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• Genetic_Heterogeneity_of_the_familial_gastric_neuroendocrine_tumors

  Gastric neuroendocrine tumors (gNETs) occur with an estimated frequency of 2 per 100,000 in the general population. Type I gastric neuroendocrine tumors (NETs) represent the 75% of gNTEs and arise from gastric enterochromaffin-like (ECL) cells. They have late age of onset and usually benigh course. Classically, hypergastrinemia in patients who have autoimmune atrophic gastritis, causes hyperplasia of gastric ECL cells that progresses into type I gastric NETs and parietal cell (PC) destruction. The genetic bases in families with this disease are unknown. We performed an exome sequencing study of an atypical aggressive familial gNETs case (with early age onset, nodal infiltrations and gastric adenocarcinomas) that followed a recessive model. We identified a deleterious mutation in homozygosis in the ATP4A gene, which encodes the proton pump responsible for acid secretion by gastric parietal cells. This mutation lead to achlorhydria first, and hypergastrinemia and gNET developing as consequence (Calvete et al. 2014). Recently, two more families with gNETs, classical clinical traits and recessive model have been studies by WES but we didn't find any mutation in the ATP4a gene. However, putative mutations affecting genes that contribute to the development and the integrity of PC have been found suggesting that genetic alterations associated to this disorder target to a unique cell type (parietal cells). In order to cinfirm this hypothesis, it is necessary the search for new genes implicated in the gNETs, more familial cases are needed to be studied. We have identified four more new familial gNETs cases. Here, we propose their study by WES. The first family is formed by thress siblings with gNETs. The other families include two siblings with gNETs. 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 EGAS00001002273

• MP2PRT: Evaluation of an Inflammation Polygenic Risk Score (iPRS) to Predict Cancer Related Cognitive Impairment and Fatigue in Patients Receiving Chemotherapy for Non-Metastatic Breast Cancer in URCC0701 and URCC10055

  This study is a secondary analysis of cancer related cognitive impairment (CRCI) and cancer related fatigue (CRF) among participants in URCC0701 and URCC10055 from the University of Rochester NCI Community Oncology Research Program (NCORP) Research Base. CRCI and CRF are common, troublesome, and dose-limiting toxicities reported by patients undergoing breast cancer chemotherapy that have an etiologic basis linked to low-grade systemic inflammation. Chronic, low-grade systemic inflammation is, in part, genetically determined with common single nucleotide polymorphisms (SNPs) capturing variation across individuals. This study aimed to 1) determine whether an inflammation polygenic risk score (iPRS) is associated with CRCI or CRF, 2) determine whether the relationship between the iPRS and CRCI or CRF is modified by exercise at the time of cancer treatment, 3) identify SNPs associated with serum cytokines measured at the time of cancer treatment, and 4) identify novel CRCI- and CRF-associated risk SNPs via genome-wide association analyses. We found that there was a significant inverse correlation between the iPRS and change in fatigue score from pre-chemotherapy to post-chemotherapy while there was no statistically significant association between the iPRS and cognitive impairment score. The inverse relationship between the iPRS and fatigue may be explained in part by the finding that the iPRS was also significantly associated with greater pre-chemotherapy fatigue, suggesting that women with a genetic predisposition to low-grade systemic inflammation (i.e., high iPRS) have more fatigue at the time of breast cancer diagnosis and, therefore, are less likely to worsen over the course of treatment. In contrast, women with a low iPRS had significantly less fatigue pre-chemotherapy and a significant worsening of fatigue from pre- to post-chemotherapy. The relationship between the iPRS and fatigue remained after adjustment for patient and cancer treatment covariates and was most pronounced in women who reported regularly exercising for at least 6 months prior to starting their cancer treatment. Exploratory genome-wide analysis identified a novel risk locus on chromosome chr6q27, tagged by rs9365961, associated with CRCI. This locus is upstream of TBXT, which encodes an embryonic nuclear transcription factor previously associated with susceptibility to neural tube defects. The genome-wide SNP data, patient-reported CRCI and CRF outcome measures, and covariate data used in this analysis are available through dbGaP.

