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• A Case-Controlled Study for Genotype-Phenotype Associations in Multiple Sclerosis (MS)

  This is a multi-centre, case-controlled study to develop a dataset containing 1000 MS cases and 1000 matched controls and to associate DNA sequence (allelic) variations with MS phenotypes. Study subjects were enrolled through a prospective effort initiated in 2003. Three MS clinical centres were involved in subject recruitment and biological specimen collection using identical inclusion/exclusion criteria, two in Europe (Vrije Universiteit Medical Center, Amsterdam; and University Hospital Basel) and one in the US (University of California San Francisco). This study recruited subjects of northern-European ancestry with a diagnosis of MS (McDonald et al., 2001), with dissemination in time and space. Patients with Clinically Isolated Syndromes (CIS) were also included if they fulfilled 3 of the 4 Barkhof criteria for dissemination in space as per application of the McDonald criteria (McDonald et al., 2001). While recruitment predominantly included subjects with a relapsing onset of MS, individuals with all clinical subtypes of the disease participated, including clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS). The control group consisted of unrelated individuals, primarily spouses/partners, friends, and other volunteers. Control subjects were of northern-European ancestry and matched as a group, proportionally with cases according to age (±5 years) and gender. A familial history or current diagnosis of MS as well as a relation to another case or control subject were considered exclusionary for this group. Protocols were approved by the Committees on Human Research at all Institutions and informed consent was obtained from all participants prior to participation in the study. Primary Study Objective:To identify DNA sequence variations (genotype) and flanking sequences that are associated with clinical factors (phenotype) which differ between study subjects with and without MS. Secondary Study Objectives: To develop a clinical dataset including quantitative measures of 1000 well-characterized cases with MS, and 1000 ethnically matched controls. To identify other genotype-phenotype associations in MS study subjects such as magnetic resonance imaging (MRI) measures of disease burden and/or severity. To identify or confirm candidate surrogate markers of neurodegeneration using a variety of techniques including biochemical assays, blood transcriptome analysis, plasma proteomics and MRI*. GenotypingGenotyping of the complete dataset was performed at the Illumina facilities using the Sentrix® HumanHap550 BeadChip. *MRI results are not available on dbGaP.

  Study phs000171

• University of Utah Pelvic Organ Prolapse Disorder Study

  The overall purpose of this University of Utah Pelvic Organ Prolapse Disorder Study was to identify and localize predisposition genes contributing to pelvic organ prolapse (POP). POP cases recruited for this study were identified by one of three methods: high-risk POP pedigree cases, POP sister pairs, and surgically-treated POP cases reporting a family history of POP. High-risk POP pedigree cases were identified using the Utah Population Database (UPDB), a genealogy database of residents in Utah that has been linked to diagnostic ICD9 and CPT codes in medical records at the University of Utah and Intermountain Healthcare. We identified families with a significant excess number of POP cases compared to matched population rates and targeted these individuals for recruitment as well as any other POP cases in the family. POP sister pair cases were identified at the University of Utah Urogyncology clinic for women who had undergone POP surgery and also self-reported one or more sisters who were also surgically treated for POP. POP affection status of all sisters was confirmed either by physical examination or by chart review. Surgically treated-POP cases reporting a family history of POP were identified at the University of Utah Urogyncology clinic by self-report of a family history of POP. Efforts were made to recruit other affected family members and confirm affection status. To obtain DNA, subjects provided either a blood specimen or saliva. Medical records were reviewed by a urogynecologist and diagnostic information for pelvic organ prolapse and stress and overactive bladder were obtained. Collected DNA was genotyped and analyzed. To maintain confidentiality of the familial data, genetic data from only one subject per family has been submitted to dbGaP. Use of the University of Utah Pelvic Organ Prolapse Disorder Study data is limited to investigators studying pelvic floor disorders. These pelvic floor disorders include pelvic organ prolapse, urinary and anal incontinence, and other conditions related to weakening or injury to the muscles and connective tissue in the pelvis as a result of pelvic surgery, pregnancy, or vaginal delivery of a child. These data will be used only for research purposes related to pelvic floor disorders. They will not be used to determine the individual identity of any person or their relationship to another person or for research on non-disease traits.

