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• eMERGE Network's Multi-Center Pilot of Pharmacogenetic Sequencing in Clinical Practice

  eMERGE-PGx is a multi-site test of the concept that sequence information can be coupled to electronic medical records (EMRs) for use in healthcare. The promise of personalized medicine - health care guided by each individual's biological characteristics - is being fostered by increasingly powerful and economical methods to acquire clinically relevant biomarkers from large numbers of people. One therapeutic area that seems especially ripe for an early test of the personalized medicine concept is pharmacogenomics (PGx) - the idea that individual variation in drug response includes a genomic component. Drug response variation is an accepted feature of virtually all drug treatments, and contemporary molecular biologic tools continue to identify key genes mediating drug metabolism, transport, and targets. Importantly, common variation in these genes is an increasingly well-recognized contributor, sometimes with large effects, to variation in drug responses. As a result, recommendations for genotype-guided therapy are increasing. These evidence-based recommendations, if implemented in health care practice, could reduce adverse drug events and improve time to therapeutic response. Through eMERGE-PGx, we are developing strategies for the optimal implementation of genetic sequence data into the clinical environment with the ultimate goal of improving patient care. Site and participants include: Children's Hospital of Pennsylvania (CHOP): The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. The PGx population selected for sequencing with the PGRNseq panel at CHOP is 1,650 children from CAG's biorepository with well-documented drug-related severe adverse events (SAEs) or EHR-based drug response profiles. SAEs were extracted from EPIC records and from CHOP's Adverse Event (AE) database, which documents every AE at CHOP. These AEs are classified by a medical review panel according to the causal relationship with the suspected drug into 'doubtful', 'possible', and 'probable'. Individuals with events classified as probable, severe and objective, were selected for sequencing. The drugs more frequently associated with adverse events are antibiotics, antineoplastics, immunosuppressants and psychotropic drugs. This cohort constitutes 50% of the target population. The remaining subjects were selected using EHR-based algorithms that we have developed and validated at CAG for identifying patients not responding to ADHD medication (primarily atomoxetine) and patients refractory to antiepileptic treatment from responders. Cincinnati Children's Hospital Medical Center/Boston's Children's Hospital (CCHMC/BCH): 811 CCHMC samples were obtained from children, adolescents or young adults exposed to medication or at risk for needing medication of study interest. 55% of participants were exposed to one or more opioids and their DNA source was a CCHMC study-specific biobank; while 27% of participants were at risk for needing an opioid for surgical pain management and were newly recruited. The remainder of the cohort was exposed to methylphenidate and their DNA samples were obtained from a CCHMC study-specific biobank. The focus of Boston Children's Hospital eMERGE PGx project is on individuals with epilepsy. Samples were taken from a current pharmacogenomics study already in place through which DMET analysis was run and used as confirmation for PGRN-Seq results. A total of 109 samples were sent for PGRN-Seq analysis at University of Washington. The remaining 141 epilepsy samples were from Children's Hospital of Philadelphia and underwent testing with PGRN-Seq at CHOP. Geisinger Health System: A research cohort of adult Geisinger Clinic patients was enrolled from community-based primary care clinics of the Geisinger Health System. Patients were eligible for enrollment if they were a primary care patient of a Geisinger Clinic physician and were scheduled for a non-emergent clinic visit. All data are from Geisinger patients who consent to participate in the MyCode project. MyCode participants agree to provide biological samples for broad research use, including genomic analysis, and for linking of sample data to information in the participant's Geisinger health record. The consent also permits sharing of de-identified data for research purposes. Group Health(GH)/University of Washington (UW): Potential GH participants for the PGx project were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N~6300). Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in GH's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at Group Health: 1. Demographics - participants with self-reported race as Asian or African ancestry were prioritized and selected to enrich for non-European ancestry; 2. Diagnosis and procedure codes - participants were selected if found to have a history of hypertension, atrial fibrillation (AF,) or congestive heart failure (CHF). Participants with a history of arrhythmia were added if the entire selection algorithm did not generate 900 individuals. We also enriched for participants with EHR evidence of actionable indications related to PGRNSeq genes. Participants were selected if found to have an ICD9 code for malignant hyperthermia, hypertension, atrial fibrillation, congestive heart failure or long QT syndrome (LQTS); 3. Laboratory values - if a participant had any laboratory event of creatine kinase (CK) > 1000, and were dispensed statins within 6 months of the event, then they were selected; and 4. Medications - participants were excluded if ever on carbamazepine or had a current regimen of warfarin. Essentia Institute of Rural Health, Marshfield Clinic, Pennsylvania State University (Marshfield): For this study, 750 subjects were selected and enrolled into PGx based on Vanderbilt's algorithm designed to enrich for patients who are most likely to receive one of three common drugs (Clopidogrel, Warfarin or Simvastatin) in the next 2-3 years. These patients were sent a letter of invitation and description of the PGx project. Follow-up phone calls were made, and interested subjects came in for a one time meeting to discuss the project and go through the informed consent with the research coordinator. If they were interested they signed the consent and HIPAA forms and gave blood. Subjects were chosen and enrolled into PGx independently of previous biobank participation. Mayo Clinic: The Right Drug, Right Dose, Right Time - Using Genomic Data to Individualize Treatment (The RIGHT Protocol) enrolled 1013 patients to test the hypothesis that prescribers could deliver genome-guided drug therapy at the point-of-care by using pharmacogenomic data preemptively integrated in the electronic medical record. Complete details regarding the study population have been previously described (Bielinski et al., 2014). Icahn School of Medicine at Mount Sinai School (Mt Sinai): Our study site is the Primary Care Associates (PCA) practice group of the Mount Sinai Faculty Practice Associates (FPA) of the Mount Sinai Medical Center in New York City. This practice has 12 physician providers. All patient encounters are documented and managed with EpicCare ambulatory electronic medical record. Active PCA Patients eligible for enrollment fulfilled the following criteria: a) age 50 or older receiving clinical care at Mount Sinai FPA PCA practice with at least one practice encounter within 18 months prior to commencement of enrollment; b) no history or current use of clopidogrel, warfarin, or simvastatin. Eligible patients were invited to participate through de novo recruitment by letter sent by their provider. Interested patients were screened for eligibility and enrolled to participate in the eMERGE PGX study on site by a dedicated research coordinator. In addition to de novo enrollment from clinical practice, patients of FPA PCA who had previously enrolled in Mount Sinai's BioMe Biobank program AND fulfilled eligibility criteria as stated under a) and b) were identified by chart review and samples sequenced at CIDR using PGRNseq platform (N=300). PGRNseq data from 291 samples passed stringent quality control and are included in the current data set. Furthermore, 56 of these patients carrying known and validated 'actionable' variants affecting prescribing of clopidogrel, warfarin, and/or simvastatin were enrolled in the eMERGE PGX study following invitation through recontacting by the Principal Investigator of the BioMe Program. Northwestern University: Participants for this study were recruited from the General Internal Medicine (GIM) clinic at Northwestern Medical Group (NMG). Patients were selected for invitation to participate if they had been seen a minimum of two times over the last four years, having a high likelihood to receive a prescription for warfarin, Plavix, or a statin, and are seeing a physician who has agreed to allow their patients to be contacted for the study. We utilized an algorithm developed at Vanderbilt and tailored to our population which uses our EHR to estimate the probability that individuals will receive a prescription for warfarin, Plavix, or a statin in the next three years. Participants were sent a letter explaining the study prior to their GIM appointment and offered participation at the time of their visit. Participants were consented on-site and blood drawn after consent was obtained. The GIM clinic consists of 39 primary care physicians who provide approximately 80,000 patient encounters per year. As with any large primary care clinic, a significant proportion of patients in GIM clinic suffer from a variety of chronic health conditions, such as diabetes, hypertension, and coronary artery disease. Over 50,000 individuals have been seen by GIM doctors in the past 5 years; 11,562 of these patients have evidence of a statin prescription in the EHR, 3,436 have evidence of a warfarin prescription, and 1,872 have evidence of a Plavix prescription. Vanderbilt University: The more than 1000 participants enrolled into Vanderbilt's eMERGE PGx study were newly recruited from the Cardiology and Internal Medicine Clinics and the Hillsboro Medical Group within Vanderbilt University Medical Center (VUMC). Patients were selected based on a predictive algorithm estimating the patient's likelihood of receiving Clopidogrel, Warfarin, and/or Simvastatin. The algorithm identifies primarily older middle-aged patients, and the mean age of the study group is 74. The cohort is approximately 45% female with 75% of subjects self-identified as EA and 24% as AA. Subjects were consented in person by study personnel following a routine clinic visit and an introduction to the study staff by their doctor. VUMC is a comprehensive health care facility dedicated to patient care, research, and the education of health care professionals. Translational research into the causes and treatment of disease as well as studying fundamental biological properties is the primary focus of discovery at Vanderbilt. Clinical research is conducted in Vanderbilt University Hospital, the Nashville Veterans Administration Hospital, Meharry General Hospital and in their associated outpatient clinics. These hospitals and clinics, all associated with the Vanderbilt system, each have full time Vanderbilt faculty and medical housestaff and provide clinical care and participate in research programs. The Vanderbilt Clinic is comprised of more than 95 adult outpatient specialty practices and received over 1.5 million ambulatory visits in 2012-13. The Vanderbilt Heart and Vascular Institute offers a comprehensive heart program offering diagnosis, medical treatment, minimally invasive therapies, surgical intervention and disease management, tailored to each individual's unique needs. All programs within the Vanderbilt Clinic have survival figures that surpass the national average.

  Study phs000906

• NHLBI Cleveland Family Study (CFS) Candidate Gene Association Resource (CARe)

  The Cleveland Family Study is the largest family-based study of sleep apnea world-wide, consisting of 2284 individuals (46% African American) from 361 families studied on up to 4 occasions over a period of 16 years. The study was begun in 1990 with the initial aims of quantifying the familial aggregation of sleep apnea. NIH renewals provided expansion of the original cohort (including increased minority recruitment) and longitudinal follow-up, with the last exam occurring in February 2006. Index probands (n=275) were recruited from 3 area hospital sleep labs if they had a confirmed diagnosis of sleep apnea and at least 2 first-degree relatives available to be studied. In the first 5 years of the study, neighborhood control probands (n=87) with at least 2 living relatives available for study were selected at random from a list provided by the index family and also studied. All available first degree relatives and spouses of the case and control probands also were recruited. Second-degree relatives, including half-sibs, aunts, uncles and grandparents, were also included if they lived near the first degree relatives (cases or controls), or if the family had been found to have two or more relatives with sleep apnea. Blood was sampled and DNA isolated for participants seen in the last two exam cycles (n=1447). The sample, which is enriched with individuals with sleep apnea, also contains a high prevalence of individuals with sleep apnea-related traits, including: obesity, impaired glucose tolerance, and HTN. Phenotyping data have been collected over 4 exam cycles, each occurring ~every 4 years. The last three exams targeted all subjects who had been studied at earlier exams, as well as new minority families and family members of previously studied probands who had been unavailable at prior exams. Data from one, two, three and four visits are available for 412, 630, 329 and 67, participants, respectively. In the first 3 exams, participants underwent overnight in-home sleep studies, allowing determination of the number and duration of hypopneas and apneas, sleep period, heart rate, and oxygen saturation levels; anthropometry (weight, height, and waist, hip, and neck circumferences); resting blood pressure; spirometry; standardized questionnaire evaluation of symptoms, medications, sleep patterns, quality of life, daytime sleepiness measures and health history; venipuncture and measurement of total and HDL cholesterol. The 4th exam (2001-2006) was designed to collect more detailed measurements of sleep, metabolic and CVD phenotypes and included measurement of state-of-the-art polysomnography, with both collection of blood and measurement of blood pressure before and after sleep, and anthropometry, upper airway assessments, spirometry, exhaled nitric oxide, and ECG performed the morning after the sleep study. Data have been collected by trained research assistants or GCRC nurses following written Manuals of Procedures who were certified following standard approaches for each study procedure. Ongoing data quality, with assessment of within or between individual drift, has been monitored on an ongoing basis, using statistical techniques as well as regular re-certification procedures. Between and within scorer reliabilities for key sleep apnea indices have been excellent, with intra-class correlation coefficients (ICCs) exceeding 0.92 for the apnea-hypopnea index (AHI). Sleep staging, assessed with epoch specific comparisons, also demonstrate excellent reliability for stage identification (kappas>0.82). There has been no evidence of significant time trends-between or within scorers- for the AHI variables. We also have evaluated the night-to-night variability of the AHI and other sleep variables in 91 subjects, with each measurement made 1-3 months apart. There is high night to night consistency for the AHI (ICC: 0.80), the arousal index (0.76), and the % sleep time in slow-wave sleep (0.73). We have demonstrated the comparability of the apnea estimates (AHI) determined from limited channel studies obtained at in-home settings with in full in-laboratory polysomnography. In addition to our published validation study, we more recently compared the AHI in 169 Cleveland Family Study participants undergoing both assessments (in-home and in-laboratory) within one week apart. These showed excellent levels of agreement (ICC=0.83), demonstrating the feasibility of examining data from either in-home or in-laboratory studies for apnea phenotyping. Data collected in the GCRC were obtained, when possible, with comparable, if not identical techniques, as were the same measures collected at prior exams performed in the participants' homes. To address the comparability of data collected over different exams, we calculated the crude age-adjusted correlations ~3 year within individual correlations between measures made in the most recent GCRC exam with measures made in a prior exam and demonstrated excellent levels of agreement for BMI (r=.91); waist circumference (0.91); FVC (0.88); and FEV1 (0.86). As expected due to higher biological and measurement variability, 149 somewhat lower 3-year correlations were demonstrated for SBP (0.56); Diastolic BP (0.48); AHI (0.62); and nocturnal oxygen desaturation (0.60). NHLBI Candidate-gene Association Resource. The NHLBI initiated the Candidate gene Association Resource (CARe) to create a shared genotype/phenotype resource for analyses of the association of genotypes with phenotypes relevant to the mission of the NHLBI. The resource comprises nine cohort studies funded by the NHLBI: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Cleveland Family Study (CFS), Coronary Artery Risk Development in Young Adults (CARDIA), Cooperative Study of Sickle Cell Disease (CSSCD), Framingham Heart Study (FHS), Jackson Heart Study (JHS), Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). A database of genotype and phenotype data will be created that includes records for approximately 50,000 study participants with approximately 50,000 SNPs from more than 1,200 selected candidate genes. In addition, a genome wide association study using a 1,000K SNP Chip will be conducted on approximately 9,500 African American participants drawn from the 50,000 participants in the nine cohorts. Some relevant CARe publications CARe Study: PMID 20400780 CVD Chip Design: PMID 18974833

  Study phs000284

• Whole Genome Sequencing of HCC

  The present series corresponds to 24 whole genome sequencing (12 Tumoral/Non-tumoral pairs). Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before.

  Dataset EGAD00001003994

• Single nucleus mRNA sequencing of immune cells from diverse CNS regions in human health and diseases

  CNS nuclei were isolated from frozen specimen, stained with anti-NeuN and anti-Olig2, FACS purified (DAPI+NeuN-Olig2-), and analyzed with single nucleus RNA-seq. One batch of samples was also labelled with CMO and allows distinguishing indivudal samples within the analysis. A combined seurat object was generated to include all the analyses and samples were integrated using Harmony integration.

  Dataset EGAD50000001835

• Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

  Critically ill infants and children with suspected monogenic conditions underwent ultra-rapid whole exome genetic testing. A molecular diagnosis was established in 51% of the patients. This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients.

