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• KRT17High/CXCL8+ Tumor Cells Display Both Classical and Basal Features and Regulate Myeloid Infiltration in the Pancreatic Cancer Microenvironment

  Recent studies have uncovered the co-existence of basal and classical subtypes within pancreatic ductal adenocarcinoma (PDAC). We sought to characterize these intermediary cells using single-cell RNA sequencing of PDAC. We performed subtyping on 18 single-cell RNA sequencing human PDAC samples to identify multiple intermediary subtypes. We compared single-cell profiling of patient-matched blood and tumor samples to measure changes in the local and systemic immune microenvironments in CXCL8-high tumors vs. CXCL8-low tumors. Finally, we leveraged longitudinally patient-matched blood over the course of chemotherapy. In our studies we identified a cluster of KRT17high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines which in turn influence the myeloid compartment both locally and systemically. We utilized sequencing data from dbGaP study accession phs002070. In addition to that, we included sequencing from new specimens which are deposited to this submission, consisting of one additional tumor specimen and 5 PBMC samples, sequenced after chemotherapy (longitudinally matched to PBMC samples in phs002071.v1.p1). FASTQ files of these sequencing runs are available through this dbGaP submission.

  Study phs003436

• Single Duplex DNA Sequencing with CODEC Detects Mutations with High Sensitivity

  Detecting mutations from single DNA molecules is crucial in many fields but challenging. Next generation sequencing (NGS) affords tremendous throughput but cannot directly sequence double-stranded DNA molecules (single duplexes) to discern the true mutations on both strands. Here, we present Concatenating Original Duplex for Error Correction (CODEC) which confers single duplex resolution to NGS. CODEC affords 1,000-fold higher accuracy than NGS, using up to 100-fold fewer reads than Duplex Sequencing. CODEC revealed mutation frequencies of 2.72 x 10-8 in sperm of a 39-year-old individual, and somatic mutations acquired with age in blood cells. CODEC detected genome-wide clonal hematopoiesis mutations from single DNA molecules, single mutated duplexes from tumor genomes and liquid biopsies, microsatellite instability (MSI) with 10-fold greater sensitivity, and mutational signatures and specific tumor mutations with up to 100-fold fewer reads. CODEC enables more precise genetic testing and reveals biologically significant mutations which are commonly obscured by NGS errors. We applied CODEC to clinical colon and breast neoplasm samples and uncovered expected mutational signatures including homologous recombination deficiency (HRD) and MSI.

  Study phs003255

• Genomic Analysis of Prostate Tumor Heterogeneity in Metastasis

  To investigate the molecular changes, mutations, and signaling pathways that characterize the initial steps of prostate cancer metastasis to the lymph nodes, we analyzed 19 discrete lymph node (LN) metastases, 97 primary tumor foci, 39 benign lymph nodes, and 10 normal adjacent prostate tissue samples from 43 patients enrolled in a clinical trial (NCT01808222) of extended lymphadenectomy and metastasis excision guided by [18F]-fluciclovine PET imaging for high risk, newly diagnosed prostate cancer conducted at Emory University. These patients fell within high or very high-risk groups (T3a, Gleason score 8-10, or PSA greater than 20 ng/ml). Of these patients, 16 had LN metastases at least 4 mm in diameter, and 20 patients had no metastases. For metastatic patients, we performed RNA and Whole Exome Sequencing (WES) on three primary tumor foci, one benign LN, and all LN metastases greater than 4mm in diameter. For non-metastatic patients, we sequenced two primary tumor foci and one benign LN. In total, RNAseq was performed on 165 tissue samples from 43 patients, and WES was performed on 137 samples from 35 patients.

