19371 results for "Cheap fc 26 coins Buyfc26coins.com is official EA Sports partner for FC 26 coins That was the fastest delivery ever..fxB4"

in 49.69 milliseconds.

• Multiple Myeloma Genomic Study (MMGS)

  Multiple Myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow (BM) infiltration and lytic bone lesions. Recent studies of massive parallel sequencing of tumor cells obtained from the BM of patients with MM have demonstrated significant clonal heterogeneity in MM. Despite this remarkable clonal heterogeneity, it could be envisioned that such clonal diversity may be even higher since single BM samples only represent a small fraction of the whole BM compartment, and the pattern of BM infiltration in MM is typically patchy. In addition, BM biopsies are painful and cannot be repeated multiple times during the course of therapy, indicating a need for less invasive methods to molecularly characterize MM patients and monitor disease progression during the therapy. Thus, optimal characterization of circulating tumor cells (CTCs) may represent a non-invasive method to capture relevant mutations present in PC clones. In addition, MM almost always progresses from precursor states of monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) to overt MM. However, some patients rapidly progress from MGUS/SMM to overt MM (progressors) with a rate of progression of up to 70% over 5 years, while others remain indolent with minimal progression over the same time period (non-progressors). Although many patients are diagnosed with earlier phases of disease, most patients do not receive treatment until their disease progresses, at which time they have overt end-organ damage. This concept of initiating therapy at the time of symptomatic disease is analogous to initiating therapy in patients with solid tumors only after the development of measurable metastatic disease. It is therefore not surprising that cure is not achieved for most patients with MM. Interestingly, studies have demonstrated that MGUS/SMM clones may already harbor chromosomal alterations (Ig loci or hyperdiploidy) and that progression to MM is mainly due to expansion of clones that were already present in the early stages of MGUS/SMM. However, the biological factors that discriminate progressors from non-progressors in MGUS/SMM are not well known. Therefore, our overarching hypothesis is that an effective therapeutic intervention will result from defining genomic and transcriptomic markers that are associated with disease progression. We believe, therefore, that focused research studies that define molecular mechanisms of clonal evolution in MGUS/SMM/MM will identify novel biomarkers of disease progression and help develop therapeutic agents that prevent or delay progression from MGUS to overt MM. Indeed, by eradicating the disease at the precursor stages, MM may become a preventable disease. Recently, a new term called Clonal Hematopoiesis of Indeterminate Potential (CHIP) has been proposed to describe asymptomatic individuals with hematologic malignancy-associated somatic mutations. Those individuals do not fulfill any diagnostic criteria for any hematological malignancy yet they have a tendency to progress into myelodysplastic syndrome (MDS) or myeloid or lymphoid neoplasia at a rate of around 0.5-1% per year, similar to MGUS. The frequency of CHIP and role of HSCs mutations in enhancing acquisition of somatic mutations in MM plasma cells, allowing progression following treatment, has not been studied. Investigating the dysregulated pathways in early progenitor cells would allow us to understand the reasons of progression and establish novel therapeutic and potentially preventive strategies. This study dissects genomic and transcriptomic characteristics of clonal evolution from MGUS/SMM to MM as well as the characteristics of the tumor microenvironment/immune cells/peripheral blood. Our hypothesis is that molecular biomarkers will be strong predictors of progression from MGUS/SMM to MM and will allow for the development of novel therapeutic agents that prevent or delay this progression. We aim to define genomic and transcriptomic markers that lead to progression from MGUS/SMM to MM in tumor cells, blood biopsies (cell free DNA and circulating tumor cells), and the tumor microenvironment.

  Study phs001323

• Rapid Early Action for Coronary Treatment (REACT-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: This multicenter controlled community study developed and evaluated the impact of a community educational intervention program on participant delay time from onset of symptoms of an acute myocardial infarction (AMI) to arrival at a hospital emergency department.Background: Although early reperfusion or thrombolytic therapy can reduce morbidity and mortality following an AMI, delayed access to medical care in participants is relatively common. Mean delay times from symptom onset to hospital arrival range from more than 4 hours to 24 hours, and the largest component of prolonged delay is participant recognition and action.Participants: A total of 20 communities from 5 field centers in the U.S. were pair-matched (10 pairs) according to geographic proximity and demographic characteristics. After initiation of a 4 month baseline surveillance period, one community in each pair was randomly selected to receive the intervention. The baseline surveillance period was followed by an 18 month community intervention and surveillance period. The community surveillance captured a total of 59,944 adults aged 30 years or older presenting to hospital emergency departments with chest pain, of whom 20,364 met study criteria for suspected acute coronary heart disease (CHD) at admission and discharged with a CHD diagnosis.Conclusions: Delay times were decreased in the intervention and reference communities. The results showed that the multicomponent community intervention program did not differentially reduce delay time from onset of AMI symptoms to arrival at a hospital, but did significantly increase the use of Emergency Medical Services by these participants in the intervention communities. (PMID:10872014).

  Study phs003885

• Atezolizumab Plus Personalized Neoantigen Vaccination in Patients with Urothelial Cancer: a Phase 1 Trial

  This is a phase 1 single center clinical trial evaluating a multi-peptide personalized neoantigen vaccine, PGV001, in combination with atezolizumab for patients with urothelial cancer. Patients were enrolled in either the adjuvant or metastatic setting. Those in the adjuvant setting included patients considered high risk of recurrence (pathological stage ypT2-T4 or ypN+ for those treated with prior neoadjuvant chemotherapy or pT3-T4 or pN+ for those not treated with prior neoadjuvant chemotherapy). Those in the metastatic setting included patients progressing after prior chemotherapy or those with at least stable disease after chemotherapy treated as “switch maintenance” therapy. The primary endpoint was feasibility (including the number of neoantigens identified per patient, vaccine production time, the proportion of patients consenting to the vaccine development phase for whom a vaccine product was prepared, and the proportion of patients eligible for the treatment phase who completed the priming cycle 1 of PGV001 plus atezolizumab) and safety. Secondary endpoints included the objective response rate, progression-free survival or disease-free survival, overall survival, and immunomodulatory effects of treatment. Urothelial tumor tissue and normal tissue or peripheral blood specimens were utilized for DNA sequencing. HLA typing was performed utilizing genomic DNA isolated from whole blood, and RNA sequencing was performed utilizing tumor tissue specimens. Neoantigen prediction and final selection for incorporation into the vaccine was determined by the OpenVax computational pipeline. 12 patients were initially enrolled into the vaccine development phase and 10 patients initiated the treatment phase. PGV001 was administered with poly-ICLC and tetanus peptide on subsequent days for up to 10 doses, including an initial priming cycle 1. Atezolizumab was administered every 3 weeks for up to 1 year in the adjuvant setting or 2 years in the metastatic setting. The vaccine was feasible and safe, the median vaccine production time was 20.3 weeks, and 100% of patients that initiated the treatment phase completed the priming cycle. The most common treatment-related adverse events were local grade 1 injection site reactions, fever, and fatigue. Three of the 4 patients in the adjuvant setting remained disease-free at median follow-up of 39.5 months. There was a 40% objective response rate among patients with measurable disease in the metastatic setting. The single patient treated as “switch maintenance” therapy remained with no evidence of disease at 39.4 month follow-up. All patients demonstrated on-treatment neoantigen-specific T cell reactivity, as measured by ELISPOT and flow cytometry assays. Overall, PGV001 plus atezolizumab was feasible, safe, and warrants further investigation. Whole exome sequencing from tumor tissue and normal tissue or whole blood specimens and RNA sequencing from tumor tissue specimens will be available through dbGaP.