  Study EGAS00001005430

• February 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  February 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001006220

• December 2016 data update (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  December 2016 data update (bam/fastq for WGBS on samples CEMT0062, CEMT0068, CEMT0072, CEMT0086, CEMT0087) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001003122

• June 2016 data update for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  June 2016 data update (bam/fastq for CEMT0062, CEMT0068, CEMT0072, CEMT0086, CEMT0087 ChIP-Seq and RNA-Seq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001002239

• March 2016 update of Whole genome bisulfite sequencing assay data (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  March 2016 update of Whole genome bisulfite sequencing assay data (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001001957

• March 2016 update of whole genome shotgun sequencing data (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  March 2016 update of whole genome shotgun sequencing data (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001001958

• March 2016 update of smRNA-Seq assays data (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  March 2016 update of smRNA-Seq assays data (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001001959

• The Longevity Genes Project

  Aging is a complex, universal condition leading to the functional decline of all cells and organisms, and to major national and global public health problems. Although aging is the major risk factor for developing most adult-onset diseases, systematic investigations into the fundamental physiology, biology and genetics of aging are only just beginning. In the Longevity Genes Project at Albert Einstein College of Medicine, Dr. Nir Barzilai and his team conducted genetic research on more than 500 healthy elderly people between the ages of 95 and 112, and on their children. The identification of longevity genes by Einstein researchers could lead to new drug therapies that might help people live longer, healthier lives and avoid or significantly delay age-related diseases such as Alzheimer's disease, type 2 diabetes and cardiovascular disease.

  Study phs000584

• NHLBI TOPMed - NHGRI CCDG: Intermountain INSPIRE Registry

  The INtermountain Healthcare Biological Samples Collection Project and Investigational REgistry for the On-going Study of Disease Origin, Progression and Treatment (Intermountain INSPIRE Registry) purpose is to collect biological samples, clinical information and laboratory data from Intermountain Healthcare patients. The registry originally collected samples in patients undergoing a coronary angiography as part of the Intermountain Heart Collaborative Study. It has been expanded to collect samples in patients diagnosed with all types of medical conditions, and patients from the general population including those who have not been diagnosed with health related issues. Just over 25,000 individuals have provided samples as part of this registry. The registry enables researchers to develop a comprehensive collection of information that may help in disease management, including determining best medical practices for predicting, preventing and treating medical conditions.

  Study phs001545

• National Institute of Mental Health (NIMH) Duke Cognition Cohort

  The overall goal is to identify genetic variants influencing normal variation between humans, with a focus on cognitive and neurosensory traits. Because of the focus of funding agencies on disease, very few studies of the genetics of non-disease traits have been performed. The genetic variation underlying the vast majority of differences between humans therefore remains not only undiscovered, but also unexplored. We have assessed >1,200 healthy volunteers for >70 diverse, non-disease phenotypes, with a focus on cognitive and neurosensory traits that are understudied and seem to have a strong biological basis. Our study includes measurements of face recognition, night vision, cognitive performance, auditory pitch discrimination, contagious yawn susceptibility, time perception, sense of direction, taste preferences, personality, sexual behaviors, sleep habits, acne, headache locations, synesthesia, and teeth sensitivity. This method is very different from the focus of most studies on collecting cohorts of patients with disease and controls with minimal phenotypic information. Because we phenotype the same healthy volunteers for multiple highly variable yet heritable traits, we can perform genetic analyses on a large number of phenotypes by just investing once in sequencing the DNA of these participants. An additional >2,000 participants in our cohort have been measured just for cognitive performance instead of for the more extensive phenotyping. Most of the genetic studies in this cohort have been about cognitive perfromance. The number of participants with genetic data generated who have undergone the more extensive phenotyping is limited. Our studies of the more novel traits like contagious yawning have therefore focused more on correlations between different phenotypes until we have a sufficient sample size to truly attempt to make genetic discoveries. . The dataset also includes two small challenge studies. In one study, the cognitive performance of 150 healthy volunteers was measured before and after an acute dose of the antiepileptic drug topiramate. In the other study, the cognitive performance of 13 healthy volunteers was measured before and after 24 hours of sleep deprivation.

  Study phs001406

• eMERGE Network Phase III Clinical Sequencing: eMERGEseq Panel

  The Electronic Medical Records and Genomics (eMERGE) Network is a National Institutes of Health (NIH)-organized and funded consortium of U.S. medical research institutions. The primary goal of the eMERGE Network is to develop, disseminate, and apply approaches to research that combine biorepositories with electronic medical record (EMR) systems for genomic discovery and genomic medicine implementation research. eMERGE was announced in September 2007 and began its third phase in September 2015. eMERGE III consists of nine study sites, two central sequencing and genotyping facilities, and a coordinating center. eMERGE Phase III aims to: 1) sequence and assess the phenotypic implication of rare variants in a custom designed eMERGEseq panel consisting of 109 genes (including 56 ACMG actionable finding list genes and the top 6 genes from each site relevant to their specific aims), as well as approximately 1400 SNPs; 2) assess the phenotypic implications of these variants by developing, validating and implementing new phenotype algorithms, 3) integrate genetic variants into EMRs to inform clinical care; and 4) create community resources. Included in this study are: ~24,000 eMERGE participants from 10 eMERGE III study sites. Corresponding demographics, body mass index measurements. Top PheWAS codes generated from a collated list of ICD codes from all study sites. Study sites and participants include: Cincinnati Children's Hospital Medical Center (CCHMC): Cincinnati Children's Hospital Medical Center (CCHMC) is a not-for-profit hospital and research center pioneering breakthrough treatments, providing outstanding family-centered patient care and training healthcare professionals for the future, and dedicated to improving health and welfare of children and to the shared purpose of discovery and practical application of new genomic information to the ordinary care of children. We bring a comprehensive electronic health record (EPIC), a deidentified i2b2 data warehouse of 680K patient records, a biobank with >261,000 consents that allow return of results to >84,000 patients and guardians who have provided DNA samples, and hundreds of faculty and senior staff who make genomics or informatics an active focus of their research. CCHMC will help the eMERGE III Steering Committee identify genes for the eMERGE III targeted sequencing panel, provide 3,000 DNA samples from CCHMC patients to be sequenced, review targeted gene panels from clinical care at CCHMC for somatic mosaicism and reinterpretation, and further develop and disseminate a software workflow suite for sequence analysis. We will also extend our work generating phenotype algorithms using heuristic and machine learning methods to many new childhood diseases. We will develop tools to evaluate adolescent return of results preferences, examine the ethical and legal obligations and potential to reanalyze results, and develop clinical decision support for phenotyping, test ordering, and returning sequencing results. Children's Hospital of Philadelphia (CHOP): The Center for Applied Genomics (CAG) is a specialized Center of Emphasis at the Children's Hospital of Philadelphia (CHOP), and one of the world's largest genetics research programs, with to state-of-the-art high-throughput sequencing and genotyping technology. Our primary goal is to translate basic research findings to medical innovations. We aim to develop new and better ways to diagnose and treat children affected by rare and complex medical disorders, including asthma, autism, epilepsy, pediatric cancer, learning disabilities, and a range of rare diseases. Ultimately, our objective is to generate new diagnostic tests and to guide physicians to the most appropriate therapies. Participants were recruited from the CAG biorepository (n>450,000), specifically from >100,000 CHOP pediatric patients and family members, which is enriched for rare-diseases (n>12,000). Center for Applied Genomics, The Children's Hospital of Philadelphia We gratefully thank all the children and their families who enrolled in this study, and all individuals who donated blood samples for research purposes. Genotyping for this project was performed at the Center for Applied Genomics and supported by an Institutional Development Award from The Children's Hospital of Philadelphia. Sequencing was supported by the National Institutes of Health through an award from the National Human Genome Research Institute's Electronic Medical Records and Genomics (eMERGE) program (U01HG008684). Columbia University: The goal of the Columbia eMERGE III project is to develop methods for integrating genomic data in EHRs and to study the impact of such genomic informatics interventions on the health of a diverse, underserved urban adult English- and Spanish-speaking patient population in Northern Manhattan served by Columbia University Medical Center/New York-Presbyterian Hospital system. The study group is 2500 patients recruited from diverse clinics and community outreach centers of self-reported White (~61%), Asian (~11%), African-American (~11%), American Indian/Alaska Native (<1%) racial and Hispanic (~33%) ethnic backgrounds. There are two subgroups in the study cohort - a retrospective group (N=1052) that includes patients from oncology and nephrology clinics, and a prospective one (N=1448) that includes healthy individuals as well as participants with diverse medical conditions. Confirmed pathogenic variants in 70 selected genes will be returned to participants and their healthcare providers through the EHR integration. Participants are able to choose the results they receive and will have the freedom to meet with a genetic counselor and a geneticist to review results. The impact of genetic testing on clinical care is determined by periodic monitoring of EHRs. Geisinger: Samples and phenotype data in this study were provided by the Geisinger MyCode® Community Health Initiative. Participants are recruited across the Geisinger System via online consents or in-person consents at a hospital or clinic visit. Enrollment is ongoing with over 100,000 individuals currently consented. Partners Healthcare (Harvard University): The Partners HealthCare Biobank is a large research program designed to help researchers understand how people's health is affected by their genes, lifestyle, and environment. This large research data and sample repository provides access to high-quality, consented blood samples to help foster research, advance our understanding of the causes of common diseases, and advance the practice of medicine. For the Partners research community (Massachusetts General Hospital and Brigham and Women's Hospital), the Biobank provides: Banked samples (plasma, serum, and DNA) collected from consented patients Blood samples that were discarded after clinical testing in the Crimson Cores maintained in the Brigham and Women's Hospital and Massachusetts General Hospital Pathology Departments Sample handling and preparation services Link to the biobank data to the Partners Research Patient Data Registry (RPDR) a research instance of our electronic clinical chart Data access through our research portal. To date, over 70,000 Partners patients have given their consent to enroll, give a blood sample, receive research results and agreed to be re-contacted for additional research studies. The Biobank has enabled Partners investigators to compete for nationally recognized grants in personalized medicine such as a clinical electronic Medical Records and Genomics network (eMERGE) site and the national All of US program. The Biobank currently supports over 120 Partners investigators and over 130 million dollars in NIH research. Kaiser Permanente Washington/ (KPWA) / University of Washington (UW): KPWA participants were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N=2,500.) NWIGM is based at the University of Washington and co-managed by the University of Washington and KPWA. The purpose of the NWIGM biorepository is to build infrastructure and resources to carry out a broad range of future genetic research. KPWA members enrolled in the biorepository are asked to provide informed consent to providing a DNA sample for storage in the NWIGM biorepository. The consent is purposefully broad to serve the dual purpose of reducing the burden on researchers who wish to use this biorepository and the IRB committees who will be responsible for reviewing these requests in the future. Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in KPWA's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at KPWA. 1) Demographics - participants with self-reported race as Asian ancestry were prioritized and selected to enrich for non-European ancestry. The KPWA eMERGE cohort includes N=1,245 members of Asian ancestry. 2) Participants were also selected for a history of colorectal cancer (N=1,255), in order to allow us to enrich germline pathogenic variants. Mayo Clinic: The Return of Actionable Variants Empirical (RAVE) Study was approved by the Mayo Clinic IRB. We recruited 2537 participants from Mayo Clinic biobanks in Rochester, MN, who had hypercholesterolemia or colon polyps, thereby enriching for Familial hypercholesterolemia (FH) and monogenic causes of colorectal cancer (CRC). Additional eligibility criteria were: 1) residents of Southeast MN who were alive and aged 18-70 years; 2) LDL-C level >155 or >120 mg/dl while on lipid-lowering therapy; 3) no known cause of secondary hyperlipidemia; and 4) no cognitive impairment or dementia that would compromise their ability to give written informed consent. Based on these criteria, we identified 5270 eligible patients and obtained informed consent from 3030 participants. Recruitment was conducted in waves and utilized mailed recruitment packets consisting of a study brochure, a written informed consent form, a baseline psychosocial questionnaire, and a return postage-paid envelope. DNA of 2537 participants was sent for CLIA-certified targeted sequencing of 109 genes including genes associated with FH and CRC. Targeted sequencing and genotyping was performed in a Central Laboratory Improvement Amendment (CLIA)-certified laboratory. Northwestern University: Samples and data used in this study were obtained from patients from Northwestern Medicine, an integrated healthcare system, formed through a partnership of Northwestern Memorial HealthCare and Northwestern University Feinberg School of Medicine. Participants include a retrospective cohort from the Northwestern Pharmacogenomics Study, funded through the eMERGE II project, NHGRI (3U01HG006388-02S1) and a prospective cohort from the Genetic Testing and Your Health Study, funded through the eMERGE III project, NHGRI (U01HG008673). Patients were eligible to participate if they were18 years or older and see a physician at Northwestern Medicine. Patients consented to genetic testing and to allow their results to be placed in their electronic medical record. Vanderbilt University Medical Center: Vanderbilt University Medical Center (VUMC) participants were enrolled in the eMERGE Network through the Vanderbilt Genome-Electronic Records (VGER) project. Patients were provided the appropriate consent to receive clinically relevant genetic results (N=2,700). Participants were eligible if aged 21 or over, had a healthcare provider at VUMC, and visited the provider at least 3 times in the past 3 years. Meharry Medical College: Inclusion of ethnic groups in genomic research is critical to identify possible reasons for health disparities. African-Americans are being enrolled in various outpatient clinics of Nashville General Hospital at Meharry, an inner city hospital primary serving a poorer patient group. A total of 500 African Americans with four cancer types demonstrating health disparities in this population - prostate, colon, breast, lung are identified and approached by clinical research coordinators. The purpose of the study is to determine if any genetic information can be identified from these patients who have or are at high risk of one of these disparate cancers. All participants provide written informed consent and HIPAA authorization to provide blood samples for broad research use and permission to access data in their hospital electronic medical record for research now and in the future. An extensive demographic profile is obtained and entered into a REDCap database. Blood samples are obtained for a panel of alleles from extracted DNA at Baylor. In addition, de-identified coded samples are processed and stored in a central biorepository for further DNA, RNA and proteomic analyses. The survey and phlebotomy are performed at the time of the initial contact and agreement to participate. Nearly all patients approached willingly agree to participate for potential benefit to themselves, family members, or humankind. Little concern is voiced of providing samples for genetic analysis. Study investigators will share results with the participants and providers if testing does not indicate high risk. Results indicating increased risk or actionable alleles for the patient and/or family will be returned by a genetic counselor. Monitoring of the patients' health in this cohort will continue to be followed in the EMR to identify any future associations that might explain health disparities in African Americans. Proposals will be reviewed from investigators to study the genetic or proteomic samples as well as the clinical and demographic information in the repository. Please note that this version of the dataset has a handful of mismatches between genotyped and provided sex. Data with the following IDs should be removed prior to analysis: 420252874213744142412243424569384245694642672223

  Study phs001616

• CIDR: NINDS High Throughput Genotyping Resource Access for Structural Hindbrain Disorders

  Recessive forms for many structural brain disorders (SBDs), including cerebellar hypoplasia (CBH), corpus callosum hypoplasia (CCH), cobblestone lissencephaly (COB), classical lissencephaly (LIS), microcephaly (MIC), and pontocerebellar hypoplasia (PCH), have been described. Patients usually present to the clinic with neurodevelopmental disorders (NDDs), including autism, epilepsy, intellectual disability, and cerebral palsy. Subsequent brain MRI usually leads to the diagnosis of an SBD. While a handful of genes that cause these diseases have been identified, most patients do not have mutations in these genes, suggesting that there is still much work to be done in identifying the genetic causes of these disorders. We have recruited a cohort of families with inherited SBDs, most from families with documented parental consanguinity with more than one affected member. Current approaches utilizing exome sequencing of SBD affected members still leave most cases unsolved, in part because there are too many possible variants to consider. Linkage analysis will allow us to extract all the useful genetic information from the family, taking advantage of each genetically informative meiosis in each family. We propose to analyze up to 100 SBD families for 500 samples per year for 4 years, through the CIDR SNP Genotyping Service, in parallel with already-funded exome sequencing of affects, leveraging off an already funded Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) effort to identify new causes of SBDs. Understanding the pathogenetic mechanisms underlying recessive pediatric SBDs will lead to better diagnostic and therapeutic opportunities for patients, and may shed light on complex NDDs. Ultimately, this work will identify new genetic disease loci to provide insight into pediatric SBD, with the hope to mitigate the impact of SBD worldwide.Public Health Significance: NDDs affect approximately 4-­6% of the general population, most notably children, and are evident in disorders, such as intellectual disability, epilepsy, and autism, with estimated yearly costs of $51.2B for intellectual disability, $11.5B for cerebral palsy, and $2.5B for visual impairment, making up >5% of total health care costs. Recessive NDDs impose enormous personal, social, and economic costs because of the early onset and the lifetime of medical dependence that often ensues. Genetic testing is critical to the diagnosis and treatment of these diseases. Many of the diseases under study have no treatment or cure. Structural brain diseases (SBDs) underlie a large percentage of these diseases, and are defined loosely as any condition in which defects in the structure or volume of a key brain component. SBDs are divided into major categories based upon the anatomical brain location. The major types involve the anatomical structures of the developing neural tube, forebrain, hindbrain, cerebral cortex, and those affecting overall brain size. For the purposes of this application, we have excluded SBDs resulting from environmental causes (i.e. prematurity-­induced), those below the brainstem, or those unlikely to be due to a germline or de novo mutation (i.e. focal SBDs or simplex disease).