  Study phs003688

• Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a Repository for Related Biologic Studies (10C0086)

  This study (10-C-0086) collected and analyzed tumor and circulating tumor omics of pediatric and young adult patients with relapsed rhabdomyosarcoma who were co-enrolled in and receiving treatment on the interventional study 17-C-0049. We sought to describe the summary genomic findings of tumors, and report on the detection of circulating tumor DNA (ctDNA) in serial samples. Tumor tissue and blood were collected and analyzed. Tumor samples were subjected to whole exome and/or whole genome sequencing paired with RNA-Seq. Cell free DNA (cfDNA) was extracted from serially collected blood samples and sequenced. Fusion status, mutations, and IGF1R and YES1 expression from tumor samples revealed the presence of a PAX3 fusion in most samples, a number of common mutations, and universal but heterogeneous expression of IGF-1R and YES1. ctDNA was detected above the 3% threshold in a majority of patients and analysis of cfDNA demonstrated an ability to monitor tumor clonal evolution.

  Study phs003243

• Lung cancer organoids

  Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here we describe a method to establish long-term culture conditions of human airway epithelial organoids that contain all major cell populations and allow personalized human disease modelling. We collected macroscopically inconspicuous lung tissue from non-small-cell lung cancer (NSCLC) patients undergoing medically indicated surgery and isolated epithelial cells to engineer 3D organoids. We exploit the potential to derive sub-clones from AOs to demonstrate the feasibility of CRISPR gene editing. Finally, we show that AOs readily allow modelling of viral infections such as RSV and for the first time demonstrate the possibility to study neutrophil-epithelium interaction in an organoid model. Taken together, we anticipate that human AOs will find broad applications in the study of adult human airway epithelium in health and disease.

  Dataset EGAD00001004013

• A Phase II Clinical Trial of the PARP Inhibitor Talazoparib in BRCA1 and BRCA2 Wild-Type Patients

  The Talazoparib Beyond BRCA (TBB), a phase II proof-of-concept clinical trial, was designed to test the efficacy of talazoparib, a potent, orally bioavailable PARP inhibitor, with an established Phase II recommended dose, in the treatment of advanced BRCA wildtype (WT), HER2-negative breast cancer and other solid tumors with homologous recombination (HR) deficiency. Eligible patients had advanced HER2-negative breast cancer or other solid tumors with a germline or somatic mutation in a gene linked to the HR pathway. Patients identified as harboring a deleterious or suspected deleterious germline or somatic mutation in the HR pathway were treated with single agent talazoparib until disease progression. Primary and metastatic tumor samples were sequenced with panel sequencing and exome sequencing to detect commonly mutated genes and those associated with DNA repair deficiency. In addition, ctDNA was sequenced at baseline and progression. Fastq files for tumor and ctDNA sequencing are deposited. 

  Study phs002803

• A Phase III Randomized Study of Nivolumab Plus Ipilimumab Versus Nivolumab in Stage IV Squamous Cell Lung Cancer

  Lung-MAP (S1400, NCT02785952) was a multicenter, open-label, phase III randomized clinical trial. The Lung-MAP-I substudy (S1400I) was conducted from December 2015 to April 2018, through the National Clinical Trials Network and led by the SWOG Cancer Research Network. The trial compared nivolumab plus ipilimumab (nivo+ipi) with nivolumab monotherapy (nivo) in patients with chemotherapy-pretreated, immunotherapy-naïve, advanced squamous non-small cell lung carcinoma (sqNSCLC). Two hundred fifty-two patients were randomly assigned to receive nivo+ipi (n = 125) or nivo (n = 127). The clinical efficacy endpoints were overall survival, progression free survival, duration of response, and best objective response by RECIST 1.1. Multi-omic translational analysis was performed in collaboration with the the CIMAC–Cancer Immunologic Data Commons (CIDC) Network using available tumor tissue samples and blood samples (n = 160) submitted for Lung-MAP screening and provided by the SWOG tissue bank.