  Study phs003404

• Transcription Factor Analysis of SLE

  Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with protean manifestations. This study identifies two histone marks of activation and the binding of p300 genome-wide in three cell types and three clinical subsets to better understand cell-specific effects and differences across clinical subsets. Results: We examined 20 patients with SLE and 8 controls and found the TNF, IL-2/STAT5, and KRAS pathways were identified across multiple cell types and ChIP data sets. Patients with cutaneous lupus and lupus nephritis generally had less dramatically altered chromatin than the general SLE group. Conclusions: NFkB and classical inflammatory pathways were strongly associated with increased peak heights across all cell types but were the highest-ranking pathway for all three antibodies in monocytes according to fgsea analysis. IL-6 Jak/STAT3 signaling was the most significant pathway association in T cells marked by H3K27ac change. Therefore, each cell type experiences the disease process distinctly although in all cases there was a strong theme of classical inflammatory pathways. These studies define important cell type differences and emphasize the breadth of the inflammatory effects in SLE.

  Study phs003713

• Transcriptomic hallmarks and RNA isoform diversity in human neurodegenerative disease

  Single-cell RNA-sequencing (scRNA-seq) has enabled high-throughput RNA analysis at an unprecedented resolution. One staple analysis in scRNA-seq is identifying differentially expressed genes (DEGs) between two populations. However, the mRNA isoforms have often been overlooked in these transcriptomic analyses due to technical limitations. In order to investigate the mRNA isoforms at the single-cell level, we used a targeted single-nucleus long-read RNA-sequencing method combining single-nucleus short-read RNA-seq (snRNA-seq), target gene enrichment, and Iso-Seq. We performed snRNA-seq and targeted single-nucleus Iso-Seq (snIso-Seq) on 25 human frontal cortices from individuals with AD, DLB, or PD, and age-matched controls. Our short-read transcriptome analysis revealed that DLB samples had more overlapping DEGs with AD than PD despite sharing pathological hallmarks with PD. We observed vast RNA isoform diversity in the 50 genes targeted, including genes that were not differentially expressed in our short-read data. We also identified several novel isoforms that are not included in the reference annotation. Our data collectively characterize the transcriptome of various neurodegenerative diseases and illuminate the mRNA isoform diversity.

  Study EGAS50000000132

• Chronic Renal Insufficiency Cohort (CRIC) Study Metabolomics and Proteomics

  The Chronic Renal Insufficiency Cohort (CRIC study) was established in 2001 by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) to improve the understanding of the relationship between chronic kidney disease and cardiovascular disease. The goals of the CRIC Study are to examine risk factors for progression of chronic kidney disease and cardiovascular disease among patients with chronic kidney disease and to develop predictive models to identify high-risk subgroups, informing future treatment trials and increasing application of available preventive therapies. This record includes plasma metabolomics and plasma proteomics data. Genotype data for 3527 CRIC Study partcipants is available at dbGaP in phs000524, "Chronic Renal Insufficiency Cohort (CRIC)-GWAS". Additional phenotypic, clinical, and outcomes data are available at the NIDDK Central Repository and can be linked to data available at dbGaP.More than 330 manuscripts have been published, reporting on the effects of a broad range of risk factors (from molecular biomarkers of disease pathways to clinical, demographic, and behavioral characteristics) on the progression of CKD and other health consequences. The full CRIC bibliography can be found at the BIBLIOGRAPHY for the Chronic Renal Insufficiency Cohort (CRIC) Study.

  Study phs003709

• Blood Group Genotypes and Phenotypes in Omani Blood Donors and Its Links With Susceptibility to Malaria

  The Omani population experienced endemic malaria prior to eradication in the late 1990's. Since malaria is known to be a strong selective pressure on the human genome, particularly at blood group associated loci, we aimed to understand how selective pressures from malaria may be affecting genetic variation at blood group loci. Blood samples were collected from 100 healthy, Omani blood donors. Serology testing for 10 clinically relevant blood groups and whole genome sequencing (WGS) to an average coverage of 16X were performed on all samples. Additionally, using the WGS data, genetic variants (SNPs and INDELs) were called for chromosomes 1 - 22 using GRCh38. We find signals of selection at the Plasmodium vivax associated locus, ACKR1 (the Duffy blood group), but not at any Plasmodium falciparum associated loci. We also characterized several previously undescribed blood group alleles in the Omani population affecting antigenic expression, mostly at the RHD, RHCE, and GYPB loci. The data available from this project include BAM files from 100 Omani samples aligned to GRCh38, per chromosome VCF files, and results from the serology tests for all 10 blood groups.