  Study phs002621

• A New Reference Panel to Boost African American Genotype Imputation

  Modern genetic studies have been conducted predominantly in cohorts of individuals of European ancestry. By 2010, there were approximately ten times as many published genome wide association studies (GWAS) in people of European ancestry than studies in people of all other ancestries combined. This research disparity has led to an uneven understanding of the genetic basis underlying disease in Europeans and non-Europeans. 23andMe's web-based, large scale research model is ideal for scaling genetics research within non-European populations and thereby bringing more parity to genetics research. Our database is composed of genotypes and phenotypes of over 1,000,000 consenting customers, including over 200,000 individuals with non-European ancestry. The data derived from non-European individuals represent a particularly valuable resource for genetic discovery of novel variants that may not be found in the European population. However, research studies in non-European populations are weakened by the lack of availability of large-scale reference datasets and, in particular, genotype imputation panels. Genotype imputation is a statistical methodology that uses observations of genotypes in a large reference panel to infer unobserved genotypes in a target dataset. This methodology is widely used within GWAS, and allows novel genetic associations to be identified and refined. Due to this utility, very large reference panels have been constructed, containing thousands or tens of thousands of whole genome sequences. Unfortunately, the largest imputation panels are composed of predominantly European genomes, reflecting the modern bias towards European studies in GWAS. This proposal aims to address this imbalance by constructing an imputation panel specifically for the African American population. In doing so, we will expand 23andMe's ability to perform genetic discovery in non-European populations, and improve the understanding of global genetic variation underlying diseases and traits. Key commercial outcomes of the research include the identification of novel genetic targets for internal and external therapeutic development. The long-term aim is to improve understanding of disease in minority populations, which we hope may eventually lead to improved treatments of disease in these historically medically understudied groups.

  Study phs001798

• Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR and PEAR-2)

  The primary aim of the Pharmacogenomic Evaluation of Antihypertensive Responses grant (funded by NIH Pharmacogenomic Research Network grant U01 GM074492) was to identify genetic determinants of blood pressure response and adverse events after antihypertensive treatments. Two different clinical trials with genomic information available were included: PEAR-1 and PEAR-2 studies. The PEAR-1 study (clinicaltrials.gov identifier NCT00246519) was a randomized controlled clinical trial evaluating genetic determinants of BP responses and adverse metabolic responses to atenolol and hydrochlorothiazide (HCTZ) monotherapy and in combination (PMID: 19249413). Briefly, PEAR-1 recruited 768 hypertension individuals with uncomplicated hypertension who were randomized to either monotherapy of atenolol 50 mg daily or HCTZ 12.5 mg daily for 3 weeks, followed by dose titration to 100 mg and 25 mg daily, then the combination therapy. BP and metabolic responses to monotherapy and combination therapy were assessed after an average of 9 weeks of antihypertensive treatment. BP was measured using three different methods: home, office and ambulatory. For the BP analysis, a composite weighted average of the office, home, ambulatory daytime and nighttime BP responses was calculated based on the row sums of the inverse of the inter-method covariance matrices. Genomic DNA from PEAR-1 participants was genotyped using the Illumina Human Omni1MQuad BeadChip (Illumina, San Diego, CA, USA). The PEAR-2 study was a multicenter sequential monotherapy clinical trial (clinicaltrials.gov identifier NCT01203852) evaluating genetic determinants of BP response to metoprolol monotherapy and chlorthalidone monotherapy. After a washout period (if necessary), eligible hypertensive patients with uncomplicated hypertension received metoprolol tartrate 50 mg twice daily for 3 weeks and the dose was increased to 100 mg twice daily for an additional six weeks if an inadequate response was observed (>120/70 mm Hg and heart rate >55 beats/min). After second washout period, patients received chlorthalidone monotherapy. Home and office BP measurements were collected in PEAR-2 study. We have previously demonstrated that home BP is the more informative single BP measurement compared to the office BP measurement. Therefore, home BP is the phenotype used for the genome-wide association analysis for PEAR-2. PEAR-2 samples were genotyped using the Illumina Human Omni2.5S Beadchip (Illumina, San Diego, CA, USA).

  Study phs000649

• Global Microbiome Conservancy Sequence Data

  The human body is a complex ecosystem, hosting tens of billions of bacteria, primarily in the gut. This community, known as the 'gut microbiome', is vital to human health, affecting functions ranging from metabolism, immunity, and development, to behavior. Conversely, reduced microbiome diversity and other imbalances of the gut community (dysbiosis) are associated with many diseases of the industrialized world, such as metabolic syndrome, asthma, and inflammatory bowel diseases among others. Microbiome-based interventions thus hold the potential to revolutionize our understanding of, and therapeutic approaches to, many aspects of human health and disease. Despite many advances, current understanding of the human microbiome is largely limited to majority ethnic groups in industrialized nations, and does not reflect the full diversity of human commensal microbiota. In addition to the scientific ramifications of minority underrepresentation, there are significant translational and ethical implications as well: first, failing to capture the full diversity of healthy human microbiota may limit our ability to understand and generate effective therapeutics for many microbiome-associated diseases. Second, underrepresented groups are less likely to benefit from microbiome-based medical advances tailored to well-studied populations, propagating healthcare inequities.  Human gut microbial diversity is diminishing around the globe, due to the spread of industrialized diets and lifestyles, which are associated with reduced microbiome biodiversity. The Global Microbiome Conservancy (GMbC) is a non-profit collaboration between scientists and communities around the world that aims to 1) preserve the full biodiversity of the human gut microbiome, 2) characterize its evolution across populations and host lifestyles and 3) investigate its interactions with the human host. We are collecting gut microbiome and human DNA samples from diverse populations around the world, from isolated groups to urbanized populations, to culture and study this essential biodiversity and to preserve it in a living "seed bank" of bacterial isolates as a long-term safeguard against future extinctions. Human genetic data for the samples sequenced in this study can be found in phs002205.

  Study phs002235

• Shanghai Breast Cancer Genetics Study (SBCGS)

  The Shanghai Breast Cancer Genetics Study (SBCGS) includes data from four population-based studies conducted among Chinese women in urban Shanghai: the Shanghai Breast Cancer Study (SBCS), the Shanghai Breast Cancer Survival Study (SBCSS), the Shanghai Women's Health Study (SWHS), and the Shanghai Endometrial Cancer Study (SECS, contributing controls only). Shanghai Breast Cancer Study (SBCS): The SBCS is a population-based, case-control study conducted in urban Shanghai. Subject recruitment in the initial phase of the SBCS (SBCS-I) was conducted between August 1996 and March 1998. The second phase (SBCS-II) of recruitment occurred between April 2002 and February 2005. Breast cancer cases were identified through the population-based Shanghai Cancer Registry and supplemented by a rapid case-ascertainment system. Controls were randomly selected using the Shanghai Resident Registry. Approximately 3500 cases and 3500 controls were recruited in the study. Shanghai Breast Cancer Survival Study (SBCSS) and Shanghai Endometrial Cancer Study (SECS): The SBCSS also used the population-based Shanghai Cancer Registry to identify newly diagnosed breast cancer cases. A total of 5,046 breast cancer patients were recruited. In-person interviews were conducted to collect information on known breast cancer risk factors and anthropometrics by using protocols and questionnaires similar to those used in the SBCS. For genetic studies, controls for the SBCSS cases came from the SECS, which recruited healthy women between January 1997 and December 2003. With the exception of a few questions related specifically to breast or endometrial cancer risk, the questionnaires used in the SECS and the SBCS were very similar. Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Breast cancer patients identified in the SWHS and non-cases were included in the current study.

  Study phs001088

• Shanghai Breast Cancer Genetics Study (SBCGS)

  The Shanghai Breast Cancer Genetics Study (SBCGS) includes data from four population-based studies conducted among Chinese women in urban Shanghai: the Shanghai Breast Cancer Study (SBCS), the Shanghai Breast Cancer Survival Study (SBCSS), the Shanghai Women's Health Study (SWHS), and the Shanghai Endometrial Cancer Study (SECS, contributing controls only). Shanghai Breast Cancer Study (SBCS): The SBCS is a population-based, case-control study conducted in urban Shanghai. Subject recruitment in the initial phase of the SBCS (SBCS-I) was conducted between August 1996 and March 1998. The second phase (SBCS-II) of recruitment occurred between April 2002 and February 2005. Breast cancer cases were identified through the population-based Shanghai Cancer Registry and supplemented by a rapid case-ascertainment system. Controls were randomly selected using the Shanghai Resident Registry. Approximately 3500 cases and 3500 controls were recruited in the study. Shanghai Breast Cancer Survival Study (SBCSS) and Shanghai Endometrial Cancer Study (SECS): The SBCSS also used the population-based Shanghai Cancer Registry to identify newly diagnosed breast cancer cases. A total of 5,046 breast cancer patients were recruited. In-person interviews were conducted to collect information on known breast cancer risk factors and anthropometrics by using a protocol and questionnaire similar to those used in the SBCS. For genetic studies, controls for the SBCSS cases came from the SECS, which recruited healthy women between January 1997 and December 2003. With the exception of a few questions related specifically to breast or endometrial cancer risk, the questionnaires used in the SECS and the SBCS were very similar. Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Breast cancer patients identified in the SWHS and non-cases were included in the current study.

  Study phs000799

• Investigating Genetics of Human Natural Short Sleepers (IGHNSS)

  Sleep is essential for life. A good night's sleep is pleasurable and sleep deprivation is stressful. Prolonged sleep loss impairs temperature control, metabolism, immunity, and ultimately leads to death. Extensive observational and epidemiological evidence indicates that optimal sleep duration of 8 hours is associated with the maintenance of good health. In our society, however, most people only get 6.5 - 7 hours. Suboptimal sleep duration has a strong association with mortality and morbidity. Lack of sleep has been linked to cardiovascular diseases, obesity, hypertension, type 2 diabetes, and other health/cognition conditions. It is clear that the biological need for sleep varies dramatically among humans. Sleep and circadian disorders can include Familial Advanced Sleep Phase (FASP), Delayed Sleep Phase (DSP), Advanced Sleep Phase (ASP), Natural Short Sleepers (NSS) or Long Sleeping. In example, Natural Short Sleepers (NSS) have a lifelong tendency to sleep only 4 - 6 hours per night and to awaken refreshed and energetic. Natural Long Sleepers biologically require 9 - 10 hours/night to feel well rested. The 'Sleep and Circadian Disorders Study' (SACDS) at the University of California San Francisco, set out to investigate the mechanisms involved in regulating sleep duration, patterns and sleep quality regulation by identifying and characterization of individuals and families with unusual sleep and circadian rhythm behavior patterns. SACDS participants were screened with a "General Sleep Questionnaire" that inquired about multiple aspects of sleep, including habitual work-day versus non-work day sleep-wake schedules, permits calculation of subjective habitual initial sleep onset, final sleep offset, and number of awakenings. There was an additional screening process including demographic data, sleep, mood, behavioral and general medical questionnaires, plus the study consent. After the extensive screening of 117 participants, blood samples were collected from 38 individuals and of those 10 samples were chosen for whole exome sequencing analysis.

  Study phs001270

• McGill Epigenomics Mapping Centre

  The McGill Epigenomics Mapping Centre (EMC) and Data Coordination Centre (EDCC) were established in 2012 at the McGill University and Genome Quebec Innovation Centre (Montreal, Canada) to support large-scale human epigenome mapping for a broad spectrum of cell types and diseases. Previous epigenetic studies have provided profiles of specific chromatin marks in relation to basic biological processes, and future studies of molecular mechanisms must build upon these proofs-of-concept by integrating sequence-based variation with multiple levels of epigenetic and transcriptional regulation across the genome of human tissues and animal disease models. This project leverages the high-throughput sequencing infrastructure and expertise in genomics and transcriptomics at the McGill Innovation Centre to carry out this research. Controlled access to the data by collaborators and the greater scientific community is gained via a portal, which takes advantage of Compute Canada high-performance computing cluster resources to manage the large volume of data associated from the generation of reference epigenome maps. McGill University is one of two Canadian mapping and data coordination centres, the other based at the Michael Smith Genome Sciences Centre in Vancouver, British Columbia. The generation of comprehensive epigenome maps at McGill University is part of a larger international effort that is coordinated by the International Human Epigenome Consortium (IHEC), whose overall long-term objective is to determine the extent to which the epigenome shapes human populations over generations and in response to the environment. This project is funded under the Canadian Epigenetics, Environment, and Health Research Consortium (CEEHRC) by the Canadian Institutes of Health Research and by Genome Quebec, with additional support from Genome Canada. The computing and networking infrastructure, and part of the software development, are provided by Compute Canada and CANARIE.

  Study EGAS00001000995

• HCA Female Reproductive Adult WSSS RNA

  HCA Endometrium_LM The endometrium regenerates monthly and its transformation is executed through dynamic changes in states and interactions of multiple cell types. Using transcriptomics methods we seek to profile changes of the endometrium across the menstrual cycle. Our map will have implications in women's health and cancer, by enabling the interpretation of GWAS analyses or the studying functional consequences of somatic mutations. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001007909

• ATAC-seq in hiPSC-derived neurons after BDNF and KCl stimulations

  Brain-Derived Neurotrophic Factor (BDNF) is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. Molecular mechanisms of BDNF promoting cellular survival and synaptic plasticity have been intensely studied, yet its role in genome regulation is obscure. Using human induced pluripotent stem cell (hiPSC)-derived neurons via lentiviral delivery of the neuronal transcription factor Ngn2, we performed a temporal profiling (1h, 6h and 10h) of chromatin accessibility upon BDNF treatment or depolarization (KCl) to identify BDNF-specific chromatin-to-gene expression programs.

  Dataset EGAD00001009100

• Biomarkers in Transplant Recipients

  Biliary atresia causes jaundice and liver failure in newborn children. In this study, single nucleotide polymorphisms were characterized in children with biliary atresia and identified ARF6 as a susceptibility gene for this disease. Knockdown of this gene in zebrafish embryos impaired formation of bile ducts and excretion of bile from the zebrafish liver. Subject enrollment: Children with biliary atresia were enrolled at Children's Hospital of Pittsburgh (CHP) after obtaining written consent from parents for the University of Pittsburgh IRB approved protocol number 0405628. At the Center for Applied Genomics (CAG), all subjects were enrolled after obtaining written consent from parents per Children's Hospital of Philadelphia IRB approval number 06-004886 Genotyping array: Genotyping of DNA obtained from blood was performed with the Infinium HumanHap550K BeadChip (Illumina, San Diego, CA). Statistical methods and software: SNP genotype frequencies were compared between cases and controls with a chi-square test statistic applied in Plink [Purcell et al, 2007] for SNPs with at least 90% call rate and 1% minor allele frequency (MAF). Cases and controls: All DNA samples had excellent data quality with call rates > 98%. A total of 63 Caucasian BA cases and 1907 controls were compared at > 550000 SNPs, and demonstrated a very low genomic inflation factor of 1.00627. Description of Cases: Biliary atresia patients had received a Kasai procedure and demonstrated histopathological features of biliary obstruction, and were recruited at evaluation for transplantation or after liver transplantation.