  Study phs001439

• Gabriella Miller Kids First Pediatric Research Program in Germline and Somatic Variants in Myeloid Malignancies in Children

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource).All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed.This project aims to sequence an unparalleled number of cases of de novo Acute Myeloid Leukemia (AML) and Down Syndrome AML (DS-AML), to establish a database comprised of genomic and transcriptome information which can be interrogated for both somatic and germline variants. Identification of the somatic variants will provide valuable data on the potential genes and pathways that can be targeted for therapeutic purposes. In addition, interrogation of the host’s constitutional genome may yield valuable information about potential germline variants that, in combination with the somatic data, might provide a more informed approach to patient care. For those patients with predisposition mutations, chemotherapy alone might not be adequate for cure, and stem cell transplantation might be required. Also, those who might be at high risk of adverse secondary events (cardiac complications, secondary malignancies, etc.) can be identified early and their therapy can be tailored to minimize anticipated complications. Thus, we propose that the optimum outcome can only be obtained through comprehensive interrogation of the somatic and germline genomes to fully annotate the genomic makeup of the leukemia and its host. Knowing the genomic and transcriptomic makeup of these patients, along with a full complement of clinical characteristics for this cohort, will be critical for making strong correlations which may aid in therapeutic development for future patients. The de novo AML, DS-AML, and Acute Promyelocytic Leukemia (APL) cases were all collected through clinical protocols conducted by the Children’s Oncology Group (COG). In addition to funding from the Gabriella Miller Kids First Pediatric Research Program, the DS-AML cohort was specifically funded by the Lifespan to Understand Down syndrome (INCLUDE) Project.

  Study phs002187

• National Institute of Arthritis and Musculoskeletal and Skin Diseases and Istanbul Faculty of Medicine Genome-wide Association Study of Behçet's Disease (Turkish)

  IntroductionBehçet's disease (BD) is a genetically complex multisystem disease of unknown etiology, characterized by recurrent inflammatory attacks affecting orogenital mucosa, eyes, skin, joints, blood vessels, and less frequently, the central nervous system and gastrointestinal tract. Family studies suggest a genetically complex contribution to BD. With the exception of HLA-B51, which explains less than 20% of the genetic risk, the identities of alleles that are responsible for the complex inheritance of this disease have remained unclear. AimTo identify genes that contribute to BD susceptibility. MethodsA genome-wide association study was undertaken with 311,459 informative and high quality SNPs in a collection of 1215 BD patients and 1278 healthy controls from Turkey using a beadchip microarray assay (Infinium SNP genotype assay, Illumina). HLA-B types were determined with a reverse sequence-specific oligonucleotide method (One Lambda). Regions with evidence for association were fine-mapped using Sequenom iPLEX gold assays. Disease-associated SNPs were genotyped in additional ethnically matched case/control collections from diverse genetic backgrounds, including a total of 2430 cases and 2660 controls, using TaqMan SNP genotype assays. Association data were combined in a meta-analysis of all the collections. ResultsWe confirmed the known association with HLA-B51 and found evidence for a second, independent susceptibility locus in the Class I region of the MHC. In addition, we identified one SNP with genome-wide evidence for disease association (P < 5.0 x 10-8) within the gene encoding the immunoregulatory cytokine, interleukin-10 (IL10). A meta-analysis of the data from all the collections established associations with the IL10 variant (rs1518111, P = 3.54 x 10-18, odds ratio 1.45 with 95% confidence interval 1.34 to 1.58) and with a variant located between the interleukin-23 receptor (IL23R) and interleukin 12 receptor β2 (IL12RB2) genes (rs924080, P = 6.69 x 10-9, odds ratio 1.28 with 95% confidence interval 1.18 to 1.39). The disease-associated IL10 variant was associated with diminished mRNA expression and low protein production by cells obtained from healthy blood donors. ConclusionsThese data suggest that genetically encoded low production of IL-10 increases risk of BD and suggest novel interventional targets in the IL-10 and IL-23 pathways. Note: The submitted data are the genotypes of the 311,459 SNPs in 1215 cases and 1278 controls.