  Study phs003412

• Unraveling the Genetic Architecture of Diabetic Retinopathy in South India

  This study aims to understand the genetic architecture of diabetic retinopathy in the South Indian population by examining participants with South Indian ancestry and type 2 diabetes (T2D) from two sources: the Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS) and prospective recruitment at Sankara Nethralaya affiliates. A total of 2393 patients were recruited and included in the genetic analysis, with 1588 patients having no diabetic retinopathy (DR) serving as the controls and 805 patients with any level of DR serving as the cases. Enrolled individuals had genome-wide genotyping from DNA extracted from blood samples. In addition, whole genome sequencing (WGS) was performed on 31 members from 2 families. Clinical data, such as age, duration of diabetes, and hemoglobin A1C (HbA1c) were recorded for study participants. Diabetic retinopathy was assessed by clinical exam and/or fundus photography. The grading of diabetic retinopathy followed the International Clinical Diabetic Retinopathy Severity Scale.

  Study phs002116

• Ipilimumab and Decitabine in Treating Patients With Relapsed or Refractory Myelodysplastic Syndrome or Acute Myeloid Leukemia

  The NCI Experimental Therapeutics Clinical Trials Network (ETCTN)/Cancer Therapy Evaluation Program (CTEP) 10026 study (NCT02890329) tested combined ipilimumab and decitabine treatment in two cohorts: Arm A consisted of patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation. Arm B consisted of patients with advanced myelodysplastic syndrome (MDS) or AML that did not previously undergo stem cell transplantation. During the study, peripheral blood and bone marrow samples were obtained from study participants at study entry (screening), following the first lead-in cycle of decitabine monotherapy, during combined treatment with decitabine and ipilimumab, and at the end of treatment.This study tested the combination of the CTLA-4 blocking antibody ipilimumab and the DNA methyltransferase inhibitor decitabine in advanced myeloid disease in the transplant-naive and post-transplant context. The samples were used for bulk and single cell RNA sequencing (scRNA-seq) as well as whole exome sequencing (WES).

  Study phs003015

• Deciphering craniopharyngioma subtypes: Single-cell analysis of tumor microenvironment and immune networks

  Craniopharyngiomas, including both adamantinomatous (ACP) and squamous papillary (PCP) types, present significant challenges in treatment due to their proximity to critical pituitary structures. In this study, we conducted a single-cell RNA analysis to examine the tumor microenvironments (TME) of ACP and PCP. Single-cell clustering revealed a wide range of cell types, which were further categorized based on gene expression patterns. For ACP, these categories included developing epithelia, calcification, and immune response, while PCP showed developing epithelia, cell cycle, and immune response as prominent categories. Subclustering analysis unveiled different types of immune cells in both ACP and PCP TMEs, with specific patterns of immune responses. Interestingly, smaller tumors were associated with particular immune cell ratios. Furthermore, we identified specific cell-to-cell interactions within the tumor cells. In conclusion, our study has led to the development of a comprehensive cell atlas, shedding light on the molecular characteristics and intricate interplay of immune cells within the TMEs of ACP and PCP.

  Study JGAS000722

• Monosomy 7 delineates a primitive acute myeloid leukemia with adverse prognosis and responsiveness to epigenetic therapy

  The mechanistic basis for adverse risk associated with monosomy 7 remains undetermined in AML. In contrast to del(7q), monosomy 7 conferred adverse prognosis independent of TP53 and complex karyotype. Single-cell RNA and ATAC-seq revealed an epigenetically remodeled landscape and expansion of multipotent progenitor (MPP)-like cells. Monosomy 7 derived progenitors were distinguished by reduced chromatin accessibility and expression of STK17A and NT5C3A, which conferred resistance to cytotoxic and venetoclax-based therapy. To circumvent resistance mediated by monosomy 7 and deficient TP53, histone deacetylase inhibitors (HDACi) effectively restored apoptotic potential and augmented the activity of venetoclax. In a randomized clinical trial including older unfit patients with AML and monosomy 7, responses were observed in the majority that received low-dose cytarabine, venetoclax and the HDACi pracinostat, some with durable remissions exceeding 3 years. Longitudinal studies highlighted diminution of MPP-like cells, linking epigenetic remodeling to clinical response and therapeutic vulnerability of monosomy 7 AML.

