcription factor motif activity, and identified treatment and cell-type specific transcription factors that drive changes in both gene expression mean and variability. We observed strong positive linear dependence between motif response and their target gene expression changes, but negative in variability changes. This result suggests that an increase of transcription factor binding tightens the variability of gene expression around the mean. We then annotated genetic variants in chromatin accessibility peaks and response motifs followed by computational fine-mapping of eQTL signals from a pediatric asthma cohort. We found that eQTLs were 5-fold enriched in peaks with response motifs and refined the credible set for 410 asthma risk genes, with 191 having the causal variant in response motifs. These results enhance the understanding of molecular mechanisms for asthma risk variants mediated by gene expression.

  Study phs002182

• Integrated Genomic Analysis of Periampullary Tumors at The Human Genome Sequencing Center, Baylor College of Medicine (HGSC-BCM)

  Adenocarcinomas arising in the complex environment of the ampulla of Vater constitute a histopathological heterogenous group, presumably originating from the different epithelial cellular constituents present at the site: pancreas, bile duct, and intestinal duodenum. These tumors have been described in many different ways: intra-ampullary, periampullary, intra-ampullary papillary-tubular neoplasm, ampullary-ductal, periampullary-duodenal, and ampullary-not otherwise specified. These varied classifications reflect the difficulty in classifying these tumors into specific groups. Only the tumors clearly localized in the bile duct or duodenum are identified as distal cholangiocarcinomas (CAC) or duodenal adenocarcinomas (DUOAC). The current classification is based on macroscopic features that may distinguish the epithelium of origin, microscopic features, clinicopathological criteria, histopathology and expression of differential markers. This classification is subjective and prone to inter-observer variability and significantly impacts on treatment selection and therapeutic development. In order to define subtypes of periampullary cancer with clinical relevance, we performed whole exome sequencing and copy number analysis of 160 cancers arising in the periampullary region, 62 of these clearly arising from either the bile duct (n = 44), or the duodenum (n = 18) and 98 periampullary cancers (AMPAC) where the epithelium of origin could not be clearly defined.

  Study phs000895

• Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia

  Fibromuscular dysplasia (FMD) is a poorly understood vascular disease that can lead to hypertension, stroke, myocardial infarction and even death. In 2013 we initiated the DEFINE study (ClinicalTrials.gov Identifier: NCT01967511), which has now recruited > 440 subjects and which aims to unravel the pathobiological mechanisms of this disease. Here, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 FMD patients and 71 matched healthy controls from the DEFINE study, and its precursor the CAUSE study, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated super network in the arterial wall. Molecular studies indicated that this super network, termed SN-A and with the top key driver gene UBR4, governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. The effects of UBR4 knockdown were also investigated in commercially available aortic smooth muscle and fibroblast cell lines by RNA sequencing, and these results are included in these datasets.Note, that of the 154 subjects in this analysis, 62 did not provide consent to have their genomic data made publicly available. Therefore the human subject data available here is from the 92 study participants who provided written informed consent to share their deidentified genomic data publicly.

  Study phs003674

• Imaging: Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

  The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multi-center epidemiologic study in Hispanic/Latino populations to determine the role of acculturation in the prevalence and development of disease, and to identify risk factors playing a protective or harmful role in Hispanics/Latinos. The study is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and six other institutes, centers, and offices of the National Institutes of Health (NIH). The goals of the HCHS/SOL include studying the prevalence and development of disease in Hispanics/Latinos, including the role of acculturation, and identifying disease risk factors that play protective or harmful roles in Hispanics/Latinos. A total of 16,415 persons of Cuban, Dominican, Mexican, Puerto Rican, Central American, and South American backgrounds were recruited through four Field Centers affiliated with San Diego State University, Northwestern University in Chicago, Albert Einstein College of Medicine in the Bronx area of New York, and the University of Miami. Seven additional academic centers serve as scientific and logistical support centers. Study participants aged 18-74 years took part in an extensive clinic exam and assessments to ascertain socio-demographic, cultural, environmental and biomedical characteristics. Annual follow-up interviews are conducted to determine a range of health outcomes.

  Study phs003963

• Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

  Immunotherapy has produced disappointing results in recurrent ovarian cancer (OC). However, the prognostic value of tumour-infiltrating lymphocytes (TILs) is largely based on the analysis of treatment-naive tumours. To understand the immunobiology of recurrent cancers, and their evolution, we profiled a total of 697 OC tumour samples (566 primary and 131 recurrent including 69 patient-matched samples) from 595 patients of five independent multi-institutional cohorts. By capturing heterogeneous TIL distributions, we identified four immune phenotypes associated with differential prognosis, TILs states and TILs:myeloid networks, which dictate malignant progression after chemotherapy and recurrence. Notably, recurrent tumours recapitulate the immunogenic landscapes of original cancers. Mirroring inflamed human OC, preclinical recurrent Brca1mut tumours maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through COX/PGE2 signaling upregulation. Conversely, recurrent Brca1wt tumours displayed loss of TILs:DCs niches and accumulated immunosuppressive myeloid networks featuring Trem2/ApoEhigh TAMs and Nduf4l2high/Galectin3high malignant states. Our study highlights that persistent immunogenicity in recurrent OC is governed by the BRCA-dependent crosstalk between dissimilar myeloid cells and TILs. We propose new targets to modulate the malignant and TAM compartments which improve efficacy of standard of care chemotherapy in mouse OC models with HR deficiency.

  Study EGAS50000001069

• Comparison of EGF and PDGF driven glioblastomas.

  Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor. Epidermal growth-factor (EGF) and platelet-derived growth-factor (PDGF) receptors are frequently amplified and/or possess gain-of-function mutations in these tumors. Despite years of research into tyrosine-kinase inhibitors, clinical trials have shown disappointing efficacy. One of the underlying reasons is intra-tumor heterogeneity. To assess the effect of intra-tumor heterogeneity on gene expression, we derived a general approach to map single-cell expression profiles to sequentially-acquired mutations identified from exome sequencing. Using 288 single cells, we constructed high-resolution phylogenies of EGF-driven and PDGF-driven GBMs, modeling transcriptional kinetics during tumor evolution. A deletion in a PDGF-receptor domain involved in dimerization correlated to an up-regulation of the PI3K/AKT pathway in a proneural GBM, and ectopic expression of this mutant PDGFRA in vitro enhanced proliferation and invasiveness. Descending the phylogenetic tree of the PDGFR-driven tumor corresponded to a progressive induction of an oligodendrocyte progenitor-like cell type that expresses growth and angiogenic factors. In contrast, phylogenetic analysis of an EGFR-amplified tumor showed a gradual up-regulation of pro-invasive genes.

  Study EGAS00001001900

• Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

  Cutaneous squamous cell carcinoma (cSCC) from the head and neck typically metastasizes to the lymph nodes of the neck and parotid glands. When a primary is not identified, they are difficult to distinguish from metastases of mucosal origin and primary salivary gland SCC. Ultraviolet radiation causes a mutation pattern that predominantly features cytosine to thymine transitions at dipyrimidine sites and has been associated with cSCC. In this study, we used whole genome sequencing data from 15 cSCC metastases and show that a UV signature mutation is pervasive across the cohort and distinct from mucosal SCC. The mutational burden was exceptionally high and concentrated in some regions of the genome, especially insulator elements (mean 162 mutations / Mb). We therefore evaluated the likely impact of UV-induced mutations on the dipyrimidine rich binding site of the main human insulator protein, CCCTC-binding factor (CTCF), and the possible implications on CTCF function and the spatial organization of the genome. Our findings suggest that mutation signature analysis may be useful in determining the origin of metastases in the neck and the parotid gland. Furthermore, UV-induced DNA damage to insulator binding sites may play a role in the carcinogenesis and progression of cSCC.

  Study EGAS00001003370

• A Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling

  Glioblastoma is a highly aggressive and lethal brain tumor, with limited treatment options. Abnormal activation of the neddylation pathway is observed in glioblastoma, and the NEDD8-activating enzyme (NAE) inhibitor, MLN4924 was previously shown to be effective in glioblastoma cell line models. However, its effect has not been tested in patient-derived glioblastoma stem cells. Immunohistochemistry and public data were analyzed to determine whether NEDD8 pathway proteins are important in glioblastoma development and patient survival. The effects of MLN4924 were evaluated in 4 glioblastoma cell lines and 15 patient-derived glioblastoma stem cells using high content analysis. Immunoblot analysis assessed the NEDD8 pathway proteins and biomarkers. Whole transcriptome analysis identified pathways associated with MLN4924 sensitivity. NAE1 and UBA3 levels increased in glioblastoma patients; high NEDD8 levels were associated with poor clinical outcomes. Glioblastoma cell lines and patient-derived stem cells were highly susceptible to MLN4924, while normal human astrocytes were resistant. Genomic analyses indicated that MLN4924 sensitive cells exhibited enrichment of ERK and AKT signaling. We verified that MLN4924 inhibits ERK and AKT phosphorylation in MLN4924 sensitive cells. Our findings suggest that patient-derived glioblastoma stem cells in the context of ERK and AKT activation are sensitive and highly regulated by neddylation inhibition.

  Study EGAS00001004018

• T cell responses of ALS patients

  In this project, we aimed to understand how T cell responses contribute to the disease progression of amyotrophic lateral sclerosis (ALS). The present data is on single-cell sequencing isolated from human cerebrospinal fluid (CSF) cells from both ALS patients (n=5) and controls (n=4). This analysis was conducted as part of a bigger project which is summarized in the section below. We used flow cytometry to define T cell subsets and phenotypes in blood and CSF samples collected at the time of diagnosis on a cohort of 89 newly diagnosed ALS patients in Stockholm, Sweden. High frequency of CD4+FOXP3- effector T cells in blood and CSF was associated with poor survival whereas high frequency of activated regulatory T (Treg) cells and high ratio between activated and resting Treg cells in blood was associated with better survival. T cell profiles also predicted disease progression rate. On an independent cohort of cases and controls, we used single cell transcriptomics data to demonstrate that ALS patients had altered T cell gene expression patterns and clonally expanded CD4+ and CD8+ T cells in CSF. In summary, T cell responses contribute to disease progression of ALS, supporting modulation of adaptive immunity as a viable therapeutic option.

  Study EGAS00001006675

• Human liver NPCs single cell project

  Independent of their inflammatory phenotype, macrophages are key orchestrators of hepatic metabolism. Non-alcoholic fatty liver disease (NAFLD) often occurs in obese individuals and is among the most common causes of cirrhosis, the terminal chronic liver disease that may necessitate liver transplantation. While multiple populations of macrophages have been described in the human liver, their function and turnover in obese patients at high risk of developing NAFLD and cirrhosis is currently unknown. Herein we identified a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation using markers of donor-recipient mismatch, we made the novel discovery that liver myeloid cell turnover differs between humans and mice. Using single cell techniques and flow cytometry we determined that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures revealed that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD.

  Study EGAS00001007194