  Study phs000960

• Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis

  Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a ‘dysplasia with multiple joint dislocations’ however, the molecular aetiology of the disorder is currently unknown. In order to identify the genetic defects underlying PDD, we performed whole exome sequencing (WES) on 3 patients from 2 unrelated families, clinically diagnosed with PDD. WES resulted in the identification of bi-allelic variants in the established skeletal dysplasia genes, B3GAT3 (Family 1) and CANT1 (Family 2). Mutations in these genes have previously been reported to cause ‘multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects’ (B3GAT3) and Desbuquois dysplasia 1 (CANT1); disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3- and CANT1- related skeletal dysplasias to include PDD, and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.

  Study EGAS00001004145

• National Cancer Institute Genome-Wide Association Study of Renal Cell Carcinoma

  The National Cancer Institute (NCI) genome-wide association study (GWAS) of renal cell carcinoma (RCC) was conducted to investigate common genetic variants associated with RCC risk. The GWAS includes 1,453 RCC cases and 3,531 controls of European background from 4 studies (3 cohort, 1 case-control), scanned using the Illumina InfiniumHumanHap 550, 610 and 660W chips. This project was supported by the Intramural Research Program of the National Institutes of Health and NCI. Data from this GWAS were pooled with those from another GWAS of RCC (2,639 cases and 5,392 controls) conducted in Europe by the International Agency for Research on Cancer and the Centre National de Gènotypage. Findings from this collaboration are described in an upcoming report (Purdue et al. Nature Genetics 2011;43(1):60-65; PMID: 21131975). Only data from the NCI scan are included in this dbGaP submission.

  Study phs000351

• The Ultrasound Study of Tamoxifen

  The Ultrasound Study of Tamoxifen is a 12-month longitudinal study to describe volumetric breast density change over time among women with and without tamoxifen exposure. Women were enrolled at the Karmanos Cancer Institute and Henry Ford Health Systems in Detroit, Michigan between 2011-2014. Enrollment included women prescribed tamoxifen for clinical indication (n=82) and a comparison group of women frequency matched on age, race, and menopausal status (n=165). Whole breast ultrasound tomography (UST) scans were used to measure volume averaged sound speed (m/s) as a surrogate of volumetric breast density. Ultrasound tomography (UST) scans were completed at baseline prior to tamoxifen initiation and were repeated at 1-3 months, 4-6 months, and 12 months after tamoxifen initiation. For the comparison group, UST scans were completed at baseline and 12 months. Questionnaires were completed at each scan.

  Study phs003183

• Women's Interagency HIV Study (WIHS)

  The Women's Interagency HIV Study (WIHS), a multicenter, prospective study, was established in August 1993 to carry out comprehensive investigations of the impact of HIV infection and its clinical, laboratory, and psychosocial effects in women. The purpose of this study is to collect and evaluate these data from HIV infected and at-risk women to better understand and provide support for women whom are currently HIV infected or who are at risk for HIV infection. Participants will have study visits every 6 months. Questionnaires regarding sexual behavior, health care utilization, medical and obstetric/gynecological history, psychosocial factors, and sociodemographics will be completed by participants. Physical, gynecological, and lipodystrophy examinations will also be conducted at each visit, and current medication regimen will be noted. Blood and other bodily fluid samples will be collected and registered in both local and national repositories of the WIHS in conjunction with NIAID.

  Study phs001503

• Yale Center for Mendelian Genomics (YCMG)

  From 2012-2021, Yale University was home to one of four national centers created by the National Institutes of Health (NIH) to study the genetics of rare inherited diseases. Researchers at Yale University, University of Washington, the Broad Institute and a center operated jointly by Baylor University and Johns Hopkins University analyzed the genomes of thousands of patients who suffer from more than 6,000 rare Mendelian disorders affecting more than 25 million individuals in United States. The Centers for Mendelian Genomics (CMG) applied next-generation sequencing and computational approaches to discover the genes and variants that underlie Mendelian disorders. The discovery of new genes that cause Mendelian conditions expanded our understanding about their biology to facilitate their diagnosis, and potentially indicate new treatments. The CMG provided free exome sequencing and analysis to collaborating investigators for qualified phenotypes.

  Study phs000744

• SUDC Registry and Research Collaborative

  The Sudden Unexplained Death in Childhood Registry and Research Collaborative (SUDCRRC), created at NYU Langone Health in 2014, connects academic investigators, forensic pathologists, and medical examiner and coroner partner offices to study sudden unexpected pediatric deaths, aged 1 month to 18 years, whose death is unexplained or unclear at the end of the public mandated investigation, including autopsy. Each case includes collection and analysis of all records (medical history from prenatal records throughout life, death scene investigation, autopsy/toxicology/ancillary death investigation reports including photographs and histology slides), biospecimens, and in-depth family interviews. Whole exome sequencing is performed on each deceased child and both biological parents. Additional studies are pursued when indicated by pathology review. Each case receives a multidisciplinary masked review process and parental written consent is obtained. The NYU institutional review board approved this study.

  Study phs003383

• SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population

  The SweGen project represents a comprehensive map of genetic variation in the Swedish population. This Study contains four datasets where the first one contains whole-genome sequencing data in CRAM-format for 942 individuals from the Swedish Twin Registry, the second one contains genetic variant frequencies in VCF-format for the same individuals, the third one contains whole-genome sequencing data in CRAM-format for 58 individuals from the Northern Sweden Population Health Study and the fourth one contains genetic variant frequencies in VCF-format for the same individuals. The data, serving as a reference dataset, is a valuable and national resource for genetics research and clinical diagnostics and can be used, for instance, to increase understanding of both rare and complex disorders. It also serves as an international resource for larger studies of human population genetics.

  Study EGAS50000000906

• Beacon v2

  Beacon v2: a tool for data discovery Motivation In the era of data-driven health research and personalised medicine, human genomic data has become extremely valuable. These are also identifiable data, as they carry information pointing to a specific individual as well as their own family; and as such, they must be protected. This makes data discovery particularly challenging: this is where “Beacon” comes in. A “Beacon” is an API aiming to enable the search of genomic variants and associated information without jeopardising the privacy of the dataset. Here, we refer to its current version, namely version 2 (v2). Definition Beacon v2 is a term that can refer to different aspects. The EGA is playing a central role in the following aspects: The Beacon v2 protocol is a Global Alliance for Health and Genomics standard. The Beacon v2 Reference Implementation (B2RI) is an “out-of-the-box” Beacon instance developed with ELIXIR, which facilitates Beacon deployment. The EGA Beacon(s) are Beacons following the v2 standard and using the B2RI, deployed on top of data hosted at the EGA and allowing for their discovery. Resources Depending on whether you are visiting us a stakeholder (you need more general information about Beacon), a deployer /implementer (you want to have your own Beacon instance), or an EGA user (you want to query Beacon and start browsing data), you will be interested in the following resources: Your role Beacon aspect Documentation type Stakeholder Beacon v2 protocol Beacon website Beacon page on the GA4GH website Deployer/Implementer Beacon v2 protocol Read the docs: Beacon v2 standard technical description GitHub repository Beacon v2 standard Beacon v2 Reference Implementation Read the docs: B2RI technical description GitHub repository B2RI Guide to deploy Beacon using B2RI EGA user EGA Beacon(s) API in construction UI in construction

  Documentation about/projects-and-funders/beacon

• T2D-GENES: Exome sequencing

  The Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) is a large collaboration effort between the University of Michigan, Broad Institute, the Wellcome Trust Centre for Human Genetics, University of Chicago, NIDDK, Texas Biomedical Research Institute, University of Texas Health Science Center, University of North Carolina, Blood Systems Research Institute, and University of Mississippi Medical Center. The goal of this study is to identify genetic variants for type 2 diabetes through multiethnic sequencing studies. In this study, we use next generation sequencing to assess the role of common, low frequency, and rare variants on type 2 diabetes risk. We preformed exome sequencing in 6,546 T2D cases and 6,457 control individuals of multiethnic origin, including individuals of African American, East Asian, South Asian, Hispanic, and European descent.

  Study EGAS00001001460

• H3Africa Chip Design - Aim of designing a cost-effective GWAS chip with content appropriate for use in genomics studies of individuals from the African continent.

  Since it is recognized that currently available chips may not be ideally suited to studying African populations, the H3Africa Genome Analysis working group undertook the task of designing a cost-effective GWAS chip with content appropriate for use in genomics research studies of individuals from the African continent. To address gaps in sequence data for some of the African populations being studied in H3Africa projects, a high coverage whole genome sequence dataset was generated at the Baylor College of Medicine with samples provided by H3Africa PIs and collaborators, funded by the National Institutes of Health. This dataset includes 350 high coverage and 160 medium coverage whole genome sequences from 348 populations. The data is accompanied by minimal metadata, including country, ethnic group and sex.

  Study EGAS00001002976

• Autozygosity_pilot___British_Pakistani_from_Birmingham_2

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 20-50%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing British-Pakistani cohort samples from Birmingham will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consists of low coverage whole exome sequencing on these samples.

  Study EGAS00001000567

• Autozygosity_pilot___Pakistani_from_Birmingham

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 50-80%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing British-Pakistani cohort samples from Birmingham will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consist of low coverage whole exome sequencing on these samples.

  Study EGAS00001000511

• Autozygosity_pilot___QMUL

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 20-50%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing British-Pakistani cohort samples will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consists of low coverage whole exome sequencing on these samples.

  Study EGAS00001000717

• Transcriptional_Consequences_of_Copy_Number_Changes_MY_HDBR_200531

  Every normal human cell has two copies of each non-sex chromosome. The gain or loss of an extra copy underlies many health conditions, including developmental syndromes and cancer. Ultimately, it is the patterns of genes that are turned on and off that determines which proteins a cell produces and its biological function. Despite the importance of changes in chromosome number (known as aneuploidy or copy number changes), little is known about how these changes impact patterns of gene expression. This project will aim to fill this gap by creating an atlas of patterns of gene expression in cells from developmental tissues with aberrant numbers of chromosomes. These gene expression profiles will then be compared to the patterns of expression in the same cells with two copies of each chromosome, directly measuring the precise, cell specific, consequences of copy number change on gene expression.

  Study EGAS00001005100

• Epithelial, fibroblast, myeloid, T cell, primary prostate cancer

  The collection and use of tissue for this study had Melbourne Health institutional review board approval and patients provided written informed consent (Melbourne Health Local Project Number: 2016.087). Following the prostatectomy of 13 patients, ranging from 52 to 78 years of age and from CAPRA-S risk score of 0 (attributed to benign tissue samples, harvested from a site far from a low grade, low volume cancer) to 7 (Supplementary file 2), a four millimeter tissue core was collected from the prostate tumour site, conditional to histopathological verification66,67. If not otherwise specified, all procedures were carried out at 4 °C. Tissue blocks were washed in Phosphate-buffered saline (PBS) solution for 2 minutes and minced for 2 minutes with a scalpel. Homogenised tissue was added to a solution (total volume of 7 ml) composed by of 1 mg/ml collagenase IV (Worthington Biochemical Corp, USA), 0.02 mg/ml DNase 1 (New England Biolabs, USA), 0.2 mg/ml dispase (Merck, USA). The tissue homogenised was serially digested at 37 °C at 180 rpm, through three steps of 5, 10 and 10 minutes of duration, with the final 3 minutes dedicated to sedimentation at 0 rpm. After each digestion step, the supernatant was aspirated and filtered through a 70 μm strainer into a pre-chilled tube, diluting the solution with 15 ml of 2% bovine serum PBS to quench the enzymatic reaction. The resulting cumulative solution was then centrifuged at 1500 rpm for five minutes, with the supernatant collected and the cell pellet resuspended into 1 ml 2% PBS-serum prior to labelling (Fig. S1).

  Dataset EGAD00001004948

• Whole-genome sequencing across 449 samples spanning 47 ethnolinguistic groups provides insights into genetic diversity in Nigeria

  African populations have been drastically underrepresented in genomics research and failure to capture the genetic diversity across the numerous ethnolinguistic groups (ELGs) found in the continent has hindered the equity of precision medicine initiatives globally. Here, we describe the whole-genome sequencing of 449 Nigerian individuals across 47 unique self-reported ELGs. Population structure analysis reveals genetic differentiation amongst our ELGs, consistent with previous findings. From the 36 million SNPs and indels discovered in our dataset, we provide a high-level catalog of both novel and medically-relevant variation present across the ELGs. These results emphasize the value of this resource for genomics research, with added granularity by representing multiple ELGs from Nigeria. Our results also underscore the potential of using these cohorts with larger sample sizes to improve our understanding of human ancestry and health in Africa.

  Study EGAS00001007036

• Clinical evaluation of long read sequencing-based episignature detection in developmental disorders

  Some developmental disorders (DD) are marked by specific genome-wide methylation changes, known as episignatures, which can support diagnosis and reveal underlying mechanisms. Current methods rely on indirect methylation profiling. Here, we assessed whether long-read whole genome sequencing with nanopore technology could directly detect both episignatures and genetic variants. We sequenced forty controls and twenty DD patients, using clustering and dimensional reduction to compare methylome patterns with microarray-based signatures. Our classifiers accurately identified episignatures in 17 of 19 patients with pathogenic variants, matching microarray results. This study shows nanopore sequencing enables comprehensive, haplotype-aware genomic and epigenomic analysis for DD diagnostics.

  Study EGAS50000000719

• Diversity of U1 small nuclear RNAs and Evaluation of Diagnostic Methods for their Mutations

  U1 small nuclear RNA (snRNA) mutations are recurrent non-coding alterations found in various malignancies, including medulloblastoma, yet their identification has proven challenging due to their repetitive nature. To establish a robust DNA-based, and RNA-based method for detecting U1 snRNA mutations, we performed targeted DNA sequencing using our original gene panel for medulloblastoma and RNA-sequencing. As an RNA-based method, we developed a random forest classifier employing splicing patterns which were massively altered as a result of U1 snRNA mutations. By using both methods, we successfully detected U1 snRNA mutation in five DNA samples and four RNA samples.

  Study EGAS50000000693

• TRACERx100 metastatic samples

  Whole exome sequencing of 10 metastatic biopsies from four TRACERx100 patients (see EGA dataset EGAS00001002247), collected either after relapse or death. The data from these samples are initially published with Abbosh, C. et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature, http://dx.doi.org/10.1038/nature22364 (2017). Abstract: Earlier detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a patient-specific approach to ctDNA profiling in the first 100 lung TRACERx (TRAcking Cancer Evolution through therapy (Rx)) study participants, including one patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release in early-stage non-small cell lung cancer and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies.