  Study EGAS50000001641

• Divergence between high metastatic tumor burden and low circulating tumor DNA concentration in metastasized breast cancer

  Circulating tumor DNA (ctDNA) was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. Here we investigated the role of ctDNA in patients with metastatic breast cancer. In an index patient with more than 100,000 circulating tumor cells (CTCs) in serial blood analyses, whole genome, exome, or targeted deep sequencing of the primary tumor, metastases, and 551 CTCs were consistent with a genetically homogeneous cancer. However, the allele fractions (AFs) of ctDNA were only 2-3% in each analysis, which did neither reflect the tumor burden nor the dynamics of this progressive disease by far. Indeed, plasma analyses of 71 further patients demonstrated highly variable AFs of mutant fragments, which frequently did not correspond to the tumor burden. These results provide insights into mechanisms involved in CTC and ctDNA release into the circulation and have important implications for diagnostic tests based on liquid biopsies.

  Study EGAS00001000625

• A biobank of patient-derived pediatric brain tumor models

  Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children’s Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and 7 cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.

  Study EGAS00001002536

• A Universal Gut Metagenomic-Derived Signature Predicts Cirrhosis

  Dysregulation of the gut microbiome has been implicated in the progression of nonalcoholic fatty liver disease (NAFLD) to advanced fibrosis and cirrhosis. To determine the diagnostic capacity of this association, stool microbiomes were compared across 163 well-characterized participants encompassing non-NAFLD controls, NAFLD-cirrhosis patients and their first-degree relatives. Interrogation of shotgun metagenomic and untargeted metabolomic profiles using the Random Forest machine learning algorithm and differential abundance analysis identified discrete metagenomic and metabolomic signatures that were similarly effective in detecting cirrhosis (diagnostic accuracy 0.91, AUC). Combining the metagenomic signature with age and serum albumin levels accurately distinguished cirrhosis in etiologically and genetically distinct cohorts from geographically separated regions. Additional inclusion of serum aspartate aminotransferase levels, which are increased in cirrhosis patients, enabled discrimination of cirrhosis from earlier stages of fibrosis. These findings demonstrate that a core set of gut microbiome species may offer universal utility as a non-invasive diagnostic test for cirrhosis.

  Study EGAS00001004600

• Resolving the Full Spectrum of Human Genome Variation using Linked-Reads

  Large-scale population based analyses coupled with advances in technology have demonstrated that the human genome is more diverse than originally thought. Standard short-read approaches, used primarily due to accuracy, throughput and costs, fail to give a complete picture of a genome. They struggle to identify large, balanced structural events, cannot access repetitive regions of the genome and fail to resolve the human genome into its two haplotypes. Here we describe an approach that retains long range information while harnessing the power of short reads. Starting from only 1ng of DNA, we produce barcoded short read libraries. The use of novel informatic approaches allows for the barcoded short reads to be associated with the long molecules of origin producing a novel datatype known as 'Linked-Reads'. This approach allows for simultaneous detection of small and large variants from a single Linked-Read library. We have previously demonstrated the utility of whole genome Linked-Reads (lrWGS) for performing diploid, de novo assembly of individual genomes. In this manuscript, we show the utility of reference based analysis using a single Linked-Read library for full spectrum genome analysis. We demonstrate the ability of Linked-Reads to reconstruct megabase scale haplotypes and to recover parts of the genome that are typically inaccessible to short reads, including phenotypically important genes such as STRC, SMN1 and SMN2. We demonstrate the ability of both lrWGS and Linked-Read Whole Exome Sequencing (lrWES) to identify complex structural variations, including balanced events, single exon deletions, and single exon duplications. The data presented here show that Linked-Reads provide a scalable approach for comprehensive genome analysis that is not possible using short reads alone.

  Study EGAS00001003121

• 'Targeted High Throughput Sequencing in Clinical Cancer Settings: Formaldehyde fixed-paraffin embedded (FFPE) tumor tissues, input amount and tumor heterogeneity'