  Study phs003922

• NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Pulmonary Arterial Hypertension)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The syndrome of pulmonary hypertension (PH) is a pulmonary disease that carries very high morbidity and mortality. Pulmonary arterial hypertension (PAH) is a category of PH (WHO Group 1) that includes several entities (idiopathic or heritable PAH, and PAH associated with other diseases such as connective tissue diseases including scleroderma-associated PAH) and carries a dismal prognosis, in particular when it relates to scleroderma-associated PAH (median survival of about 4 years). It is believed that the severity of structural changes involving the pulmonary vasculature and right ventricular failure are genetically determined. The 'Genomics and Genetics of Pulmonary Arterial Hypertension' study at Johns Hopkins University aims to identify genetic determinants associated with risk of PAH in a cohort of European American and African American participants with and without PAH. The study also focuses on patients with scleroderma, who are further stratified according to those who have or do not have PAH. The broad goals of the Lung GO/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 PAH. The Johns Hopkins University PAH cohort offers a unique opportunity to elucidate genetic variants that cause PAH.

  Study phs000290

• Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

  Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG is frequently developed in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-seq, we identified ectopic expression of neuromuscular molecules in MG-associated thymoma (MG-thymoma). These molecules were originated from a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we named neuromuscular mTECs (nmTECs). MG-thymoma also exhibited microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicted the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma was further confirmed by immunohistochemically and by cellular composition estimation from MG-thymoma transcriptome. Altogether, this study suggests that nmTECs play a significant role in MG pathogenesis via ectopic expression of neuromuscular molecules.

  Study JGAS000482

• Transcriptome profiling of human plucked frontal and occipital hair follicles

  Androgenetic alopecia (AGA) is characterized by a progressive and androgen-dependent loss of hair from the frontal and vertex regions of the scalp. Although large-scale genetic analyses have identified >300 genetic risk factors, the underlying causal genes and pathways, and their involvement in core pathophysiological mechanisms, remain unclear. In the present study, systematic profiling of differential mRNA and microRNA expression was performed in human hair follicle samples from frontal and occipital scalp regions. Taken together, the present data improve understanding of the genomic regions, genes, and pathways that are implicated in AGA pathobiology.

  Study EGAS00001002832

• Molecular defects in pseudohypoparathyroidism or related disorders

  Maintaining calcium levels within a narrow normal range is of critical importance for numerous different cellular functions. One of the most important regulators of blood calcium levels is parathyroid hormone (PTH), which mediates its actions through the PTH/PTHrP receptor, a Gαs-coupled receptor. Few inherited disorders are characterized by diminished blood calcium levels and elevated blood phosphate levels; some of these disorders are caused by too little PTH synthesis and/or secretion (hypoparathyroidism, HP), while others are caused by resistance towards PTH (pseudohypoparathyroidism, PHP). Only few of the inherited forms of HP (<10%) have been defined at the molecular level. In contrast, genetic mutations have been identified for several inherited forms of PHP. For example, PHP type Ia (PHP-Ia) is caused by maternally inherited mutations in those GNAS exons that encode Gαs, while autosomal dominant PHP type Ib (AD-PHP-Ib) is caused by maternal inherited deletions within or up-stream of GNAS, which are associated with abnormal GNAS methylation. However, a large number of patients with PTH-resistance and thus hypocalcemia show GNAS methylation changes, but their underlying genetic defects have not yet been defined at the DNA level. These "sporadic" patients may be affected by an autosomal recessive form of PHP-Ib (AR-PHP-Ib), which is most likely not linked to the GNAS locus. In our studies, we propose to search through exome sequence analyses for novel genetic mutations responsible for novel autosomal dominant forms of HP that are not caused by mutations in the known disease-causing genes; some of these families are large enough to perform genetic linkage studies. We furthermore propose to search for the genetic mutation(s) responsible for the autosomal recessive variant of PHP-Ib through the analysis of whole exome sequences; for these studies we focus particularly on patients, whose parents are likely to be consanguineous. The proposed efforts are expected to lead to the identification of novel genes that are involved in parathyroid development and function (HP) and genes that are involved in the establishment or maintenance of GNAS methylation (AR-PHP-Ib).

  Study phs000476

• NHLBI TOPMed: Outcome Modifying Genes in Sickle Cell Disease (OMG)

  Sickle cell disease (SCD) is caused by homozygosity for a single mutation of the beta hemoglobin gene. Despite the constancy of this genetic abnormality, the clinical course of patients with SCD is remarkably variable. SCD can affect the function and cause the failure of multiple organ systems through the pathophysiologic processes of vaso-occlusion and hemolysis. These pathophysiological processes are complex and expected to impact multiple organ systems in a variety of ways. This study, therefore, was designed to identify genetic factors that predispose SCD patients to develop specific end-organ complications and to experience more or less severe clinical courses. We enrolled > 700 patients with Hb SS, Hb S-beta0 thalassemia and HbSC being followed primarily at three southeastern U.S. regional institutions (Duke University Medical Center, University of North Carolina Medical Center, and Emory University Medical Center). Medical information obtained included the presence or absence of specific targeted outcomes (overall disease severity as well as specific types of end organ damage). Clinical data include medical status (history, physical, examination, and laboratory results) and information regarding potentially confounding environmental factors. Limited plasma samples are available for correlative studies (e.g. of cytokine levels, coagulation activation). Targeted SNP for candidate gene analysis as well as GWAS has been performed on most samples. Whole genome sequencing has been conducted through the TOPMed Consortium. The subjects in this analysis were collected as part of a larger study, "Outcome Modifying Genes in Sickle Cell Disease" (OMG-SCD) aimed at identifying genetic modifiers for sickle cell disease. More information about the study can be found in Elmariah et al. (2014), PMID: 24478166. Clinical and genetic data have been used to identify genetic characteristics predisposing patients with SCD to a more or less severe overall clinical course as well as to individual organ-specific complications. It is anticipated that identification of such genetic factors will reveal new therapeutic targets individualized to specific complications of SCD, leading to improved outcomes and increased life expectancy for patients with SCD.