  Study phs003694

• Genetic Studies of Homologous Recombination Deficiency in Hispanic Gastric Cancer

  Approximately 10% of gastric cancer cases show familial clustering and a hereditary cause is likely, however, only 1-3% cases result from known hereditary syndromes – which are predominantly associated with CDH1 and CTNNA1 genes. Hispanics are > 2 times more likely to be diagnosed and to die from gastric cancer compared to non-Hispanic whites. Not only does gastric cancer precision medicine lag behind other cancers – there is an urgent need to understand its etiology. Germline mutations in homologous recombination genes have been implicated as important risk factors for gastric cancer. The purpose of this study is to continue to generate knowledge to improve gastric cancer outcomes and disparities by 1) characterizing prevalence of germline mutations in homologous recombination genes and identify new genes associated with gastric cancer 2) perform molecular characterization of gastric tumors in Hispanic patients. Participants for germline analysis were enrolled from Chile, Colombia, Mexico, Portugal, Spain, Uruguay.Whole exome sequence capture was performed for all germline and somatic samples using Agilent SureSelect Human All Exon v7 Kit. All sequencing was performed on an Illumina NovaSeq 6000. Germline Analysis: Whole exome sequencing was performed on 536 Hispanic patients (290 males, 246 female)

  Study phs003251

• Jackson Heart Study - Images

  The Jackson Heart Study (JHS) is a large, community-based, observational study that recruited 5,306 African American adults from three counties (Hinds, Madison and Rankin) in the Jackson, MS area. Participants age 35-84 years at baseline were enrolled from each of 4 recruitment pools: (1) random, 17%, (2) volunteer, 30%, (3) currently enrolled in the Atherosclerosis Risk in Communities (ARIC) Study, 31%, and (4) secondary family members, 22% (family study participants were age≥21 years). Data available include medical history, physical examination, blood/urine analytes, and interview questions on areas such as physical activity, stress, coping and spirituality, racism and discrimination, socioeconomic position, and access to health care. Extensive clinical phenotyping includes anthropometrics, electrocardiography, carotid ultrasound, ankle-brachial blood pressure index, echocardiography, CT chest and abdomen for coronary and aortic calcification, liver fat, subcutaneous and visceral fat measurements, and cardiac MRI. Participants have been contacted annually by telephone to update information, confirm vital status, document interim medical events, hospitalizations and functional status, and obtain sociocultural information. Ongoing cohort surveillance includes abstraction of medical records and death certificates for relevant International Classification of Diseases (ICD) codes and adjudication of nonfatal events and deaths.

  Study phs003747

• Synovial Fibroblast Gene Expression in Response to Fibronectin Fragment

  Osteoarthritis (OA) is a prevalent joint disease characterized by the progressive degradation of articular cartilage, hypertrophy of neighboring bone, and varying degrees of synovial inflammation. Recent research has highlighted the potential role of synovial fibroblasts in the pathogenesis of OA, particularly their inflammatory properties that disrupt cartilage homeostasis. Notably, degraded cartilage matrix components, such as fibronectin fragments (FN-f), have been identified in the synovial fluid of OA patients, suggesting that FN-f signaling influences the synovium where synovial fibroblasts reside. Despite affecting over 500 million individuals globally, our limited understanding of the underlying mechanisms of OA has significantly impeded the development of effective treatment strategies. To investigate this, we obtained deidentified surgical waste material from individuals undergoing knee replacement for OA. Synovial tissue was used to isolate synovial fibroblasts for cell culture studies. We generated bulk RNA-seq data from primary synovial fibroblasts (N=5 individuals) treated at passage 3 with either Phosphate-Buffered Saline (PBS) as control or FN-f for 18h to model the OA synovial fibroblast phenotype. We identified differentially expressed genes at an adjusted p-value of

  Study phs003999