  "Background: Massively parallel sequencing technologies have brought an enormous increase in sequencing throughput. However, these technologies need to be further improved with regard to reproducibility and applicability to clinical samples and settings. Methods: Using identification of genetic variations in prostate cancer as an example we address three crucial challenges in the field of targeted re-sequencing: Small nucleotide variation (SNV) detection in samples of formalin-fixed paraffin embedded (FFPE) tissue material, minimal amount of input sample and sampling in view of tissue heterogeneity.Results: We show that FFPE tissue material can supplement for fresh frozen tissues for the detection of SNVs and that solution-based enrichment experiments can be accomplished with small amounts of DNA with only minimal effects on enrichment uniformity and data variance. Finally, we address the question whether the heterogeneity of a tumor is reflected by different genetic alterations, e.g. different foci of a tumor display different genomic patterns. We show that the tumor heterogeneity plays an important role for the detection of copy number variations, but is of minor importance for the detection of somatic variations.Conclusions: The application of high throughput sequencing technologies in cancer genomics opens up a new dimension for the identification of disease mechanisms. In particular the ability to use small amounts of FFPE samples available from surgical tumor resections and histopathological examinations facilitates the collection of precious tissue materials. However, care needs to be taken in regard to the locations of the biopsies taken, which can have an influence on the prediction of copy number variations. Bearing these technological challenges in mind will significantly improve many large-scale sequencing studies and will - on a long-range - result in a more reliable prediction of individual cancer therapies."

  Study EGAS00001000136

• Analysis of error profiles in deep next-generation sequencing data

  BackgroundSequencing errors are key confounding factors for detecting low-frequency genetic variants that are important for cancer molecular diagnosis, treatment, and surveillance using deep next-generation sequencing (NGS). However, there is a lack of comprehensive understanding of errors introduced at various steps of a conventional NGS workflow, such as sample handling, library preparation, PCR enrichment, and sequencing. In this study, we use current NGS technology to systematically investigate these questions.ResultsBy evaluating read-specific error distributions, we discover that the substitution error rate can be computationally suppressed to 10-5 to 10-4, which is 10- to 100-fold lower than generally considered achievable (10-3) in the current literature. We then quantify substitution errors attributable to sample handling, library preparation, enrichment PCR, and sequencing by using multiple deep sequencing datasets. We find that error rates differ by nucleotide substitution types, ranging from 10-5 for A>C/T>G, C>A/G>T, and C>G/G>C changes to 10-4 for A>G/T>C changes. Furthermore, C>T/G>A errors exhibit strong sequence context dependency, sample-specific effects dominate elevated C>A/G>T errors, and target enrichment PCR led to aprox 6-fold increase of overall error rate. We also find that more than 70% of hotspot variants can be detected at 0.1% - 0.01% frequency with the current NGS technology by applying in-silico error suppression.ConclusionsWe present the first comprehensive analysis of sequencing error sources in conventional NGS workflows. The error profiles revealed by our study highlight new directions for further improving NGS analysis accuracy both experimentally and computationally, ultimately enhancing the precision of deep sequencing.

  Study EGAS00001003444

• An exome sequencing study of the HIV elite-long term non progressors and rapid progressors (CASCADE cohorts)

  Background: A rare subgroup of HIV infected individuals naturally controls infection without treatment. These ?elite controllers? constitute an important model for the natural control of HIV infection. Indeed, the study of these individuals may provide insights into strategies for the development of HIV vaccines. Although several HLA and chemokine alleles are known to be over-represented in elite controllers, only a small portion of HIV phenotypic variation is explained by known genetic variants. The elite controller phenotype is rare and distinct, representing the extreme of an infectious disease trait. As such, this phenotype may be partly explained by variation in host immune control, which may be characterized by differences in rare functional genetic variants. Genomic regions underlying elite control can be potentially identified by comparing the presence or frequency of variants in this group to that representing the opposite extreme. In this context, ?rapid progressors? is a group defined by its rapid immunological and clinical disease progression. Aim: To extend an existing study, in order to identify DNA sequence variants involved in the control of HIV infection with greater statistical resolution. Specifically, we aim to sequence up to 200 exomes from multiple cohort studies within the EuroCoord CASCADE collaboration (a collaboration of 25 HIV seroconversion cohort studies across Europe).

  Dataset EGAD00001002179

• To profile the landscape of sebaceous tumours_WES

  Sebaceous tumours are a rare cutaneous cancer with potential for aggressive behaviour. However, limited information is available on these cancers with few published cases. Here we wish to exome sequence these cancers to define the first genomic landscape for this malignancy. We will extract DNA from formalin-fixed, paraffin-embedded (FFPE) cores. Cores may be obtained from lesional and non-lesional tissues of primaries as well as matching metastases. The extracted DNA will be used for exome sequencing. Please note that the dataset was last revised on October 16, 2025.