  Study phs001608

• A small cell lung cancer genome reports complex tobacco exposure signatures

  Cancer is driven by mutation. Worldwide, tobacco smoking is the major lifestyle exposure that causes cancer, exerting carcinogenicity through 60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. 22,910 somatic substitutions were identified, including 132 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in-frame, and another two lines carrying PVT1-CHD7 fusion genes, suggesting that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.

  Study EGAS00000000051

• Neoadjuvant immunotherapy leads to pathological responses in MMR proficient and MMR deficient early stage colon cancers

  PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.

  Study EGAS00001004160

• CUT&RUN-sequencing identifies PTK7 as a direct Wnt target in patient-derived colorectal cancer organoids

  The aberrant activation of Wnt/β-catenin signaling by APC mutations is a hallmark of colorectal cancer (CRC), but targeting Wnt signaling therapeutically has proven challenging. Deciphering the molecular effects of mutant APC-driven Wnt activation is crucial to enable the discovery of novel therapeutic targets. Here, we employ CUT&RUN-sequencing in patient-derived CRC organoids derived from two donors to dissect the transcriptional regulation by β-catenin in CRC. This analysis identified several genes of interest for CRC development as potential β-catenin target genes. Among these, we characterize PTK7, a co-receptor of the Wnt pathway and stem cell marker, as a main transcriptional target of β-catenin in CRC. We confirm that the expression of PTK7 is directly regulated by β-catenin in a comprehensive panel of CRC models. We demonstrate that APC mutations introduced by CRISPR/Cas9 result in the upregulation of PTK7 expression in human colon organoids, underlining the relevance of this upregulation during CRC carcinogenesis. Finally, we show that PTK7 promotes proliferation in CRC models without definitively affecting canonical Wnt signaling. Together, these results suggest that PTK7, which can be potentially targeted by existing drugs, is a Wnt target gene that contributes to oncogenic growth in CRC.

  Study EGAS00001008295

• A Phase I Study of the Treatment of Recurrent Malignant Glioma with CAN-3110 (AKA rQNestin34.5v.2), a Genetically Engineered HSV-1 Virus

  This study is a "first-in-human" phase 1 trial of recurrent, IDH wild-type glioblastoma (rGBM) patients treated with CAN-3110 (aka rQNestin34.5v.2), a genetically modified oncolytic herpes simplex virus 1 (HSV-1). The study was a 3+3 dose-escalation study starting at a single intra-tumoral injection of 106 PFU CAN-3110 going up to 1010 PFU in half-log increments (cohorts 1-9). An expansion cohort (cohort 10) was treated with 109 PFU injected into up to 5 sites within a single tumor. Principal findings of the study conclude that:CAN-3110 was safe at all tested doses (no dose-limiting toxicities reached)HSV-1 seropositive patients survived significantly longer than HSV-1 seronegative patients in this study - longer than expected based on historical rGBM controlsHSV-1 seropositive patients were significantly more likely to clear CAN-3110 (HSV-1) antigen from their tumors based on immunohistochemical stainingCAN-3110 treatment-induced CD8+/CD4+ T-cell recruitment to injected tumor sites altered TCR beta diversity in both tumor infiltrating leukocytes (TILs) and PBMCs, and initiated changes in specific TCR beta clonotypes and immune gene signatures which were associated with post-treatment survival.Data provided in dbGaP for this study include:Bulk RNA-Seq data for 13 pre/post-treatment pairs of rGBM tumors corresponding to 12 unique patients (patient 28 was treated with CAN-3110 at two different timepoints). This data is provided as raw sequencing reads (.fastq), kallisto pseudoalignment transcript-level read counts (abundance.tsv files), gene-level abundance matrix (Gene_Level_Expression_Matrix.tsv), and immune gene signature scores matrix (Immune_Gene_Signatures_Matrix.tsv). Sequencing was performed as paired 150bp sequencing on NovaSeq6000 S4 Illumina flow cells. Library preparation varied by batch as described in the included RNAseq_Metadata.xlsx table.TCR beta DNA sequencing performed by Adaptive Biotechnologies for 21 pre/post-treatment pairs of rGBM tumors and PBMCs representing 20 unique patients (patient 28 was treated with CAN-3110 at two different timepoints). Note that all tumor pairs with TCR beta sequencing data also have available bulk RNA-Seq data. The TCR beta sequencing data is provided as an excel spreadsheet (TCRbeta_Sample_Overview.xslx), which provides a broad level summary of the sequencing on a per-sample basis (# of TCRbeta templates, T cell fraction, TCR beta diversity metrics, etc.) and as a large tab separated value file (Full_TCRbeta_Rearrangement_Details.tsv), which provides information per sample at the level of each unique TCR beta sequence (amino/nucleic acid sequence, VDJ gene usage, etc.).An excel table of de-identified metadata for the patients involved in this study.

  Study phs003378

• Homozygous Duplication Identified by Whole Genome Sequencing Causes LRBA Deficiency

  In more than one third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole exome sequencing (WES) fails to identify the genetic defect. Whole genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation and hypogammaglobulinemia, typical of lipopolysaccharide (LPS)-responsive and beige-like anchor protein (LRBA) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4) deficiencies. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene.

  Study phs002557

• The subclonal architecture of metastatic breast cancer: Results from a prospective community-based rapid autopsy program 'CASCADE'

  Background: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. The majority of work in this area has targeted primary tumours however, and very few studies have performed comprehensive profiling of advanced disease. Evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. Methods and Findings: Three patients with ER-positive, HER2-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program. Cases represented a range of management problems in breast cancer, including late relapse after early stage disease; de novo metastatic disease; discordant disease response and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing.Between cases, there were significant differences in mutational burden, driver mutations, mutational processes and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross seeding was found in each case and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases, and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the key role of mutational processes in subclonal evolution.Limitations of this study include the potential for bias introduced by joint analysis of formalin fixed archival specimens with fresh specimens, and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. Conclusions: This study highlights the variety of mechanisms that shape the genome of metastatic breast cancer, and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm.