  Study phs000272

• Phase II Study of Cryoablation and Post-Progression Immune Checkpoint Inhibition in Metastatic Melanoma

  Percutaneous cryoablation guided by imaging is a well-established, minimally invasive treatment for oncological conditions. We posited that cryoablation could alter the immune microenvironment by directly influencing the tumor, potentially eliciting an anti-tumor response in cases resistant to immune checkpoint inhibition (ICI). In this non-randomized phase II single-center study (NCT03290677), individuals with unresectable melanoma experiencing progression on ICI underwent cryoablation in a single progressing metastasis, while ICI was continued for at least two additional cycles. The main objectives were to assess safety and feasibility and to evaluate tumor response in non-ablated lesions. Between May 2018 and July 2020, 17 patients participated in the study. The treatment regimen proved safe, revealing an objective response rate of 23.5% and a disease control rate of 41% (comprising 4 partial responses and 3 stable diseases). In our investigation into the factors influencing response to cryoablation therapy in ICI-resistant melanoma, we conducted single-cell RNA sequencing (scRNA-seq) using both 10x Genomics and Smart-seq2 technologies on biopsies from metastatic sites of 15 patients. We collected pre-treatment samples from all patients and post-treatment samples from 5 patients, totaling 20 samples. After quality control, excluding cells specific to anatomical sites or rare cell types (e.g., alveolar type II, neurons), and batch correction, we analyzed 49,071 single cells spanning melanocyte, endothelial, stromal, T, myeloid, and B/plasma cell lineages. Differential gene expression (DGE) analysis between myeloid cells identified the genes MARCKS and IL10, two genes involved in anti-inflammatory responses that can inhibit macrophages activation to be associated with failed response. Moreover, DGE analysis of T cells identified the gene TXK, which acts as a Th1 transcription factor, and the gene CMKLR1 (chemerin-like-receptor-1), which triggers migration of CD8 T-cells to be upregulated in patients who benefited from cryoablation treatment. In contrast, MTHFD2 and GGH, two genes involved in one-carbon metabolism and the folate cycle, were upregulated in T cells from patients who did not respond to therapy. Our analysis revealed a significant increase in B/plasma cells in patients who responded positively to the therapy combination, along with an enrichment of oxidative phosphorylation in T cells among non-responsive patients with progressive disease. These findings advocate for further investigation into this innovative and synergistic therapeutic approach.

  Study phs003579

• Changes in Oral and Gut Microbiota and Incidence and Severity of Patient-Reported Symptoms in Pre- and Post-Kidney Transplant Patients

  This novel prospective cohort explores the relationships between oral and fecal microbiome features (alpha and beta diversity, differential relative abundances of bacterial taxa, and functional genes) and the incidence and severity of psychoneurological symptoms (e.g., pain, fatigue, depression, anxiety, and sleep disturbance) before and after patients receive a kidney transplant from a live donor. Thirty-five subjects provided fecal and saliva specimens for shotgun metagenomic sequencing of gut and oral microbiomes at 3 timepoints: 1) within 4 weeks prior to the transplant surgery (at end-stage kidney disease), 2) 1-3 weeks after the transplant surgery, and 3) at 3 months after the transplant (after restoration of kidney function). Subjects were enrolled between October, 2018, to November, 2021, and all study visits were completed by March, 2022. Data collected includes: Demographic (age, biological sex at birth, race/ethnicity, marital status); clinical data (body mass index, dialysis status, type of dialysis, high vs. low risk immune-suppression protocol, antibiotics during study period); laboratory data (serum creatinine; estimated glomerular filtration rate; serum blood urea nitrogen; immunosuppression trough levels), and outcome data (symptoms such as pain interference, pain intensity, fatigue, anxiety, depression, sleep disturbance, acute rejection, delayed graft failure, graft loss, post-transplant infections, and health-related quality of life). Incidence and severity of symptoms, including pain interference, pain intensity, fatigue, sleep dysfunction, and anxiety/depression-like symptoms, were measured using the Patient Reported Outcome Measurement Systems (PROMIS) 57 v2.1. Health related quality of life was assessed using the Kidney Disease Quality of Life Short Form (KDQOL-SF v1.3). The objective of this longitudinal study is to characterize changes in microbial features at baseline, before restoration of kidney function, and over time, after restoration of kidney function via kidney transplantation, and to identify relationships between microbiome features and transplant outcomes (rejection, infection, delayed graft function, graft failure), symptom burden, and health-related quality of life. Shotgun metagenomic sequencing of the oral and gut microbiomes will allow a higher-resolution examination of the gut microbiome compared to 16S rRNA gene amplicon sequencing, and will provide direct evidence of metabolic capabilities of the microbiota. This approach will allow us to explore the dynamic nature of symptom burden, and the effects of demographic and clinical variables on the oral and gut microbiomes before and after restoration of kidney function.