  Dataset EGAD00001003301

• High-Risk Breast Cancer GWAS

  The GWAS includes High Risk Women from the following epidemiological studies of breast cancer, comprising a total of 3,719 cases and 3,642 controls (cases/controls: MEC, 0/200; ABCFR, 326/418; FCCC, 56/3; BCFR-UT, 66/32; CNIO-BC, 87/92; GESBC, 65/0; LIFE, 164/0; MARIE, 41/105; MAYO, 208/210; MNYR, 293/409; MSKCC, 310/0; NC-BCFR, 234/233; OFBCR, 553/560; POSH, 377/0; HBOC, 47/47; BBCS, 612/1333; UPENN, 280/0 This study was funded by a grant CA165038 to Christopher Haiman (University of Southern California) and John Hopper (University of Melbourne) from the National Cancer Institute, National Institute of Health. The contributing studies: Multiethnic Cohort (MEC). This study was supported by grant UM1 CA164973 from the National Cancer Institute, National Institute of Health. Ontario Familial Breast Cancer Registry, the Ontario site of the Breast Cancer Family Registry Cohort (OFBCR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Utah Breast Cancer Family Registry (BCFR-UT). This study was supported by grant UM1 CA164920 from the National Cancer Institute. New York site of the Breast Cancer Family Registry (MNYR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Northern California site of the Breast Cancer Family Registry (NC-BCFR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Australian Breast Cancer Family Registry (ABCFR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Breast Cancer Study (CNIO-BC). This study has been partially funded by The Spanish Network on Rare Diseases (CIBERER) and the Spanish National Genotyping Center (CEGEN). Genetic Epidemiologic Study of Breast Cancer (GESBC). The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and German Cancer Research Center (DKFZ). Mammary Carcinoma Risk Factor Study (MARIE). This study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). Funding for the POSH study was provided by Cancer Research UK (grant refs A7572, A11699, C22524), the Breast Cancer Campaign (grant number: 2013MayPR044) and from 2003-2006 by a grant from The Wessex Cancer Trust. Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). Funding for the POSH study was provided by Cancer Research UK (grant refs A7572, A11699, C22524), the Breast Cancer Campaign (grant number: 2013MayPR044) and from 2003-2006 by a grant from The Wessex Cancer Trust. Hereditary Breast and ovarian Cancer: Genetic and Molecular Studies (HBOC). This study was supported by National Cancer Institute grant CA58860 and The Lon V Smith Foundation: LVSF-44528. Mayo Clinic inherited breast and ovarian cancer study (MAYO). This study was supported by the Breast Cancer Research Foundation, NIH grants CA192393, CA176785, and an NIH CA116201 Specialized Program of Research Excellence (SPORE) in Breast Cancer. British Breast Cancer Study (BBCS); Mammographic oestrogens and growth factor study (MOG). The BBCS and the MOG study are funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledge NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). Genotyping of non-BRCA1/2 mutation carriers (UPENN). The study is supported by the Basser Research Center at the University of Pennsylvania, Rooney Family Foundation, NIH grants CA176785 and CA192393, the Breast Cancer Research Foundation, the Susan G. Komen Foundation for the Cure and Macdonald Family Foundation. Clinical Significance of Germline BRCA Mutations (MSKCC). The study is supported by the Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative, The Breast Cancer Research Foundation, and the Cancer Center Support Grant from the National Institute of Health, National Cancer Institute 5P30 CA08748-40. Women's Learning the Influence of Family and Environment (LIFE). This study was supported by grants CA17054 and CA74847 from the National Cancer Institute, National Institutes of Health, No. 4PB-0092 from the California Breast Cancer Research Program of the University of California. Philadelphia site of the Breast Cancer Family Registry at Fox Chase Cancer Center (FCCC). This study is supported by NIH grant CA164920.

  Study phs000929

• An epidemiological study examining the relationship among food, health, and genome

  We conducted a cohort-based study to investigate the association between the genetic background and diet/lifestyle in 962 healthy Japanese. We analyzed the Ebetsu cohort and some participants living in Tokyo. The SNP array (Japonica Array v2) was used for genotyping. Shotgun metagenomic sequencing of fecal microbiome and metabolome of feces and blood were analyzed.

  Study JGAS000678

• Donor InSight III study: Participants typed during UK Biobank version 2 array development phase

  The Donor InSight III study, undertaken by Sanquin research, recruited 3,046 Dutch blood donors between 2015 and 2016. The purpose of the study was to gain more insight into characteristics of donors, their motivations and health. All participants were at the time of recruitment active blood donors. Genotyping data was produced using the Thermo Fisher Scientific Axiom Genotyping platform. The UK Biobank version 2 array design was used, content on this array has been added to allow for accurate DNA based identification of human blood group antigens.

  Dataset EGAD00001005026

• Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform

  We used 200 ccRCC samples from 51 tumors to simultaneously isolate DNA, RNA, and protein according to established protocol. RNA quality was assessed using an Agilent Bioanalyzer, and total RNA with RIN>7 was used for further RNA sequencing. 184 ccRCC samples from 49 tumors passing initial quality control underwent RNA sequencing at Admera Health Inc. (Genohub Inc., Austin, TX). RNA sequencing libraries were prepared using the Illumina TruSeq Stranded mRNA high throughput (HT) sample preparation kit following the manufacturers’ protocol. Pair-end RNA Seq data was deposited in this cohort.

  Dataset EGAD00001005356

• March 2017 data update (bam/fastq) (containing H3K27ac for CEMT_87, RNA-Seq for CEMT_141, CEMT_142, CEMT_145, CEMT_146, H3K27me3, H3K9me3, H3K4me3, H3K4me1, ChIP-Seq Input for CEMT_88, CEMT_90 and CEMT_91) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  March 2017 data update (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001003272

• RNA-seq of Liver Cancer

  The present series corresponds to 161 RNA-seq samples from tumors with matched WES or WGS. Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before.

  Dataset EGAD00001003993

• Whole genome sequence of third generation family member (SFHS)

  Previously we performed deep WGS on 6 parents and 13 children from 3 large families from the Scottish Family Health Study to identify de novo mutations. This prelim is cover the additional sequencing of one grandchild from one of these three families. The inclusion of a third generation individual will provide additional experimental validation for the de novo mutations found in the initial trio. As in the previous study, the DNA will be WGS to a depth of approximately 25X to achieve this purpose.These data can only be used for the investigation of the genetic causes of the reported clinical phenotypes in these patients

  Dataset EGAD00001001454

• Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT)

  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 determine efficacy (reduction in severity of epistaxis), tolerability, and improvement in quality of life of pomalidomide compared to placebo after 24 weeks of treatment.Background: This study addresses the efficacy of pomalidomide in the treatment of epistaxis in patients with Hereditary Hemorrhagic Telangiectasia (HHT) who have anemia and/or require blood transfusion or iron infusion for treatment of bleeding-induced anemia and iron deficiency. HHT (also known as Osler-Weber-Rendu disease) is an inherited bleeding disorder. Over 95% of patients develop recurrent epistaxis, which may be severe and result in chronic anemia, need for iron infusions and blood transfusions, substantial psychiatric comorbidity (including depression and post-traumatic stress disorder) and reduction in health-related quality of life (HRQoL). HHT is clinically diagnosed using the Curacao criteria, which consists of 1) spontaneous and recurrent epistaxis, 2) telangiectasias at characteristic sites, 3) visceral arteriovenous malformations (AVMs) or telangiectasias, and 4) a first degree relative with HHT (inheritance is usually autosomal dominant). Patients with three criteria are considered to have definite HHT, and those with 2 criteria probable HHT. HHT affects approximately 1 in 3,800 individuals. Significant manifestations of HHT often do not appear until the third or fourth decades, sometimes later.Participants: 144 patients from 11 clinical centers were enrolled.Design: This is a multi-center, double blind, randomized placebo-controlled trial that investigated the efficacy and safety of pomalidomide in patients with HHT and chronic epistaxis leading to iron-deficiency anemia or requiring intravenous iron infusions or blood transfusion.Screening evaluation included the Epistaxis Severity Score (ESS) with three-month recall, which reflected the patient's history of epistaxis and bleeding over the prior three months, as well as detailed review of iron infusion and red cell transfusion over the preceding six months. Eligible patients were provided a diary to record the duration of each epistaxis event that occurred during the 4 weeks prior to the baseline visit, and then returned for the baseline randomization visit, at which time patients underwent genetic testing, if this had not been previously performed, and completed an ESS with 4-week recall and quality of life assessments. Patients were randomized 2:1, stratified by study site, to either pomalidomide 4 mg/day or matching placebo during each of six 28 day cycles (24 weeks). Patients were seen every four weeks during treatment, and at a 4-week post-treatment follow-up visit to measure the ESS (with 4-week recall), laboratory assessments including iron stores and need for iron infusion, CBC, and metabolic profile. Patients were assessed for adverse events (AE) throughout the study. Treatment dosage could be reduced, or temporarily or permanently discontinued following AE-specific guidelines related to fatigue, cytopenias or other toxicities.Quality of life assessments were completed at baseline, and the 12- and 24-week visits, and the 4-week post-treatment follow-up visit using validated NIH instruments of 1) Neuro-QOL satisfaction with social roles and activities, 2) PROMIS emotional distress – depression, and 3) PROMIS fatigue, and the HHT-specific quality of life instrument developed specifically for this study. The effect of pomalidomide on duration of epistaxis was assessed via diary between weeks 8-12, 20-24 and the 4-week post-treatment period.Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified (Al-Samkari et al., 2024; PMID: 39292928)

  Study phs003948

• MILK-Omics: Systems Biology of Human Milk and Its Links to Maternal and Infant Health

  The primary objective of the project is to generate a systems-level view of human milk in the context of healthy mothers and their term infants. The study uses biospecimens and clinical data from the Mothers and Infants LinKed for Healthy Growth Study (MILk Study), a prospective observational cohort of approximately 500 exclusively breastfeeding women and their infants who are followed to 6 months of age. The project focuses on mature milk samples collected at 1 month postpartum and infant gut microbiome samples collected at 1 and 6 months of age. Specific Aim 1 is to identify maternal genetic and clinical factors that shape human milk gene expression. Using bulk and single-cell RNA sequencing of the milk cell pellet and genotypes from maternal DNA, we will identify novel genetic determinants of the milk transcriptome and assess potential modification of these genetic associations by gestational weight gain, diet, and other clinical factors. Specific Aim 2 is to describe key features of the normative human milk biosystem and their interactions with one another. Specifically, machine learning techniques will be used to characterize interaction networks and correlational structures among the following features of human milk: transcriptomics, microbiomes, oligosaccharides, metabolomics, lipidomics, and milk macronutrient composition. Specific Aim 3 is to establish how the milk biosystem is related to variation in infant gut microbiomes and health. dbGaP will house the maternal genotype and milk transcriptomics data.The infant microbiome sequence data are associated with BioProject PRJNA1019702.

  Study phs003408

• Pharmacological improvement of CFTR function rescues airway epithelial homeostasis and host defense in cystic fibrosis children

  Rationale: Recent clinical trials have shown that elexacaftor/tezacaftor/ivacaftor (ETI) provides significant benefit to patients with cystic fibrosis (CF) by improving CFTR function. Despite these promising clinical findings, the specific effects on the airway inflammatory status leading to structural damage and impaired lung function, remain elusive. Objectives: We investigated the transcriptional changes at the single cell level of airway epithelial and immune cells that underlie the clinical improvement by ETI therapy in children with CF. Methods: Nasal swabs from thirteen children with CF and at least one F508del allele aged 6 to 12 years were collected at baseline and three months after initiation of ETI and subjected to scRNA-seq. In addition, we collected nasal swabs from 12 age- and sex-matched controls. Sweat chloride concentrations, spirometry and multiple breath washout were used for clinical evaluation of CF children. Measurements and main results: ETI significantly reduced sweat chloride concentrations (-52.2 ± 14.3 mmol/L, P < 0.001) and improved the lung clearance index (-1.3 ± 1.8, P < 0.05). Single cell transcriptomics revealed an impaired interferon signalling in epithelial cells of CF children at baseline, which was partially restored by ETI in conjunction with an ETI-induced increase in expression of MHC I and II encoding genes similar to control levels. Additionally, ETI markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Conclusions: Improvement of CFTR function by ETI restores epithelial homeostasis and reduces immune cell inflammatory responses in the upper airways of children with CF, highlighting the potential of early initiation of ETI therapy.

  Study EGAS50000000128

• Role of Tobacco Smoke in Clear Cell Renal Cell Carcinoma

  Background. Clear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognoses. ccRCC is also characterized by distinguished metabolic reprogramming. Tobacco smoking (TS) is an established risk factor for ccRCC with unknown effects on tumor pathobiology.Methods. We investigated the landscape of ccRCCs and paired normal kidney tissues (NKTs) using integrated transcriptomic, metabolomic and metallomic approaches in a cohort of never smokers (NS) and long-term current smokers (LTS) Caucasian males. Results. All three Omics domains consistently identified a distinct metabolic subtype of ccRCCs in LTS, characterized by activation of oxidative phosphorylation (OxPhos) coupled with reprogramming of the malate-aspartate shuttle and metabolism of aspartate, glutamate, glutamine and histidine. Cadmium, copper and inorganic arsenic accumulated in LTS tumors showing redistribution among intracellular pools, including relocation of copper into the cytochrome c oxidase complex. Gene expression signature based on the LTS metabolic subtype provided prognostic stratification of The Cancer Genome Atlas (TCGA) ccRCC tumors that was independent from genomic alterations.Conclusions. The work identified the TS related metabolic subtype of ccRCC with vulnerabilities that can be exploited for precision medicine approaches targeting metabolic pathways. The results provided rationale for the development of metabolic biomarkers with diagnostic and prognostic applications using evaluation of OxPhos status. The metallomic analysis revealed the role of disrupted metal homeostasis in ccRCC highlighting the importance of studying effects of metals from e-cigarettes and environmental exposures.

  Study phs002083

• National Heart Lung and Blood Institute Exome sequencing in SCID

  Analysis of the molecular etiologies of severe combined immunodeficiency (SCID) has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in some cases, the molecular etiology remains unclear. To identify the cause of SCID in a patient known to lack the protein tyrosine phosphatase CD45, we utilized single nucleotide polymorphisms (SNP) arrays and whole exome sequencing. The patient&#39;s mother was heterozygous for an inactivating mutation in CD45, while the paternal alleles lacked mutations. The patient exhibited a single CD45 mutation identical to the maternal allele. Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the CD45 mutation. Non-lymphoid blood cells and other mesoderm and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient who had undergone successful bone marrow transplantation. Exome sequencing revealed mutations in 7 additional genes bearing nonsynonymous SNPs predicted to have deleterious effects. These findings represent the first reported case of SCID caused by UPD and suggest UPD should be considered in SCID and other recessive disorders, especially when the patient appears homozygous for an abnormal gene found in only one parent. Evaluation for alterations in other genes affected by UPD should also be considered in such cases.

  Study phs000479

• Early Methamphetamine Abstinence: fMRI and Brain Function

  This study included two groups of subjects, methamphetamine-dependent and healthy control participants, with the purpose of characterizing brain structure and cognition during the first month of abstinence from methamphetamine. Participants were able to participate in one or both phases of the study. Methamphetamine abusers were held as inpatients and abstained from methamphetamine use during the entirety of the study. Phase I covered the 1st week of abstinence and Phase II covered the next 3-4 weeks of abstinence. Control subjects participated as outpatients at timeframes which corresponded to the assessments taken of methamphetamine users. The following outlines the procedures in more detail. After initial telephone screening, in-person screening and recruitment procedures took place at the UCLA Neuropsychiatric Institute. Each methamphetamine abuser subject entered the study after completing an interview and questionnaires on drug use history, and providing a positive urine test for methamphetamine. The evaluation included a psychiatric diagnostic interview according to the Structured Clinical Inventory for DSM-IV (SCID-IV), a medical history and physical examination, blood tests [including a complete chemistry panel, hepatic panel, and tests for hepatitis-C and HIV]. Urine samples were also taken for drug screening of illicit drugs, and to test for pregnancy (female subjects). The methamphetamine abusers were then admitted to the General Clinical Research Center (CRC) and participated on a residential basis, where they were administered daily questionnaires about drug craving, withdrawal and mood. The current study makes available phenotype and genotype data, and interested investigators may contact the principal investigator regarding potential sharing of fMRI data.