  Study EGAS00001002153

• Linking genes, genomic instability and molecular subgroups in medulloblastoma

  Brain tumors are the second most common pediatric cancer and carry the highest mortality rates in this age group. Medulloblastoma is the most frequent malignant brain tumor of childhood. Recent studies indicate that medulloblastoma comprises at least four sub-entities (SHH-signaling, WNT-signaling, Group-C, Group-D) that differ in molecular alterations, cell of origin, clinicopathological features and outcome. Further characterization of the entire spectrum of genomic alterations underlying the formation of these distinct groups is urgently needed to identify diagnostic and prognostic biomarkers for clinical management and uncover novel therapeutic targets.

  Study EGAS00001000085

• DNA and RNA sequencing of single human haploid germ cells

  Our goal was to look at allele-specific gene expression in single spermatids from two human donors. We first genotyped and phased each donor using a combination of linked-read sequencing (one sample per donor, 10X Chromium), and single haploid whole genome sequencing (53 spermatids for the first donor, and 19 for the second). We then sequenced mRNA from single spermatids (302 from the first donor, and 164 from the second), using the Smart-Seq2 protocol. We used these gene expression data, in combination with the haplotype data, to look for gene products that exhibit allele-specific bias reflecting the haploid genotype of the cell. We find a large class of human genes that show such allele-specific bias in spermatids, indicating that these gene products are not fully shared across the cytoplasmic bridges that connect spermatids. We term these genes “genoinformative markers” (GIMs).

  Study phs002279

• Genomic Wide Scans for Female Osteoporosis Genes

  Osteoporosis is a condition of excessive skeletal fragility which results in high risk to low trauma fractures. It is the most prevalent metabolic bone disease and is a major public health problem which may result in devastating morbidity and mortality. The most powerful, measurable determinant of fracture risk is bone mineral density (BMD). More than 60% of BMD variation is attributable to genetic factors. There are gender differences in BMD that contribute to a substantially higher fracture risk among women than men. Genetic studies demonstrate that some osteoporosis risk genes/genomic regions are gender specific. However, specific such genes contributing to female BMD and to the sex differences of BMD are largely unknown. Recent rapid progresses in SNP genotyping technology, in our knowledge about human genome diversity and linkage disequilibrium (LD) patterns in the human genome as revealed have made it feasible and timely to pursue a powerful whole genome-wide association study (GWAS) to identify genes for BMD. The major goal of this project is to perform a powerful GWAS study in a large sample of US Caucasian subjects. Gender specific effects of the genetic variants will be examined. The significant genetic variants discovered will be used to design diagnostic DNA chips for prognosis for potential health problems of osteoporosis later in life.

  Study phs000390

• Queensland Melanoma Genomic Biomarker Study

  There is a clinical need to identify melanoma patients not likely to benefit from current targeted and immuno-therapy and identify biomarkers that can predict patient outcome. Genomic biomarkers are not yet part of staging but show promising results. The aim of this study was to determine genomic and image-based biomarkers as adverse prognostic factors in stage III/IV melanoma patients with resected disease. We found combining genomic and PET/CT derived biomarkers with current clinical assessment may offer additional prognostic tools to stratify patients in the clinic.

  Study EGAS00001004619

• National Institute of Dental and Craniofacial Research (NIDCR) Sjögren's International Collaborative Clinical Alliance (SICCA): Center for Inherited Disease Research (CIDR) Genome-Wide Genotyping

  The Sjögren's International Collaborative Clinical Alliance (SICCA) is a multisite observational cohort study that recruited a large cohort of geographically diverse participants. Enrollment of participants began in late 2004 at five (one domestic and four international) sites, in which all groups used the same protocol-directed methods to provide uniform evaluations; collect oral, ocular, and rheumatologic data; and collect specimens. The sites were located at the University of Buenos Aires, Argentina; Peking Union Medical College, Beijing, China; Rigshopitalet (formerly at Glostrup Hospital), Copenhagen, Denmark; Kanazawa Medical University, Ishikawa, Japan; King's College, London, UK (joined in 2007); and the University of California, San Francisco (UCSF). In 2009, Aravind Eye Hospital, Madurai, India; Johns Hopkins University, Baltimore, MD; and University of Pennsylvania, Philadelphia, PA were added as additional SICCA sites. UCSF is the coordinating center for SICCA. All specimens and data collected for SICCA are housed at UCSF. To facilitate the research focused on understanding the genetics of Sjögren'sSjögren's syndrome, high-density SNP genotype data and SICCA clinical information are being made available to the research community. This includes participants recruited from all SICCA research groups (RG). These participants (3,382), blood relatives (439), and unrelated healthy controls (25) had their whole blood or saliva sample (Oragene) extracted for DNA for the GWAS at the UCSF DNA Bank. Eighty eight percent of the participants are women, most are of European or Asian ancestry and the median age is 55. To assess potential batch effects when doing case-control comparisons using planned external controls, 30 DNA samples from each of three studies were genotyped with SICCA DNA samples: The Genetic Architecture of Smoking and Smoking Cessation - Collaborative Genetic Study of Nicotine Dependence (COGEND) - PI: Laura Bierut. NEI-Age-related disease study (AREDS) - Genetic Variation in Refractive Error Substudy - PI: Dwight Stambolian. Controls from the National Institute of Mental Health's (NIMH's) Human Genetics Initiative. Genome-Wide Association Study of Schizophrenia - PI: Pablo V. Gejman. Molecular Genetics of Schizophrenia - nonGAIN Sample (MGS_nonGAIN) - PI: Pablo V. Gejman. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data quality control, dbGaP preparation and posting, and imputation to 1000 Genomes to increase SNP density was performed by the Center for Biomedical Statistics at the University of Washington. Data analysis was performed at UCSF using software PLINK, EIGENSOFT, and SNPTEST.

  Study phs000672

• Investigation of respiratory chain integrity in skeletal muscle in Parkinson's disease

  The aim of this study is to investigate mitochondrial dysfunction in skeletal muscle as a potential biomarker for identifying a distinct subtype of Parkinson’s disease (PD) characterized by mitochondrial complex I (CI) deficiency (CI-PD). Based on previous post-mortem findings, the study hypothesizes that widespread CI deficiency is present in a subset of PD patients and could be detectable in clinically accessible muscle samples. By analyzing mitochondrial function in muscle biopsies from individuals with PD and healthy controls, the study seeks to explore the extent of mitochondrial dysfunction in PD and identify a stratification marker for future diagnostic and therapeutic interventions. This study is part of the STRAT-PARK initiative, a longitudinal cohort study that aims to stratify neurodegenerative parkinsonisms into biological subtypes using a biomarker-based approach (https://doi.org/10.1016/j.pneurobio.2024.102603).