  Study phs002199

• Immune-Related Adverse Events after Immune Checkpoint Blockade-Based Therapy are Associated with Improved Survival in Advanced Sarcoma

  Immune activation after immune checkpoint blockade (ICB) can lead to a unique group of adverse events (AEs), which have been associated with improved outcome in many carcinomas. The association between immune-related AEs (irAEs) and outcome in patients with sarcoma is not well studied. This study has two components: (1) a retrospective clinical study of irAEs among 131 patients treated with ICB at Memorial Sloan Kettering Cancer Center and (2) an analysis of a subset of these patients who have whole transcriptome sequencing available for analysis. In the clinical study portion, we reviewed a cohort of patients with advanced sarcoma treated on prospective clinical trials utilizing ICB-based therapy between April 2017 and January 2020. The objectives were to pool the safety data from each trial, identify irAEs, and correlate them with best overall response by RECIST 1.1, progression-free survival (PFS) and overall survival (OS). Association of irAEs with response and survival was assessed using a Cox regression model. A total of 131 patients were included. Forty-two (32%) had at least one irAE of any grade and 16 (12%) had at least one Grade ≥ 3 irAE. On Cox analysis adjusting for clinical covariates that were significant in the univariate setting, the hazard ratio (HR) for an irAE (HR 0.662, 95% CI 0.421 - 1.041) approached, but did not reach statistical significance for PFS (P = 0.074), while patients had a significantly lower HR for OS (HR 0.443, 95% CI 0.246 – 0.798; P = 0.007) compared to those without or before an irAE. Tumor samples with available RNA sequencing data were stratified by presence of an irAE to identify patterns of differential gene expression. In total, 71 unique patients had RNA sequencing available for analysis. The transcriptomes of 31 of these patients have been previously uploaded to dbGaP (phs002852), leaving 36 unique transcriptomes that have not been previously publicly shared. Three patients did not agree for their sequencing to be publicly shared. Therefore, 33 unique patient samples will be uploaded to this dbGaP study. Overall, this study found that gene expression profiling on baseline tumor samples from patients who had an irAE had higher numbers of tumor-infiltrating dendritic cells, CD8+ T cells, and regulatory T cells as well as upregulation of immune and inflammatory pathways.