  Study phs001198

• A Functional Network of Gastric-Cancer-Associated Splicing Events Controlled by Dysregulated Splicing Factors

  Except for a few genes known to have oncogenic spliceforms in gastric cancer, the full scope of aberrant splicing in gastric oncogenesis remains unclear. In this study, we elucidated the alternative splicing events associated with gastric carcinogenesis and identified upstream regulators governing these events. We performed RNA-seq on 19 matched tumor/normal pairs and a panel of gastric cancer cell lines, and identified 361 tumor associated (TA) alternative splicing events (ASEs), which included known oncogenic ASEs in genes such as INSR, FGFR2, CD44 and KRAS. We further identified 8 splicing factors dysregulated in gastric tumors, the expression of which are correlated to the splice ratio of the TA ASEs. We thereby constructed a dysregulated splicing network in gastric cancer, consisting of alternative splicing changes correlated to their potential regulators. This network featured three potential regulatory modules centered around the splicing factors ESRP2, MBNL1 and PTPB1. Knockdown of each splicing factor led to the expected changes in splicing of approximately half of the ASEs assayed. Thus, dysregulation of the splicing factors indeed was the cause of many of the TA ASEs. Pathway enrichment analysis showed that genes affected by tumor associated splicing were pre-dominantly involved in cytoskeletal organization. Concordant with this, knockdown of the splicing factors regulating the TA ASEs led to the expected changes in trans-well migration activity. Thus, we have established for the first time a comprehensive splicing network that likely drives gastric tumor progression, based on which novel therapeutic targets can be identified for further evaluation.

  Study EGAS00001002256

• A higher ctDNA fraction decreases survival in regorafenib-treated metastatic colorectal cancer patients

  The predictive effect of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) treatment is still highly discussed. The primary objective of this study was to investigate a possible prognostic/predictive value of ctDNA under regorafenib treatment. This prospective multicenter translational biomarker phase II pilot study enrolled 30 metastatic CRC patients (67% men, 33% women) treated with regorafenib. ctDNA was assessed in plasma before treatment start and at defined time points during administration. Measurement of tumor fraction as well as mutation and copy number analysis of CRC driver genes were performed by next generation sequencing approaches. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG. Disease control rate was 30%. Median tumor fraction at baseline was 18.5% (0-49.9). Mutations in CRC driver genes or genes involved in angiogenesis were identified in 25 patients (83.3%). KRAS mutations were detected in 13 out of 14 KRAS positive tumors, in three patients without KRAS mutation in the respective tumor acquired mutations as a consequence of prior anti-EGFR treatment were detected. In a subset of patients, novel occurring mutations or focal amplifications were detected. A tumor fraction of 5% and higher at baseline was significantly associated with a decreased OS (p=0.022; HHR 3.110 (95%CI: 1.2-8.2). ctDNA is detectable in a high proportion of mCRC patients. Higher ctDNA levels are associated with survival among regorafenib treatment. Moreover, our data highlight the benefit of a combined evaluation of mutations and somatic copy number alterations (SCNA) in advanced cancer patients.

  Study EGAS00001004491

• Robust methylation-based classification of brain tumours using nanopore sequencing

  Background: DNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumours. In fact, DNA methylation profiling of human brain tumours already profoundly impacts clinical neuro-oncology. However, current implementations using hybridization microarrays are time-consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification. Here, we demonstrate that this approach allows to discriminate a wide spectrum of primary brain tumours. Results: Using public reference data of 82 distinct tumour entities, we performed nanopore genome sequencing on N=382 tissue samples covering 46 brain tumour (sub)types. Using bootstrap sampling in a cohort of N = 56 cases, we find that a minimum set of 1,000 random CpG features is sufficient for high-confidence classification by ad hoc random forests. We implemented score recalibration as confidence measure for interpretation in a clinical context and empirically determined a platform-specific threshold in a randomly sampled discovery cohort (N = 185). Applying this cut-off to an independent validation series (N = 184) yielded 148 classifiable cases (sensitivity 80.4%) and demonstrated 100 % specificity. Cross-lab validation demonstrated robustness with concordant results across four laboratories in 10/11 (90.9%) cases. In a prospective benchmarking (N = 15), median time to results was 21.1 hours. Conclusions: In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumours. Platform-specific confidence scores facilitate clinical implementation for which prospective evaluation is warranted and ongoing.

  Study EGAS00001006540

• Development and Validation of a Disability Severity Index for Charcot-Marie-Tooth Disease (CMT)

  In Charcot-Marie-Tooth Disease (CMT) or inherited neuropathy research studies, it is the researcher who has selected what they believe to be important markers of impairment in function in patients. For example, it has been inferred that the wearing of ankle-foot-orthosis (AFOs), the use of walking aids such as canes, or the use of wheelchairs, are appropriate markers for &#8220;mild&#8221;, &#8220;moderate&#8221; or &#8220;severe&#8221; disability, respectively. Whether patients agree with this classification is unknown. By understanding what patients classify as mild, moderate and severe disability in CMT, we will know what our treatments need to target, to have a meaningful impact on the patients&#39; functional status. Primary objective: The purpose of this study is to compare patient and healthcare provider impressions of what constitutes mild, moderate and severe disability in CMT. Target population: 200 patients who have self-registered at the Inherited Neuropathy Consortium Contact Registry, a web-based contact registry developed and supported by the Data Management and Coordinating Center (DMCC) for the Rare Diseases Clinical Research Consortium (RDCRN), located at the University of South Florida, and 200 health care professionals attending conferences about CMT, such as the 4th International CMT Consortium to be held in Potomac, Maryland, June 29-July 1, 2011 and the MDA Clinic Directors meeting in Las Vegas, NV March 4-7, 2012. Methods: A brief, anonymous, 20-item survey, in which we measure what the physician and the patient think are important indicators of disability in CMT, will be distributed by paper to 200 health care professionals, and via an online link to 200 patients self-registered with the RDCRN contact registry. Out of the 200 patients, approximately 25 patients will be requested to take the survey twice in a 2 to 4 week period. Analysis: We will measure the agreement between items in the physician and patient groups, and use items with high agreement in a Disability Severity Index.

  Study phs001295

• Genetics and Functional Studies of Autosomal Recessive Neurological Disorders

  Neurological conditions account for over 6% of the global disease burden. There are more than 600 neurological disorders, and cognitive dysfunction, also referred to as intellectual disability (ID), occupies a prominent position in this list. Cognitive dysfunction arises from the failure of neuronal cells to organize into a complex network and remodel this network in response to learning and experience. It is manifested by deficits in adaptive behaviors in everyday social and practical skills. Due to its high prevalence and the lifetime cost of care per individual, in the range of $1-2 million in United Sates (CDC), it presents a significant health burden. Genetic and functional studies of the genes and protein determinants of ID have helped to elucidate the molecular pathways of human brain development in health and disease. However, the identity of a large number of essential molecular and cellular components still remain elusive. The objectives of our study are to expand the genetic repertoire of causal ID genes and characterize their role in neuronal structure and cognitive function. The rationale is that identification and functional elucidation of causative gene variants that lead to cognitive dysfunction will be essential for understanding brain function and for developing improved diagnostic tools and efficacious preventive and therapeutic agents for neurological disorders, including ID. There are 3 aims of our comprehensive research program: 1) Ascertain and clinically phenotype members of extended families segregating autosomal recessive intellectual disability (ARID); 2) identify new ARID genes and gene products; and 3) determine the functions of prioritized novel ARID genes using multifaceted approaches, including analysis of spatiotemporal expression patterns in mouse brain, targeting in cultured rat hippocampal neurons, effects on cell morphology and synapse abundance, synaptic transmission and plasticity in neuronal cells by electrophysiology and live-cell imaging assays. The project will advantageously combine human clinical assessment, genetic and functional analyses relevant to brain development and function. Impact: Execution of the proposed studies will generate new knowledge that is clinically relevant, with high potential to impact ID molecular diagnosis, prognoses, and identify novel therapeutic targets to slow progression, delay onset, and possibly devising precision medicine approaches for ID.

  Study phs003298

• Geisinger Health System - MyCode, eMERGE III Exome Chip

  DNA samples were obtained from participants of the Geisinger MyCode biobank. Phenotype data to determine case or control status for abdominal aortic aneurysm or extreme obesity were derived from Geisinger electronic medical record data through an enterprise data warehouse. Samples were genotyped using the Illumina Human CoreExome-12 v1.0 Array. Genotype data were filtered using standard quality control measures.

  Study phs000957

• COVID Response Study 2 (COVRES-2)

  COVID Response Study 2 (COVRES-2) - is a collaborative effort between researchers at Ulster University and the Western Health and Social Care Trust. The study aims to identify temporal immune responses associated with COVID-19 severity. A total of n=20 individuals (10=Hospitalised/10=Non-hospitalised) were recruited following a positive PCR result for COVID-19. Current studies 1. Distinct Omicron longitudinal memory T cell profile and T cell receptor repertoire associated with COVID-19 hospitalisation At 3 months post-infection T Cell Receptor (TCR) sequencing and RNA Sequencing were preformed to investigate immunopathological signatures associated with clinical outcome and recovery. This dataset contains both TCR-seq and RNA-seq data for all participants that took part in this study.

  Dac EGAC50000000594

• cfDNA in health

  This study investigates baseline methylome and fragmentomic profiles in circulating cell-free DNA (cfDNA) from healthy individuals. Two cohorts were assembled: a diurnal cohort to evaluate temporal variation in cfDNA features, and a cross-sectional cohort to assess inter-individual variability. The project’s goal was to generate a reference dataset for plasma cfDNA to support future studies in biomarker discovery and disease detection.

  Study EGAS50000001209

• The Causes of Clonal Blood Cell Disorders Study - SCOR_Custom (2018-04-19)

  We took a bone marrow aspirate and peripheral blood samples from a healthy patient aged around 60, and use flow cytometry to isolate 100 HSCs, 50 MEPs, and 50 GMPs. We grew these up into colonies, then whole genome sequenced each colony. Somatic mutations act as a unique barcode for each clone. We have designed a panel for targeted resequencing of the mutations that we find. We are now looking for these mutations in the peripheral blood, to see the dynamics of how HSCs contribute to the peripheral blood in health. This dataset contains all the data available for this study on 2018-04-19.

  Dataset EGAD00001004087

• North American Mitochondrial Disease Consortium Patient Registry and Biorepository

  Mitochondrial diseases are caused by dysfunction of the mitochondria, which are specialized compartments that are present in every cell of the body except red blood cells. Mitochondria generate more than 90% of the energy that the body needs to sustain life and support growth. When they fail, less and less energy is generated within the cell. This injures the cell and can cause its death. If this process is repeated throughout the body, whole organ systems begin to fail, and the life of the person in whom this is happening is severely compromised. Mitochondrial diseases primarily affect children, but adult onset is becoming more and more common. Mitochondrial diseases are probably the most diverse human disorders at every level: clinical, biochemical, and genetic. Some affect only the nervous system but most affect many body systems, including the brain, heart, liver, skeletal muscles, kidney, and the endocrine and respiratory systems. Although mitochondrial disorders vary in severity, they are usually progressive, and often crippling. They can cause paralysis, seizures, mental retardation, dementia, hearing loss, blindness, weakness and premature death. Because of the range of symptoms and the frequent involvement of multiple body systems, mitochondrial diseases can be a great challenge to diagnose. Even when accurately diagnosed, they pose an even more formidable challenge to treat, as there are very few therapies and most are only partially effective. About this Study The first objective of this study is to establish a clinical registry of patients with suspected or confirmed mitochondrial diseases. We are collecting medical and family history, diagnostic test results, and prospective medical information for these patients and, using agreed procedures developed by the leading research clinicians in the field, providing, for the first time, standardized diagnoses of these complex disorders for the patients. The clinical information we collect from the participants will be used to learn about the spectrum of mitochondrial disorders and their prevalence. We will also develop studies which allow us to better understand how these diseases progress, which we do not understand well enough. When we begin clinical trials for mitochondrial diseases, patients enrolled in the registry who are identified as potentially eligible will be offered enrollment. Patients will only be included in studies if they give their consent in advance. The second objective of this study is to establish a biorepository for specimens and DNA from patients with mitochondrial diseases, in order to make materials easily available to consortium researchers.

  Study phs001538

• Assessing Neural Mechanisms of Injury in Inborn Errors of Urea Metabolism Using Structural MRI, Functional MRI, and Magnetic Resonance Spectroscopy

  Urea cycle disorders represent a group of rare inborn errors of metabolism that lead to accumulation of ammonia, a toxic product of protein metabolism. Individuals with urea cycle disorders cannot metabolize the ammonia that accumulates due to enzyme deficiency. The symptoms of these disorders may present at birth, childhood or adulthood (milder deficiencies). There are currently eight enzyme deficiencies that constitute the range of inborn errors of ureagenesis. This project will focus on the most common enzyme disorder of the urea cycle, ornithine transcarbamylase deficiency, inherited as an X-linked trait. This project will study cognitive and motor dysfunction in patients who are female carriers of ornithine transcarbamylase deficiency (OTCD) or are males with late onset presentation of OTCD, utilizing state of the art MRI (magnetic resonance imaging), a non -invasive technique. This project seeks to improve our understanding of the underlying neural mechanisms that contribute to metabolic, cognitive, sensory and motor abnormalities in urea cycle disorders, which although individually rare, collectively constitute a major cause of neonatal encephalopathy, leading to significant morbidity and mortality. As a result of this study, a greater understanding of the anatomic, cognitive, motor, and biochemical underpinnings of neurologic damage attributable to this metabolic disorder will be gained. Experimental approaches will combine sensory, cognitive and motor testing with structural, functional and molecular magnetic resonance imaging to study symptomatic and asymptomatic heterozygous female carriers of X-linked ornithine transcarbamylase deficiency (OTCD), and late onset hemizygous males. Participants to be included in the studies will range from ages 18-60 years and will be compared to an age-matched typically developed (TD) comparison group. For our research, we use anatomic MRI, functional Magnetic Resonance Imaging (fMRI), and magnetic resonance spectroscopy (MRS) to monitor brain activity. The technique of fMRI provides detailed maps of the brain areas underlying human mental activities. By using fMRI, we are able to observe how the brain is functioning while a person is performing a specific task, such as reading. We can not only observe differences in the structure of the brain, but can also measure differences in brain function and activity as well. This information will ultimately be used to provide a basis for designing more effective interventions and methods for early identification of learning disabilities in patients with OTCD and related disorders. We will also use MRS to study various brain chemicals such as glutamine using the non-invasive MRI imaging techniques.

  Study phs001108

• Genome-wide evaluation of the maturation of the immune response to the tuberculin skin test from day 2 to day 7

  The tuberculin skin test (TST) is a standardised human challenge model to evaluate the immune response to Mycobacterium tuberculosis (Mtb) antigens in vivo. To study the temporal evolution of the TST, we recruited healthy volunteers with evidence of peripheral blood Mtb reactive T cells, to undergo a TST in each arm that was sampled on day 2 at one site and on day 7 at the contralateral site on day 7. Genome-wide TST transcriptomes at day 2 and day 7 were defined by differential gene expression compared to transcriptomes from the site of control saline injections performed in a separate subset of volunteers.

  Study EGAS50000000822

• Multiomic spatial landscape of innate immune cells at central nervous system borders

  The innate immune compartment of the human central nervous system (CNS) is highly diverseand includes several immune cell populations such as macrophages that are frequent in the brain parenchyma (microglia) and less numerous at the brain interfaces as CNS-associated macrophages (CAMs).Due to their scantiness and particular location, little is known about the presence of temporally and spatially restricted CAM subclasses during development, health and perturbation. Here, we combined single-cell RNA-sequencing, time-of-flight mass cytometry and single-cell spatial transcriptomics with fate mapping and advanced immunohistochemistry to comprehensively characterize the immune system at human CNS interfaces. We also provide a comprehensive analysis of resident and engrafted myeloid cells in the brains of 15 individuals with peripheral blood stem cell transplantation, revealing compartment-specific engraftment rates across different CNS interfaces... Our results highlight myeloid diversity at the interfaces of the human CNS with the periphery and provide insights into the complexities of the human brain’s immune system.