  Study EGAS50000000671

• POPRES: Population Reference Sample

  POPRES version 1 and 2 Technological and scientific advances, stemming in large part from the Human Genome and HapMap projects, have made large-scale, genome-wide investigations feasible and cost-effective. These advances have the potential to dramatically impact drug discovery and development by identifying genetic factors that contribute to variation in disease risk as well as drug pharmacokinetics, treatment efficacy, and adverse drug reactions. In spite of the technological advancements, successful application in biomedical research would be limited without access to suitable sample collections. To facilitate exploratory genetic research, we have assembled a DNA resource from a large number of subjects participating in multiple studies throughout the world. This resource was initially genotyped using the Affymetrix 500K SNP panel. This project includes nearly 6,000 subjects of African American, East Asian, South Asian, Mexican, and European origin. POPRES version 3 The discovery and development of novel drugs is challenging and with high attrition rates. Selection of the right target and optimal indications for novel therapeutics represent key decision points in this process, and are often hampered by our limited understanding of the biology of the target in humans. Building a robust body of knowledge of variation within drug target genes has in several cases increased the probability of success for novel therapeutics. Our knowledge of variation within drug target genes and their influence on traits of medical interest is still very limited. In an effort to fill this gap, we resequenced the exons of 202 known or suspected drug target genes in over 16,000 well-phenotyped individuals. A total of 863,883 bases were targeted, including 351 kb of coding and 323 kb of untranslated exon regions. The sequenced subjects included 3,381 from two studies that were part of the Population Reference Sample (POPRES) project: CoLaus (N = 2,059) and LOLIPOP (N = 1,322). Genotyping data generated through the targeted next generation sequencing is available through the dbGaP.

  Study phs000145

• Age related Macular Degeneration (AMD) - Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: Association and Sequencing Studies

  Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with the disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Study 1: To identify genetic variants and haplotypes that are associated with AMD, we submitted and obtained usable genotyping data on 2185 patients and 1155 controls from the Center for Inherited Disease Research (CIDR). Study 2: To identify rare coding variants associated with a large increase in risk of AMD, 10 candidate loci spanning 57 genes were sequenced in 2,335 cases and 789 controls. Probes were designed to capture 96.5% of the coding sequence and 35% of total locus sequence, generating an average 123Mb of on-target sequence per individual at 127x average depth. Substudies: phs000182 AMD-MMAP Cohort Study: A Joint Genome-Wide Asscociation Study phs000246 Fuchs' Corneal Dystrophy GWAS phs000457 MMAP Methylation in AMD phs000685 Age-Related Macular Degeneration Targeted Sequencing Study

  Study phs000684

• NCI's Datasets for General Research Use

  This collection contains all of NCIs authorized individual-level genomic datasets currently in dbGaP that are approved for General Research Use (GRU) and have no further limitations beyond those outlined in the model Data Use Certification Agreement. Access to this study will include any additional authorized individual-level GRU datasets that become available. Renewal of this study is required annually.

  Study phs003014

• Human Blastocyst 10X Single Cell RNA Sequencing

  Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. One limitation of our first protocol for human blastoid generation was relatively low efficiency. We now report an optimized protocol for the efficient generation of large quantities of high-fidelity human blastoids from naive pluripotent stem cells. This enabled proteomics analysis that identified phosphosite-specific signatures potentially involved in the derivation and/or maintenance of the signaling states in human blastoids. Additionally, we uncovered endometrial stromal effects in promoting trophoblast cell survival, proliferation, and syncytialization during co-culture with blastoids and blastocysts. Side-by-side single-cell RNA sequencing revealed similarities and differences in transcriptome profiles between pre-implantation blastoids and blastocysts, as well as post-implantation cultures, and uncovered a population resembling early migratory trophoblasts during co-culture with endometrial stromal cells. Our optimized protocol will facilitate broader use of human blastoids as an accessible, perturbable, scalable, and tractable model for human blastocysts. In addition, this study is the first to use the 10X Genomics platform for human blastocysts, and we anticipate this resource will be widely used by the community as a reference for future studies.

  Study phs003122

• 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

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

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

  Study phs003985

• Patient-derived tumor organoids for personalized medicine in a rare case of hepatocellular carcinoma with neuroendocrine differentiation.

  We report the case of a 74-year-old man with a very rare subtype of hepatocellular carcinoma with neuroendocrine differentiation (HCC-NED). The patient presented with two independent tumors, a gastrointestinal stromal tumor in the stomach and a hepatocellular carcinoma in the liver. Both tumors were surgically removed in curative intent. Histopathological work-up of the liver tumor revealed poorly differentiated hepatocellular carcinoma (Edmondson-Steiner grade IV) with diffuse expression of neuroendocrine markers synaptophysin (SYP) and chromogranin (CHGA). Three months after resection, multifocal recurrence of the HCC with neuroendocrine differentiation (HCC-NED) was observed. In the meantime, tumor organoids have been generated from the resected HCC-NED and extensively characterized. Sensitivity to a number of drugs approved for the treatment of HCC or neuroendocrine carcinomas was tested in vitro. Based on their in vitro efficacy, etoposide and carboplatin were used as first line palliative combination treatment. Because genomic analysis revealed a NTRK1-mutation (kinase domain) and tumor organoids were sensitive to entrectinib, a pan-TRK inhibitor, the patient received entrectinib as second line therapy. After only two weeks, treatment had to be discontinued due to deterioration of the patient’s general condition. In conclusion, we demonstrate for the first time that preclinical drug testing using organoids is feasible in selected HCC cases.

  Study EGAS00001005887

• LLDeep DAG2+ scRNA-seq in PBMCs

  Single cell transcriptomics of PBMCs of 47 donors from the Lifelines Deep cohort (general population, Northern part of the Netherlands). Cells of five or six different donors were pooled together in one sample pool, resulting in eight different sample pools. In total, 28.855 cells were captured and their transcriptomes were sequenced to an average depth of 74k. Genotype data was available for each donor, which allowed us to use the Demuxlet method that uses variable SNPs between the pooled individuals to determine which cell belongs to which individual. Since genotype information is lacking of 2 individuals, the transcriptome of only 45 individuals could be retrieved.