  Dataset EGAD00001015367

• SINGLE CELL ANALYSIS OF IN VITRO ERYTHROPOIESIS

  We are developing a protocol to differentiate mouse and human induced pluripotent stem (IPS) and embryonic stem (ES) cells towards the haematopoietic pathway to generate erythrocytes in vitro. This system has many applications such as the study of the role of specific genes and human polymorphisms in infectious diseases such as malaria, as well as haematological diseases such as myelodysplastic syndrome. The nature of the in vitro differentiation process means that a heterogeneous population of cells is generated. In order to understand the types of cells produced with our protocol, we have performed a single cell analysis, which has the power to reveal the different populations of cells and their characteristics. For this, a cDNA library has been made that needs to be sequenced to obtain the gene expression profiles of the different cells. With this information we will be able to assess the quality of the differentiation protocol and improve it in order to produce better cells for the downstream applications.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/

  Dataset EGAD00001000979

• Combination therapies for personalized cancer medicine

  It is the ambition of the team formed by members of the Netherlands Cancer Institute (NKI) and the Cancer Genome Project at the Wellcome Trust Sanger Institute (WTSI) to unravel the genomic and phenotypic complexity of human cancers in order to identify optimal drug combinations for personalized cancer therapy. Our integrated approach will entail (i) deep sequencing of human tumours and cognate mouse tumours; (ii) drug screens in a 1000+ fully characterized tumour cell line panel; (iii) high-throughput in vitro and in vivo shRNA and cDNA drug resistance and enhancement screens; (iv) computational analysis of the acquired data, leading to significant response predictions; (v) rigorous validation of these predictions in genetically engineered mouse models and patient-derived xenografts. This integrated effort is expected to yield a number of combination therapies and companion-diagnostics biomarkers that will be further explored in our existing clinical trial networks.

  Dataset EGAD00001000869

• Immune Profiling in Patients with High-Risk Smoldering Myeloma

  Single-cell RNA-sequencing identifies immune biomarkers of response to immunotherapy in patients with high-risk Smoldering Multiple Myeloma (SMM). We conducted a Phase II trial of the immunotherapeutic anti-SLAMF7 antibody, Elotuzumab, in combination with Lenalidomide and Dexamethasone (E-PRISM study), to determine the utility and safety of early immunotherapy in patients with high-risk SMM and develop biomarkers for optimal patient selection and monitoring of response to treatment.There is an overlap in subjects between this study and dbGaP accession phs001323.

  Study phs002476

• The Nephrotic Syndrome Study Network (NEPTUNE)

  The Nephrotic Syndrome Study Network (NEPTUNE) is a collaborative investigational infrastructure of 40 North American sites for conducting clinical and translational research in Focal Segmental Glomerulosclerosis (FSGS), Membranous Nephropathy (MN), and Minimal Change Disease (MCD). NEPTUNE provides prospective, un-blinded, standardized evaluation of clinical and molecular outcomes in two cohorts: A) adults and children with incident or prevalent, biopsy-proven FSGS, MN, or MCD, recruited at the time of first biopsy, and B) children with incident Nephrotic Syndrome without a diagnostic kidney biopsy.

  Study phs003210

• A Phenotypic and Genomics Approach in a Multi-Ethnic Cohort to Subtype Systemic Lupus Erythematosus

  Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems and varies in severity across different populations. To examine the clinical heterogeneity of SLE, we sought to identify different lupus subtypes within our multi-ethnic cohort using a clustering approach. Additionally, with genome-wide methylation and genotype data generated for our cohort, we applied integrative methods to investigate genetic and epigenetic risk factors. This integrative and computational approach revealed molecular differences associated with phenotypic clusters.

  Study phs001850

• 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

• Pharmacogenomics of Rheumatoid Arthritis Therapy

  Rheumatoid arthritis (RA) is the most common autoimmune inflammatory arthritis worldwide and affects 1.3 million adults in the USA. It has previously been studied using phenotype algorithms to identify electronic health records (EHR) case cohorts. Early genetic studies of EHR-linked cohorts of RA patients have been replicated in known associations. Further development of collections of EHR-linked cohorts for RA and other phenotypes may enable not only enhanced understanding of disease risks but also the investigation of outcomes and treatment responses.

  Study phs000983