  Study EGAS50000000030

• Genetic Study of Inflammatory Bowel Disease (IBD) in African Americans

  Association studies have previously identified 200 genome-wide significant (GWS) IBD susceptibility loci in European ancestry populations. At least thirty-five loci have been identified in Asians and a handful appear Asian specific. AAs have a higher risk for developing disease complications in IBD and worse disease outcome, suggesting that significant differences in pathological and molecular mechanisms may exist in AAs. It was therefore imperative to use more comprehensive genotyping platforms in more highly powered samples to detect AA-specific IBD loci and associations. We conducted two independent GWAS using a total of 2345 AA IBD cases and 5002 controls population from unrelated, self-identified AAs individuals. GWAS1 included 1258 IBD cases (843 CD, 368 UC, 47 IBD-U) and 1678 controls derived from the dbGaP Health and Retirement Study (phs000428). GWAS 2 included 1087 IBD cases (803 CD, 215 UC, 69 IBD-U) and 3324 controls obtained from the Kaiser RPGEH study (phs000788).

  Study phs001571

• Mitochondrial Abnormalities in Schizophrenia and Bipolar Disorder

  Mitochondrial DNA structural variation is one proposed indicator of mitochondrial dysfunction. The large common deletion of mitochondrial DNA (mtDNA) increases with aging across multiple brain regions. We found other large deletions of mtDNA in brain at levels comparable to the common deletion (PMID: 30869147). Since mtDNA molecules replicate independently of nuclear division, the mtDNA copy number is a measure of mitochondrial health; levels are negatively correlated with age and all-cause morbidity. Complex I activity is another functional measure of mitochondria. We previously published a subset of this data from DLPFC (PMID: 29594135) for three indicators (common deletion, mtDNA copy number, Complex I activity). For this study, four indicators (common deletion, large deletions, mtDNA copy number, Complex I activity) were measured in four brain regions from subjects with schizophrenia (SZ) and bipolar disorder (BD) and compared to controls. The four brain regions were: the dorsolateral prefrontal cortex, superior temporal gyrus, primary visual cortex (V1), and nucleus accumbens.&nbsp; &nbsp;&nbsp;

  Study phs002395

• RNA-Seq of PBMC's from rUTI Patients and Healthy Controls

  Recurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with and without history of rUTIs, from whom we collected urine, blood and monthly fecal samples for multi-omic interrogation. The rUTI gut microbiome was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions, though Escherichia coli gut and bladder dynamics were comparable between cohorts. Blood samples revealed signals of differential systemic immunity, leading us to hypothesize that rUTI susceptibility is in part mediated through a syndrome involving the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms. This work highlights the potential for microbiome therapeutics to prevent and treat rUTIs.&nbsp; (Reprinted from medrxiv.org&nbsp;)&nbsp;

  Study phs002728

• SEER Remote Access Pilot Test Data (2018)

  This is a limited use Surveillance, Epidemiology, and End Results (SEER) file for use in a pilot test of remote data access. The SEER Program of the National Cancer Institute (NCI) is an authoritative source of information on cancer incidence and survival in the United States. SEER currently collects and publishes cancer incidence and survival data from population-based cancer registries covering approximately 34.6 percent of the U.S. population. The SEER Program registries routinely collect data on patient demographics, primary tumor site, tumor morphology and stage at diagnosis, first course of treatment, and follow-up for vital status. The mortality data reported by SEER are provided by the National Center for Health Statistics. The population data used in calculating cancer rates is obtained periodically from the Census Bureau. The SEER research data files include SEER incidence and population data associated by age, sex, race, year of diagnosis, and geographic areas.

  Study phs002012

• Functional Dynamics of the Elderly Gut Microbiome During Probiotic Consumption

  A mechanistic understanding of the health benefits conferred by consumption of probiotic bacteria has been limited by our knowledge of the resident gut microbiota and its interaction with the host. We used fecal samples from a study of twelve healthy individuals aged 65-80 to characterize the structure and functional dynamics of the gut microbiota associated with consumption of the single-organism probiotic, Lactobacillus rhamnosus GG ATCC 53103 (LGG). Samples were collected prior to probiotic consumption (day 0), on day 28 immediately after consuming 10^10 CFU of LGG twice daily for 28 days and day 56, one month after stopping LGG consumption. Our integrative approach incorporated bacterial 16S rRNA gene sequencing, whole-community expression profiling using RNA-seq, and metagenomic sequencing. We highlight the value of combinatorial &#39;omics methods and concomitant high-resolution informatics to probe the role that probiotics may play on the structure and function of the resident microbiota.

  Study phs000896

• Immune Response to Life-Threatening Respiratory Infections in Children and Young Adults

  This is a cross sectional study describing age-related differences in the nasal mucosal immune response to SARS-CoV-2. We collected nasal mucosal samples from six groups: healthy children, children infected with SARS-CoV-2, children infected with respiratory syncytial virus, children infected with influenza virus, healthy adults, and adults infected with SARS-CoV-2. Samples were obtained by mucosal scrape biopsy of the inferior turbinate using a sterile plastic curette. We performed bulk RNA-sequencing to obtain gene expression data. Clinical data was extracted from the electronic health record including: demographics, medical history, clinical presentation, duration of symptoms, intensive care unit admission, hospital and intensive care unit length of stay, type and duration of respiratory support at sample collection and peak illness. Our analysis described the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compared it to the host response to respiratory syncytial virus and influenza virus.

  Study phs002579

• Genomic Profiling of Melanoma

  This study reports on genomic profiling [whole-exome sequencing (WXS), bulk RNA sequencing (RNA-seq), and/or single-cell RNA sequencing (scRNA-seq)] of patient-derived melanoma samples and matched normal samples. The goal is to elucidate the genetic and cellular basis of sun-exposed and sun-shielded melanomas and to relate these findings to survival and regional metastasis. Specimens were collected by the Tissue Resource Core of the Yale SPORE in Skin Cancer with participants' informed signed consent according to Health Insurance Portability and Accountability Act (HIPAA) regulations with a Human Investigative Committee protocol. The melanomas used for sequencing were from fresh or snap-frozen tumors, or from short-term cell cultures. The cell cultures were routinely checked for mycoplasma contamination and were discarded when found positive. Matching normal DNA was from circulating lymphocytes or normal skin. We also include 77 WES-sequenced samples from the Yale Spitzoid neoplasm repository, which collects specimen and data according to a protocol approved by the Yale Human Investigative Committee.

  Study phs000933

• NHLBI TOPMed: MWCCS: Sex Differences in the Role of Multi-Omics in HIV-Associated Carotid Artery Atherosclerosis

  The MACS-WIHS Combined Cohort Study (MWCCS) is a multicenter prospective cohort study of men and women in the U.S. that aims to understand and reduce the impact of chronic health conditions, including heart, lung, blood, and sleep (HLBS) disorders that affect people living with HIV. MWCCS, which currently has over 5000 active study participants, is designed to investigate a spectrum of questions relating to the basic science, clinical science, and epidemiology of HIV infection in the U.S., with a focus on comorbidities among men and women living with HIV. The current substudy, nested within the MWCCS, integrates detailed metabolomics and proteomics data, among other "omics" measures, to improve the understanding of the etiology of atherosclerosis and cardiovascular disease in women and men with HIV, guide mechanistic studies, and provide insights to more efficient intervention strategies. Data on 374 men are included in the current substudy.

  Study phs003651

• Single cell RNA sequencing of human embryonic forebrain after slice culturing for between four weeks and one month

  With the aim of verifying normal tissue development in our Organotypic Timelapse recording with Transcriptomic Readout (OTTR) live tissue imaging method, we performed single cell RNA sequencing in organotypic slice cultures containing labelled cells from virally delivered ubiquitous Enhanced yellow fluorescent protein (EYFP)-expression. Human fetal cortices of PCW 7.5-10.5 were cut into strips along the dorso-ventral axis and directly placed en face, ventricular side down, on PTFE culturing membranes. To assess tissue health with our culturing method, we performed single cell RNA-seq analysis of the cortical explants (using adjacent slices from the same samples subjected to timelapse imaging). We cultured these control slices for four days in vitro (mimicking the start of a live imaging experiment after lentiviral infection and expression of EYFP), 11 days in vitro (corresponding to the end of one week of live imaging), and for two weeks and one month in vitro.

  Study EGAS50000001185

• RNA_seq_of_Toxoplasma_gondii_response_in_human_macrophages

  Toxoplasmosis is a zoonotic disease caused by a ubiquitous protozoan parasite called Toxoplasma gondii, which caninfect all mammal and bird species throughout the world. seroprevalence varies widely between countries. Studieshave estimated that between 7-34% of people in the UK have been infected with T. gondii. The vast majority of thesepeople will not have noticed any symptoms, however about 10% of people develop a mild to moderate self limitingflu-like illness. Following the acute active stage of the infection the parasite persists in the body in the form of cysts,particularly in heart and skeletal muscle and nervous system tissues, for many years, and usually for life. Inimmunocompetent persons these cysts do not pose a health risk. We will use RNA-seq to quantify the transcriptionalresponse of macrophages to T gondii infection.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001708

• Whole Exome Sequencing of 60 tumor/normal matched liver Cancers (HCC)

  The French ICGC project on liver tumors is coordinated by Pr Jessica Zucman-Rossi and funded by Inca (French Institute for Cancer). The aim of the present project is to identify the catalog of somatic and germline mutations in liver tumors using whole genome (WGS) and whole exome sequencing (WGS), integrated with DNA methylation and RNA sequencing (RNA-seq) data. The present series corresponds to 60 whole exome tumor/normal pairs with matched RNA-seq. Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before.

  Study EGAS00001003063

• Autozygosity_pilot_Born_in_Bradford

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 20-50%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing cohort samples from the Born In Bradford study will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consist of low coverage whole exome sequencing on these samples.

  Study EGAS00001000462

• RNA-seq of Liver Cancer

  The French ICGC project on liver tumors is coordinated by Pr Jessica Zucman-Rossi and funded by Inca (French Institute for Cancer). The aim of the present project is to identify the catalog of somatic and germline mutations in liver tumors using whole genome (WGS) and whole exome sequencing (WGS), integrated with DNA methylation and RNA sequencing (RNA-seq) data. The present series corresponds to 161 RNA-seq samples from tumors with matched WES or WGS. Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before.

  Study EGAS00001002879

• Whole Genome Sequencing of HCC

  The French ICGC project on liver tumors is coordinated by Pr Jessica Zucman-Rossi and funded by Inca (French Institute for Cancer). The aim of the present project is to identify the catalog of somatic and germline mutations in liver tumors using whole genome (WGS) and whole exome sequencing (WGS), integrated with DNA methylation and RNA sequencing (RNA-seq) data. The present series corresponds to 24 whole genome sequencing (12 Tumoral/Non-tumoral pairs). Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before.

  Study EGAS00001002888

• SARS‐CoV‐2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells

  The SARS‐CoV‐2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID‐19 pathogenesis, especially host factors facilitating virus infection and replication. SARS‐CoV‐2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is strongly expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to RHO GTPase function and viral processes suggesting increased vulnerability for SARS‐CoV‐2 infection. Our data provide a rich resource for future investigations of COVID‐19 infection and pathogenesis.

  Study EGAS00001004419

• Coronary Artery Risk Development in Young Adults (CARDIA) Study - Cohort

  CARDIA is a study examining the etiology and natural history of cardiovascular disease beginning in young adulthood. In 1985-1986, a cohort of 5115 healthy black and white men and women aged 18-30 years were selected to have approximately the same number of people in subgroups of age (18-24 and 25-30), sex, race, and education (high school or less and more than high school) within each of four US Field Centers. These same participants were asked to participate in follow-up examinations during 1987-1988 (Year 2), 1990-1991 (Year 5), 1992-1993 (Year 7), 1995-1996 (Year 10), 2000-2001 (Year 15), 2005-2006 (Year 20), and 2010-2011 (Year 25); the proportions of the surviving cohort that have returned for the seven follow-up examinations were 90%, 86%, 81%, 79%, 74%, 72%, and 72%, respectively. In addition to the follow-up examinations, participants are contacted regularly for the ascertainment of information on out-patient procedures and hospitalizations experienced between contacts. Within the past five years, 95% of the original surviving cohort has been contacted. While the specifics of each examination has differed somewhat, data have been collected on a variety of factors believed to be related to heart disease. These include conditions with clear links to heart disease such as blood pressure, cholesterol and other lipids. Data have also been collected on physical measurements such as weight and skinfold fat as well as lifestyle factors such as substance use (tobacco and alcohol), dietary and exercise patterns, behavioral and psychological variables, medical and family history, and other chemistries (e.g., insulin and glucose). In addition, subclinical atherosclerosis was measured via echocardiography during Years 5, 10, and 25, computed tomography during Years 15 and 20, and carotid ultrasound during Year 20. The CARDIA Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000285 CARDIA Cohort. phs000236 PAGE_CALiCo_CARDIA phs000309 GENEVA_CARDIA phs000399 GO-ESP HeartGO_CARDIA phs000613 CARDIA_CARe

  Study phs000285

• A Genome-Wide Association Study in Patients Experiencing Breast Events While Receiving Adjuvant Aromatase Inhibitors for Early Breast Cancer on NCIC CTG Trial MA.27

  Source of patients:The source of the patients for this genome-wide case-control study was MA.27, which was conducted as a multi-cooperative group effort under the auspices of the NCI Breast Cancer Intergroup of North America. The NCIC Clinical Trials Group (CTG) serves as the coordinating group, with participation by the NCI-sponsored North Central Cancer Treatment Group, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group, and Cancer and Leukemia Group B (CALGB). MA.27 involved postmenopausal women with histologically confirmed and completely resected invasive breast cancer with surgical margins clear of invasive carcinoma in the following TMN categories (AJCC Version 6): pT1, pT2, pT3; pNx, pN0, pN1, pN2, pN3 (only when the sole basis is presence of 10 or more involved axillary nodes); MO. The primary tumor must have been estrogen receptor (ER) and/or progesterone receptor positive. Patients were stratified by lymph node status at diagnosis, prior adjuvant chemotherapy, and trastuzumab use and were randomized to 5 years of adjuvant therapy with anastrozole or exemestane. The trial was activated on May 26, 2003, and reached its accrual objectives on July 31, 2008, after the randomization of 6827 North American patients, with the majority (79%) providing DNA and consent for genetic testing. Non-North American patients were also entered by the International Breast Cancer Study Group but they did not contribute DNA. From 2003 to December 21, 2004, patients also underwent a second randomization to celecoxib 400 mg twice daily or placebo but, after the entry of 1,622 patients, this treatment was discontinued because of reports of increased cardiovascular risk associated with celecoxib. The final results of this study have been published, see Goss et al., 2013 (23358971). The patients in this analysis came from three cohorts: Cohort 1 consisted of 870 patients genotyped on the Illumina Human610-Quad BeadChip studied in a GWAS with the phenotype of musculoskeletal adverse event, see Ingle et al., 2010 (20876420), Cohort 2 consisted of 882 patients genotyped on the Illumina OmniExpress platform studied in a GWAS with the phenotype of fragility fractures, see Liu et al., 2014 (25148458), and the remaining 2913 patients were genotyped with the Illumina OmniExpressExome platform.