  Dataset EGAD00010001315

• Copy-Number Analysis of Understudied Black Women Ovarian Cancers

  Two general types of genetic alterations drive cancer progression: mutations and copy number alterations (CNAs). With the exception of p53, single nucleotide variant mutations (here, simply "mutations") are not drivers of 80% of tumors within the most frequent and deadly histotype of ovarian cancer: serous ovarian cancer (SOC). Rather, CNAs are more prevalent in SOC than any other cancer type studied by phs000178 The Cancer Genome Atlas (TCGA). Fully two-thirds of genes are altered by CNAs in the average SOC. Bioinformatic methods have shown that these CNAs modulate specific molecular pathways, such as autophagy, and this finding enabled effective pathway-targeted therapies1. Unfortunately, TCGA ovarian cancer data lacks racial diversity. Only 6% of SOC tumors (n=32) studied are from African origin. Black women diagnosed with ovarian cancer are more likely to die from their disease than white women. Five-year survival after diagnosis is 31% among blacks versus 42% among whites, and this disparity is seen in every age group and tumor stage distribution. Dr. Kelemen examined data from 365 white and 95 black ovarian cancer patients from the Hollings Cancer Center (HCC) Cancer Registry between 2000 and 2015 and found that black women had an 81% higher risk of death after diagnosis compared to white women (HR 1.81, 95% CI 1.35-2.43), independent of diagnosis center (98% were treated at HCC but half were diagnosed elsewhere), tumor stage, histology, extent of residual tumor remaining following surgery, insurance status, smoking, type of treatment for ovarian cancer, and age-adjusted Charlson comorbidity index. This disparity remained even when restricted to women who received the standard of care, surgery-chemotherapy sequence (HR 1.79, 95% CI 1.10-2.89). Despite receiving the same treatment, black race was still associated with inferior survival. A similar disparity has been reported by others, indicating that the HCC experience is representative of national data. Here, an additional set of high-grade serous ovarian cancer primary tumors were acquired from biorepositories with a focus on expanding data originating from African American women. Data were analyzed for copy-number alterations using exome sequencing and control-FREEC software.

  Study phs002313

• Integrated Personal omics Processing (iPoP) Longitudinal multi-omics profiling of prediabetes

  Type 2 diabetes mellitus (T2D) is a significant health problem. Close to 20 million individuals in the United States have T2D, and 79 million aged 20 years or older are clinically pre-diabetic, with a 5-year conversion rate of 10% to 23% from prediabetes to T2D. In a collaborative effort to systematically understand diabetes and its etiology, the team is comprised of leading experts in research on both the human host as well as the microbiome, as properties of both are likely relevant in T2D development. For a better elucidation of mechanisms of onset and progression of T2D disease, the group is performing a detailed analysis of the biological processes that occur in the microbiome and human host by longitudinal profiling of patients at risk for T2D. Both microbiome and host profiles are being analyzed by state-of-the-art omics platforms, and these large-scale and diverse data sets will be integrated to determine the dynamic pathways that change during the onset and progression of T2D, especially during viral infections and other stresses. This longitudinal study is expected to reveal changes in the microbiome and host at an unprecedented level of detail, and identify molecules and pathways that play important roles in diabetes onset and progression.

  Study phs001719

• Molecular Subtyping Reveals Immune Alterations Associated with Progression of Bronchial Premalignant Lesions

  Exposure to cigarette smoke creates a field of injury throughout the entire respiratory tract inducing genomic alterations that lead to an "at-risk" airway where lung cancers develop. Lung squamous cell carcinoma (SCC) arises in the epithelial layer of the bronchial airways and is often preceded by the development of premalignant lesions (PMLs). Effective tools to identify and treat premalignant lesions at highest risk of progression to invasive carcinoma are not available. Endobronchial biopsies and brushings were obtained from high-risk subjects undergoing lung cancer screening at approximately 1-year intervals by white light and auto-fluorescence bronchoscopy and computed tomography at the Roswell Park Cancer Institute in Buffalo, NY. Subjects were selected that had biopsies collected in repeat locations via serial bronchoscopies. mRNA sequencing was performed on a discovery cohort (DC) of samples comprising endobronchial biopsies and brushes collected between 2010 and 2012 (n=30 subjects, n=197 biopsies, and n=91 brushings). mRNA sequencing was subsequently performed on a validation cohort (VC) of samples comprising endobronchial biopsies and brushes collected between 2010 and 2015 (n=20 subjects, n=111 biopsies, and n=49 brushings). Data analysis identified four distinct molecular subtypes (Proliferative, Inflammatory, Secretory, and Normal) in the bronchial biopsies that correspond to a spectrum of biological and morphological alterations. The Proliferative subtype was enriched with dysplastic PMLs from current smokers that exhibit up-regulation of metabolic and cell cycle pathways and down-regulation of cilium-associated processes. Molecular subtype classification in the validation cohort biopsies replicated these significant clinical and biological associations. Airway brushes from normal fluorescing areas of the large airway classified as the Proliferative subtype specifically predict the presence of biopsies of this same subtype. Within the Proliferative subtype, genes associated with interferon signaling and antigen processing and presentation were observed to be down-regulated among dysplastic biopsies that persist or progress in the future. Innate and adaptive immune cells were computationally predicted to be depleted in these biopsies and this was confirmed via immunofluorescence staining of adjacent biopsies. These findings provide a proof of concept that molecular biomarkers of endobronchial biopsies can enhance histopathological grading and that immunoprevention strategies are an important future direction in intercepting the progression of PMLs to lung cancer.FASTQ files from the RNA sequencing of these biopsies and brushings will be available via dbGaP.

  Study phs003185

• Molecular Etiology of Early-Onset Dystonia

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

  Study phs001733

• Early on-treatment changes in circulating tumor DNA fraction and response to enzalutamide or abiraterone in metastatic castration-resistant prostate cancer

  On-treatment circulating tumor DNA (ctDNA) quantification is touted as a surrogate biomarker for understanding metastatic cancer response to systemic therapy, but there is relatively little supporting data from standardized patient cohorts. Here, in a prospective observational cohort, we demonstrate that 4-week on-treatment changes in plasma ctDNA levels can accurately identify metastatic castration-resistant prostate cancer that will progress within 6 months of initiating first-line abiraterone or enzalutamide treatment. On-treatment ctDNA measurements outperformed existing clinical variables for predicting disease response and were also closely associated with differential overall survival. Although optimal timing of blood collections and thresholds for ctDNA detection will require further testing, our data highlights the potential for sequential ctDNA measurements to provide an early and reliable read-out for therapy response. The high accuracy of this information suggests that ctDNA could be useful for guiding clinical trials of therapy changes in initially non-responsive metastatic cancers.