  Study phs003284

• Proteomic Biomarkers of Progressive Fibrosing Interstitial Lung Disease: a Multicentre Cohort Analysis (PF-ILD Proteomics-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: To identify novel plasma biomarkers of progressive fibrosing interstitial lung disease and develop a proteomic signature to predict this phenotype. Background: Progressive fibrosing interstitial lung disease (ILD) is a devastating condition characterized by parenchymal scar formation, leading to deteriorating lung function and early death. Whereas almost all patients with idiopathic pulmonary fibrosis (IPF) progress, a variable proportion of patients with other common ILDs, including connective tissue disease associated ILD, chronic hypersensitivity pneumonitis, and unclassifiable ILD, develop progressive fibrosing ILD. There are criteria that effectively identify those experiencing ILD progression. However, the criteria do not allow patients who are at risk to be identified before progression occurs. Several blood-based biomarkers have been linked to differential progression in patients with IPF and other fibrosing ILDs. Inflammatory signaling also appears to have a prominent role in fibrotic-predominant ILDs. As such, cytokines, interleukins, and other immune mediators might serve as useful biomarkers of progressive fibrosing ILD. The PF-ILD Proteomics study was a targeted investigation of inflammation-related proteins to identify and validate novel biomarkers of progressive fibrosing ILD in patients with fibrotic connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, and unclassifiable ILD. Participants: There were 589 participants. The discovery cohort comprised 385 participants and the validation cohort comprised 204 participants. Design: PF-ILD Proteomics was a multicenter cohort analysis study. Peripheral blood was collected from consenting patients and plasma was isolated according to center-specific protocols. Relative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative, targeted proteomic platform. Patients from UC Davis and UCSF comprised the discovery cohort and those from UTSW comprised the validation cohort. Participants who were alive with less than 10% relative decline in forced vital capacity (FVC) at 12 months-after blood draw were considered to have non-progressive ILD. Participants who died of any cause, underwent lung transplant, or experienced 10% or greater relative FVC decline within 12 months of blood draw were deemed to have progressive fibrosing ILD. Conclusions: 17 plasma biomarkers of progressive fibrosing interstitial lung disease were identified and showed consistent associations across ILD subtypes.

  Study phs003954

• CRCbiome: Gut metagenome of Norwegian screening participants using FIT sampling

  The study aims to characterize the gut metagenome of Norwegian screening participants and assess the ability of the gut metagenome to identify those at need for colonoscopy. Background: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions. Methods: The CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50–74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period. Discussion: The CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome-based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high.

  Study EGAS50000000170

• Comparison of the treated celiac disease microbiome to that of controls

  Coeliac disease (CeD) is an immune-mediated disorder primarily affecting the small intestine, characterised by an inflammatory immune reaction to dietary gluten. CeD onset results from a multifaceted interplay of genetic and environmental factors. While recent data show that alterations in gut microbiome composition could play an important role, many current studies are constrained by small sample sizes and limited resolution. To address these limitations, we analysed faecal gut microbiota from two Dutch cohorts, CeDNN (128 treated CeD patients (tCeD), 106 controls) and the Lifelines Dutch Microbiome Project (24 self-reported tCeD, 654 controls), using shotgun metagenomic sequencing. Self-reported IBS (570 cases, 1710 controls) and IBD (93 cases, 465 controls) were used as comparative conditions of the gastrointestinal tract. Interindividual variation within the case and control groups was calculated at whole microbiome and strain level. Finally, species-specific gene repertoires were analysed in tCeD patients and controls. Within-individual microbiome diversity was decreased in patients with self-reported IBS and IBD but not in tCeD patients. Each condition displayed a unique microbial pattern and, in addition to confirming previously reported microbiome associations, we identify an increase in the levels of Clostridium sp. CAG:253, Roseburia hominis, and Eggerthella lenta, amongst others. We further show that the observed changes can partially be explained by gluten-free diet adherence. We also observe increased interindividual variation of gut microbiome composition among tCeD patients and a higher bacterial mutation frequency in tCeD that contributes to higher interindividual variation at strain level. In addition, the immotile European subspecies of Eubacterium rectale, which has a distinct carbohydrate metabolism potential, was nearly absent in tCeD patients. Our study sheds light on the complex interplay between the gut microbiome and CeD, revealing increased interindividual variation and strain-level variation in tCeD patients. These findings expand our understanding of the microbiome’s role in intestinal health and disease. Note that some of the data in this study belong to the Lifelines cohort. Access to this dataset can be requested via the page of the EGA data access committee EGAC00001001996. The phenotype data can be requested, for a fee, by filling the application form at https://www.lifelines.nl/researcher/how-to-apply/apply-here.

  Study EGAS50000000959