  Study EGAS00001006856

• NHLBI TOPMed: The Cleveland Family Study (CFS)

  The Cleveland Family Study (CFS) is one cohort involved in the WGS project. The CFS was designed to provide fundamental epidemiological data on genetic and non-genetic risk factors for sleep disordered breathing (SDB). In brief, the CFS is a family-based study that enrolled a total of 2284 individuals from 361 families between 1990 and 2006. The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first degree relatives, spouses and available second degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first degree relatives. Each exam, occurring at approximately 4 year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in the participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. The GCRC exam (n=735 selected individuals) included more comprehensive phenotype data on a focused subsample of the larger cohort, to permit linking SDB phenotypes with cardio-metabolic phenotypes, with an interest in identifying genetic loci that are associated with these related phenotypes. In this last round of data collection, a subset of 735 individuals was selected based on expected genetic informativity by choosing pedigrees where siblings had extremes of the apnea hypopnea index (AHI). Participants underwent detailed phenotyping including laboratory polysomnography (PSG), ECG, spirometry, nasal and oral acoustic reflectometry, vigilance testing, and blood and urine collection before and after sleep and after an oral glucose tolerance test. A wide range of biochemical measures of inflammation and metabolism were assayed by a Core Laboratory at the University of Vermont. 994 individuals were sequenced as part of TOPMed Phase 1, including 507 African-Americans and 487 European-Americans. Among the sequenced individuals, 156 were probands with diagnosed sleep apnea, an additional 706 were members of families with probands, and 132 were from neighborhood control families. 298 individuals were sequenced as part of TOPMed Phase 3.5, including 169 African-Americans and 129 European-Americans. Among the newly sequenced individuals, 33 were probands with diagnosed sleep apnea, an additional 214 were members of families with probands, and 51 were from neighborhood control families. Please note: Phenotype and pedigree data are available through "NHLBI Cleveland Family Study (CFS) Candidate Gene Association Resource (CARe)", phs000284.

  Study phs000954

• Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity

  We studied a patient with recurrent respiratory infections and hypogammaglobulinemia and identified a germline homozygous missense mutation in IKZF2 encoding Helios (p.Ile325Val). We show that HeliosI325V retains DNA-binding and dimerization properties, but loses interaction with several partners, including epigenetic remodelers HDAC1, HDAC3 and the ATAC complex. Single-cell RNA-sequencing of peripheral blood mononuclear cells revealed gene expression signatures indicative of a shift towards pro-inflammatory, effector-like status in the patient’s T cells. We observed an upregulation of the anti-inflammatory gene, TSC22D3, encoding the glucocorticoid-induced leucine zipper (GILZ), whose expression was reported to increase upon IL-2 deprivation. We validated this finding in primary T cells, where we observed a pronounced reduction in IL-2 production upon their stimulation, together with a defect in their ability to proliferate, rendering them more anergic. Collectively, we identify a novel germline-encoded inborn error of immunity and define a role for Helios in conventional T cells, whereby interactions with specific binding partners is necessary to mediate the transcriptional programs that enable T-cell homeostasis in health and disease.

  Study EGAS00001005675

• Genome-wide mutational consequences of nucleotide excision repair-deficiency through XPC deletion in a human adult stem cell culture

  Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Deficiency in this pathway can contribute to the development of cancer and accelerate aging. NER-deficiency is an important determinant for cancer treatment outcome, as NER-deficient tumors are selectively sensitive to cisplatin treatment. While NER-deficiency has been linked to mutational Signature 5, not all NER-deficient tumors are characterized by a high Signature 5 contribution, illustrating the importance to further characterize the mutational consequences of NER-deficiency. Here, we analyzed the mutational profile of a human adult stem cell (organoid) culture that is deficient in NER through XPC deletion by CRISPR-Cas9 gene-editing, and subsequent whole-genome sequencing analysis of a clonally derived organoid. We found that XPC deletion results in an increase in base substitution load and specifically induces Signature 8 mutations, a mutational signature with previously unknown etiology. Presence of Signature 8 may, therefore, serve as a novel biomarker for NER-deficient tumors and could improve personalized treatment strategies.

  Study EGAS00001002681

• Center for Common Disease Genomics (CCDG)-Neuropsychiatric: A Study of the Genetic Causes of Complex Pediatric Disorders (CAG)

  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 here 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 phs002004

• Center for Common Disease Genomics (CCDG) Neuropsychiatric: The Autism Simplex Collection (TASC)

  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 here 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 phs001741

• Honolulu Heart Program (HHP-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from HHP include DNA, plasma, serum, and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: The initial objectives of the Honolulu Heart Program were to: 1) estimate morbidity and mortality from coronary heart disease and stroke among Japanese men in Honolulu; 2) compare morbidity and mortality from coronary heart disease and stroke among Japanese men in Japan, Honolulu, and San Francisco; 3) investigate relationships among risk factors, coronary heart disease, and stroke in Japanese men in Honolulu; 4) compare distributions of risk factors among men in Japan, Honolulu, and San Francisco, and relate similarities and differences in risk factors to the occurrence of disease in these areas and in other populations, including Framingham and Puerto Rico; 5) conduct an autopsy study, and to relate pathological findings to morbidity and mortality data; and 6) investigate relationships between risk factors and pathological evidence of atherosclerosis and its complications.Background: The Honolulu Heart Program was initiated in 1965 by the NHLBI as a prospective study of environmental and biological causes of cardiovascular disease among Japanese Americans living in Hawaii. This population was known to have low incidence of coronary heart disease and higher incidence of stroke. The study provided opportunities to investigate relationships among disease frequencies, pathologic findings, and disease predictors in the cohort and to compare the findings in this population with those in other populations, especially cohorts of Japanese men resident in Japan or the U.S.Participants: There were 8006 participants.Design: The study began in 1965 with the first examination of a cohort of 8,006 Japanese-American men residing on the island of Oahu, Hawaii who were born during the period 1900-1919. The first examination was completed in 1968 and was followed by the initiation of a second examination that same year. Three subsequent sub-examinations (Lipoprotein Exams I, II and III) were conducted between 1970 and 1982 to collect lipid measurements on a subset of those who participated in Exam II. The fourth examination of surviving members of the original cohort was conducted during 1991-93 and collected data on 3,741 men. Morbidity and mortality follow-up continues through grant and contract-supported efforts, and the current HHP dataset includes events through 1998.

  Study phs003907

• A targeted gene panel that covers coding, noncoding, and short tandem repeat regions improves the diagnosis of patients with neurodegenerative diseases

  Genetic testing for diagnosis of neurodegenerative diseases (NDs) is highly challenging because of genotype heterogeneity and overlapping clinical manifestations. Targeted-gene panels (TGPs), coupled with next-generation sequencing (NGS), can facilitate the profiling of a large repertoire of ND-related genes and help with differential diagnosis. Due to the technical limitations inherent in NGS and TGPs, short tandem repeat (STR) variations are often ignored. However, STR expansions are known to cause such NDs as Huntington’s disease and several types of spinocerebellar ataxias, such as SCA type 3 (SCA3).Here, we studied the clinical utility of a custom-made TGP that targets 199 NDs and 311 ND-associated genes on 118 undiagnosed patients. At least one known pathogenic or likely pathogenic variation was found in 54 (45.8%) patients; 27 (22.9%) of the 118 patients demonstrated clinical profiles that matched the variants. Based on the findings from the TGP, we refined the original diagnosis of 16 patients. A high concordance of single-nucleotide polymorphisms (99.9%) and small insertions and deletions (93.2%) were observed when comparing the results from TGP and whole-exome sequencing of four patients. We tested an in-house STR detection algorithm, and it reached a specificity of 0.88 and a sensitivity of 0.82 in our SCA3 cohort. This study also uncovered a trove of novel and recurrent variants that may enrich the repertoire of ND-related genetic markers. We propose that a combination of comprehensive TGPs and the bioinformatics analysis pipeline can improve the clinical diagnosis and accelerate the diagnosis of NDs.

  Study EGAS00001003737

• Cell-Free, Methylated DNA in Blood Samples Reveals Tissue-Specific, Cellular Damage from Radiation Treatment

  Radiation therapy is an effective cancer treatment, although damage to surrounding healthy tissues can also occur. Cell-type specific DNA methylation patterns can be used to decode the cellular origins of cell-free DNA fragments, allowing for minimally-invasive monitoring of tissue damage. To evaluate whether changes in cell-free DNA methylation can indicate damages to tissues in patients treated with radiation, we collected serum samples from 15 breast cancer patients at three timepoints during their standard-of-care radiation therapy after surgery. A baseline sample was taken for each patient before onset of radiation therapy and a second End-Of-Treatment (EOT) sample was taken 30 minutes after the last treatment fraction. Finally, a recovery sample was taken one month after completion of radiation therapy. From serum samples, cell-free DNA was isolated and bisulfite capture-sequencing DNA methylation data were generated. Bisulfite capture-sequencing DNA methylation data were also generated from buffy coat and tissue-specific endothelial gDNA samples as well as from serum/plasma samples of healthy controls. The analysis of serum samples from breast cancer patients undergoing radiation treatment revealed distinct tissue-specific epithelial and endothelial responses to radiation across multiple organs. In conclusion, as a proof of concept we show that cell-type specific methylation signatures can be applied to detect cellular injury from radiation treatment using minimally invasive cell-free DNA in blood samples.

  Study phs003290

• Natural Killer Cell Therapies for Hematologic Malignancies

  The "Natural Killer Cell Therapies for Hematologic Malignancies" study is an umbrella repository for data pertaining to multiple related clinical trials that aim to assess NK cell therapies as part of treatment strategies for a range of hematologic malignancies. Here, data from two trials, NCT03068819 and NCT02782546, are presented.Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML after Allogeneic Hematopoietic Cell Transplant in Children and Adults (NCT03068819)Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLI) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), IL-15, and IL-18 to generate memory-like (ML) NK cells with enhanced anti-leukemia responses. We treated nine pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells on a phase I trial. Patients received fludarabine, cytarabine, and filgrastim followed two weeks later by infusion of DLI and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical, matched-related and matched-unrelated donors. Following infusion, donor-derived ML NK cells expanded and maintained ML multidimensional mass cytometry phenotype for over 3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered IFN-gamma production. Following DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for over 3 months with one patient in remission for greater than two years. No significant toxicity was experienced. This study demonstrates that in a compatible immune environment post-HCT, donor ML NK cells robustly expand and persist with potent anti-leukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://www.clinicaltrials.gov/study/NCT03068819.A Phase II Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy after Haploidentical Donor Hematopoietic Cell Transplantation (NCT02782546)Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced anti-tumor function following stimulation with IL-12, IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on Day 7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in the clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well-tolerated and 87% of patients achieved a composite complete response at Day 28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for two months post-HCT with prolific expansion (1104-fold) over 1-2 weeks. Multidimensional mass cytometry and CITE-seq identified donor ML NK cells as distinct from conventional NK cells and persisting for over two months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patient and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML, with ML NK cells demonstrating enhanced in vivo persistence and functionality, overcoming barriers in the field.

  Study phs002681

• Joint Addiction, Aging, and Mental Health (JAAMH) Data Access Committee General Research Use Datasets

  This collection contains all the Joint Addiction, Aging, and Mental Health (JAAMH) Data Access Committee General Research Use Datasets authorized individual-level genomic datasets currently in dbGaP that are approved for General Research Use (GRU) and have no further limitations beyond those outlined in the model Data Use Certification Agreement. The public posting of Genomic Summary Results is allowed. Access to this study collection will include additional authorized individual-level GRU datasets that become available. Renewal of this study collection is required annually. To request access to this study collection, select phs003202 in the dbGaP Authorized Access System.

  Study phs003202

• An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors

  We undertook an empirical approach to dissect the tumor microenvironment by developing a bulk tumor dissection algorithm, DisHet, and leveraging RNA-Seq data of tumorgrafts (patient-derived tumors implanted in mice), in which only the tumor cell component expands. We found that approximately 65% of previously defined immune signature genes are not abundantly expressed in the Renal Cell Carcinoma (RCC) microenvironment, and we identified more than two times as many novel immune/stromal transcripts. By using refined immune/stroma-specific genes and genomics, electronic medical record data and imaging data of 1084 RCC patients, we discovered a highly-inflamed pan-RCC subtype enriched for Treg cells, NK cells, Th1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. This inflamed subtype (IS) is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. Interestingly, IS is correlated with systemic manifestations of inflammation in patients such as thrombocytosis and anemia, whose pathogenesis were poorly defined and have been predictors of poor prognosis in RCC. Indeed, we discovered that IS is a strong predictor of poor survival. Lastly, our analyses show that tumor cells may drive stromal immune response. Overall, these data provide a missing link between the tumor cells, the tumor microenvironment, and systemic factors.

  Study EGAS00001002786

• Center for Common Disease Genomics (CCDG) Neuropsychiatric: Multimodal Developmental Neurogenetics of Females

  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 here 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 phs002043

• Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Genomics of Autism Spectrum Disorder (GASD)

  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 here 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 New York Genome Center (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 phs002509

• Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Simons Searchlight

  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 here 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 New York Genome Center (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 phs002512

• Center for Common Disease Genomics (CCDG) Neuropsychiatric: Autism Center of Excellence (ACE II)

  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 here 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 phs002042

• Center for Common Disease Genomics (CCDG) Neuropsychiatric: Study of Autism Genetics Exploration (SAGE)

  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 here 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 phs001740

• Center for Common Disease Genomics (CCDG) Neuropsychiatric: Autism Genetic Resource Exchange

  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 here 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 phs001766