  Study phs001043

• Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study

  This data comes from a genome-wide association study in 1090 cases of scarring trachoma and 1531 controls from a non-selected multi-ethnic sampling of The Gambia. The data constitutes hard base calls at 1457295 features from the HumanOmni2.5-8 (Omni2.5) BeadChip. Three genotype-calling algorithms were used : Illuminus (Bioinformatics 2007, 23:2741–6), GenCall (Patent US7035740, 2006) and GenoSNP (Bioinformatics 2008, 24:2209–14). Data from each calling algorithm was filtered to retain only SNPs with a call rate ≥ 0.98. To obtain a merged set of SNPs, all genotypes that matched across call-sets were retained, whilst those that mismatched between call-sets were set to missing. Genotypes that were present in one call set and missing in others were also retained. The merged SNP set contained 1467876 SNPs, which were filtered for call rate ≥ 0.99 and Hardy-Weinberg equilibrium P value &lt; 5 x 10-8. The case and control groups were approximately equivalent with respect to gender and ethnicity. 70% of cases and 63% of controls were female. Self-described ethnic composition of the cases was 29% Jola, 27% Mandinka, 21% Wolof, 10% Fula and 13% other/no data. In controls the composition was 25% Jola, 24% Mandinka, 21% Wolof, 8% Fula and 22% other/no data. Median age was 49 (range 32-60) in cases and 37 (range 12-52) in controls (t = -3.6019, P = 0.0003). This data set has substantial levels of population structure, which reflects extensive networks of pairwise kinship between participants. First pass tests of association in EMMAX (Nat Genet 2010, 42:348–54) led to genome-wide deflation of the test statistics (λ = 0.982 SE = 1.74e-05) that could be directly attributed to the differing age and gender distributions between cases and controls. Modelling the phenotype to adjust for age and gender successfully controlled for this and no genome-wide deviation from the null was subsequently observed (λ = 1.001, SE = 8.7 x 10-7). Neither principal components analysis (PCA) nor tests of proportional identity by state (IBS) variance in PLINK identified significant levels of within or between group genetic variance. The phenotypes submitted in the phenotypes file include both uncorrected (case/control status) and corrected (age and gender corrected case/control status) phenotypes, as well as age and self-described ethnicity.

  Study EGAS00001001516

• National Eye Institute (NEI) Age-Related Eye Disease Study (AREDS)

  The Age-Related Eye Disease Study (AREDS) was initially designed as a long-term multi-center, prospective study of the clinical course of age-related macular degeneration (AMD) and age-related cataract. In addition to collecting natural history data, AREDS included a clinical trial of high-dose vitamin and mineral supplements for AMD and a clinical trial of high-dose vitamin supplements for cataract. AREDS participants were 55 to 80 years of age at enrollment and had to be free of any illness or condition that would make long-term follow-up or compliance with study medications unlikely or difficult. On the basis of fundus photographs graded by a central reading center, best-corrected visual acuity and ophthalmologic evaluations, 4,757 participants were enrolled in one of several AMD categories, including persons with no AMD. The clinical trials for AMD and cataract were conducted concurrently. AREDS participants were followed on the clinical trials for a median time of 6.5 years. Subsequent to the conclusion of the clinical trials, participants were followed for an additional 5 years and natural history data were collected. The AREDS research design is detailed in AREDS Report 1. AREDS Report 8 contains the mainline results from the AMD trial; AREDS Report 9 contains the results of the cataract trial. Blood samples were also collected from 3,700+ AREDS participants for genetic research. Genetic samples from 600 AREDS participants (200 controls, 200 Neovascular AMD cases, and 200 Geographic Atrophy cases) were selected using data available in March 2005 and then were evaluated with a genome-wide scan. These data, as well as selected phenotypic data, were made available in the dbGaP. DNA from AREDS participants, which is currently being stored in the AREDS Genetic Repository, is available for research purposes. However, not all of the 3,700+ AREDS participants who submitted a blood sample currently have DNA available. In addition to including the data from the genome-wide scan on the 600 original samples, this second version of the AREDS dbGaP database provides a comprehensive set of data tables with extensive clinical information collected for the 4,757 participants who participated in AREDS. The tables include information collected at enrollment/baseline, during study follow-up, fundus and lens pathology, nutritional estimates, quality of life measures and measures of morbidity and mortality. In November 2010, over 72,000 high quality fundus and lens photographs of 595 AREDS participants (of the original 600 selected for the genome-wide scan) were made available in the AREDS dbGaP. In addition to the genome-wide scan data, the fundus and lens grading data for these participants are also available through the AREDS dbGaP. Details about the ocular photographs that are available may be found in the document "Age-Related Eye Disease Study (AREDS) Ocular Photographs". In January 2012, a measure of daily sunlight exposure was added in a separate &#34;sunlight&#34; table. Furthermore, the &#34;followup&#34; table has been revised. The visual acuity for the right eye was inadvertently missing at odd-numbered visits (01, 03, 05, etc.). This data is now part of the table. In February 2014 over 134,500 high-quality fundus photographs (macular field F2) of 4613 AREDS participants were added to the existing AREDS dbGaP resource. The AREDS dbGaP image archive already contains over 72,000 high quality fundus and lens photographs of 595 AREDS participants for whom dbGaP-accessible genotype data exist. Information about the available ocular photographs found in the document "Age-Related Eye Disease Study (AREDS) Ocular Photographs" has been updated with an addendum. It is hoped that this resource will better help researchers understand two important diseases that affect an aging population. These data may be applied to examination and inference on genetic and genetic-environmental bases for age-related diseases of public health significance and may also help elucidate the clinical course of both conditions, generate hypotheses, and aid in the design of clinical trials of preventive interventions. Definitions of Final AMD Phenotype Categories Please see phd001138.1 for a detailed description of how AREDS participants&#39; final AMD phenotype was categorized. User&#39;s Guide for AREDS Phenotype Data A detailed User&#39;s Guide for the AREDS phenotype data is available. This User&#39;s Guide is meant to be a comprehensive document which explains the complexities of the AREDS data. It is recommended that all researchers using AREDS phenotype data make use of this User&#39;s Guide.

  Study phs000001

• FEGA and European GDI: working together to improve human health

  The Federated EGA is a global resource for discovery of and access to sensitive human omics and associated data consented for secondary use, through a network of human data repositories to accelerate biomedical research and improve human health. The Federated EGA network was launched in September 2022 with five inaugural nodes, and since 2023 seven operational nodes can share data across national borders in adherence to European and national laws. A few weeks after FEGA's official launch, in November 2022, the European Genomic Data Infrastructure (GDI) project was kicked-off . This European Commission co-funded project, coordinated by ELIXIR, is aimed to deliver federated, sustainable and secure data infrastructure to access genomic and related phenotypic and clinical data across Europe. This project supports the aim of the 1+MG initiative (25 EU countries, Norway and UK) to enable personalised medicine and health through a shared framework and infrastructure for securely accessing and integrating high quality genomic data and other health data across borders.1+MG will be an integral component of the European Health Data Space (EHDS) for secondary use (Healthdata@EU) as an authorised participant. How are Federated EGA and GDI similar? Given their shared visions, the Federated EGA and European GDI networks have a lot in common. To begin, they share the same overall goal of establishing networks of “nodes” that host sensitive human data within a jurisdiction and connecting these nodes in a global network to support data discovery and promote human genome data access for research and healthcare. FEGA and GDI are both initially focused on enabling access to human genomic data, while FEGA ambition is to expand the scope to clinical research data and other omics data in the future. FEGA and GDI are both built on open and interoperable software solutions, a subset of which are based on the LocalEGA components. FEGA and GDI implementation solutions are based on international community standards, for example those developed by the Global Alliance for Genomics and Health, which contributes to making them interoperable. Both FEGA and GDI allow for the nodes to make use of any solution that is fully compatible. As illustrated in Figure 1, a final key point is the significant overlap of institutions involved in envisioning and operating FEGA and GDI nodes, with the clear wish to keep them interoperable in the future. What distinguishes Federated EGA from GDI? Despite being largely similar, there are some differences between the FEGA and GDI networks, which we aim to clarify in this post. The first difference is the governance model that the nodes will operate to comply with national laws and GDPR. In the FEGA network, nodes have taken inspiration from the EGA data access model, where the infrastructure is a data processor of the hosted data and data controllership remains with the originating Data Access Committees (i.e. Data controllers) for each dataset. On the other hand, in the GDI network the controllership of datasets will be transferred to a 1+MG European Digital Infrastructure Consortium (EDIC) legal entity created by the Member States (MS), who will make data access decisions, with data holders having veto powers for their datasets. Importantly, FEGA nodes have the flexibility to choose another model to fit with their data protection framework, including becoming data controllers for their datasets. The second difference is the inclusion criteria for data. While FEGA nodes are designed to accept almost any type of omics data in need of control access (e.g. genomics, transcriptomics, genotyping, single cells sequencing, patient-tracked metagenomics), GDI nodes are initially, but not only, focused on accepting whole genome and exome sequencing data and affiliated data from sources such as (i) the Genome of Europe use case of the 1+MG initiative which specifically aims to fulfil the mission of building “a European network of national genomic reference cohorts of at least 500,000 citizens”) (ii) data collection of other types of genomic data identified by countries through the 1+MG dashboard and (iii) genomic data coming from data holders which would need to fulfil EHDS requirements. The third difference is the maturity of the software stacks. The FEGA network provides a set of software for data and metadata submission, storage, permissions management, and file distribution (the LocalEGA package). GDI is building a complete set of open source reference for the five functionalities covering the full data life cycle (a few more compared to the LocalEGA) including federated processing (analytics, AI/ML), which is still under active development. Notably, one of the GDI functionalities - storage and interfaces - can be satisfied by using the LocalEGA storage solution, highlighting the ability of FEGA and GDI to be interoperable. In both FEGA and GDI, nodes are allowed to use alternative solutions as long as they are fully interoperable with the networks. Figure 1 provides a simple overview of these described commonalities and differences. Figure1: schematic overview of the main commonalities and difference among a FEGA and a GDI node Can the same institute run a FEGA and a GDI node at the same time? The answer is Yes! We believe this is entirely possible and encouraged. As long as 1+MG requirements are continuously fulfilled in the implementation. The same trained personnel could operate the infrastructure and leverage the same national funding to run a FEGA and a GDI node. Several European nodes, especially GDI vanguard nodes like Norway, Sweden, Finland and Spain are following this model. The idea is that a lot of the work can be reused, given the overlapping scope and the interoperable technology. Thus, the hosted datasets can be discovered via the two catalogues, perhaps accessible under the same or different governance models. From a FEGA node perspective, the GDI datasets could simply be a subset of the datasets hosted in the FEGA node, which have their specific governance as any other. What's next? So, the amazing teams of people building the Federated EGA network and the European GDI network are working together to create infrastructures able to provide secure access to human genomic and associated data around Europe. Because we all know how much human genomics can improve healthcare and precision medicine. And we all want to collaborate to make it happen. This article has been reviewed collectively by members of the EGA and the GDI coordination team.

  Blog fega-and-gdi

• Harnessing the Electronic Health Record to Predict Risk of Cardiovascular Disease: Sangre Por Salud (SPS) Biobank GWAS Data

  These data are from subjects in the Sangre Por Salud (SPS) Biobank, a Latino population from the Southwest United States. Subjects were genotyped in 2 batches on the Illumina Multi-ethnic Global Array. Data from this study were used for testing a new cardiovascular risk score and evaluating polygenic risk scores. SPS biobank GWAS data is available on 3699 subjects.

  Study phs003553

• Collagen Proteostasis in Health and Disease

  This study uses human iPSC-derived cartilage to investigate the effects of the p.Arg719Cys mutation in the COL2A1 gene, which is linked to precocious osteoarthritis. Using a CRISPR-edited isogenic cell line pair, we compared wild-type and mutant cartilage for matrix defects and cellular stress responses. We performed RNA-sequencing and quantitative proteomics to characterize changes in gene expression, protein interactions, and collagen folding.

  Study phs004112

• November 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  November 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001007529

• Mechanism of Action of Vitamin E in NAFLD

  We conducted a single-center prospective mechanistic randomized trial (clinicaltrials.gov NCT01792115). Adult patients with NAFLD were enrolled between May 2013 and November 2016. All patients underwent a 12 weeks run-in period of lifestyle intervention. Following the run-in phase, patients underwent a baseline evaluation including blood tests, glucose tolerance testing, measurement of liver fat content by 1H-magnetic resonance spectroscopy (MRS) and a percutaneous liver biopsy. Patients with no evidence of NAFLD on the entry liver biopsy ended their participation in the study at that point. Patients with histological confirmation of NAFLD (either NAFL or NASH) on the baseline biopsy were randomized at a 1:1:1 ratio to receive one of 3 doses of natural vitamin E (RRR-alpha-tocopherol, Pharmavite), 200, 400 or 800 IU/d, for 24 weeks, and were followed at a 1-8 week intervals in a parallel assigned design. While on vitamin E treatment, patients were encouraged to continue and adhere to the lifestyle and dietary guidelines of the run-in phase. On week 4 of vitamin E treatment, a repeat MRS and liver biopsy were performed. On week 24, a final MRS was performed to assess treatment response. The primary endpoint was the reduction of liver fat content by MRS from baseline (immediately prior to starting vitamin E) to week 24 of treatment, and a response was defined as a relative reduction of &#8805;25% in liver fat content by MRS between baseline and week 24. Early changes in the hepatic transcriptome were investigated at week 4 comparing non-responders to responder in a nested design.

  Study phs001930

• Type 1 Diabetes Genetics Consortium (T1DGC): Copy Number Variant (CNV) Study

  Type 1 Diabetes Genetics Consortium (T1DGC) was formed to address issues of limited sample size and consistency of phenotyping that had limited genetic investigations on risk of type 1 diabetes (T1D). The T1DGC first collected affected sib pair (ASP) families from four geographic networks (Asia-Pacific, Europe, North America, United Kingdom). In addition, T1D parent-offspring trios as well as cases and controls were ascertained from existing and de novo collections. For T1D, the genome-wide association study (GWAS) design has been successful at detecting ~50 loci that contribute disease risk. However, in the case of T1D as well as almost all other traits, the sum of these loci does not fully explain the heritability estimated from familial studies. One possibility for the undiscovered contribution to familial aggregation is that additional variants exist but have not yet been found because they have not effectively been targeted by the GWAS design. In this study, we focus on a specific class of large deletions/duplications -- copy number variants (CNVs) - and particularly to the subset of these loci that mutate rapidly, are not tagged by SNPs, and are highly polymorphic. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, that were eligible for this study. All samples included in this series have reported or self-declared European ancestry. All DNA samples were collected after approval from relevant institutional research ethics committees. Importantly, the source of DNA for CNV evaluation was uniform within a family (either all from PBMC or from EBV-transformed cell lines). We use a family based design that was optimized to capture these previously untested variants. We then perform a genome-wide scan to assess their contribution to T1D.

  Study phs000910

• Discovery and validation of an ancillary genomic test of malignancy for primary melanocytic tumors

  Background:Pathological diagnosis of melanocytic tumors can be difficult and prone to error. More accurate and reliable ancillary investigations than those currently available are required to improve diagnostic accuracy. Goals: (1) to generate a genomic model for distinguishing benign (nevi) from malignant (melanoma) melanocytic skin tumors, developed from a customized gene panel evaluated on a cohort of 250 nevi and melanomas. (2) To evaluate the performance of the genomic model in melanocytic tumors of uncertain diagnosis/behavior. Details: The cohort of 250 melanomas and naevi was split into a discovery set and a validation set. Our genomic model obtained an area under the curve of 95% in the discovery cohort and 96% for the validation cohort. Based on a Youden index threshold, the resulting classifier shows high specificity (>95% in the discovery and validation cohorts), with sensitivities >80% in the discovery and validation cohorts. Evaluation of the genomic model on a cohort of 110 melanocytic tumors identifies key driver mutations in agreement with the likely pathway of origin of the tumors. The probability of melanoma (p=0.02) from the genomic model was significantly associated with pathology-based estimates of malignancy for melanocytic tumors lacking pathway-defining genomic aberrations (conventional tumors). The genomic model identified 8/36 (22%) conventional tumors with unresolved malignancy to have a high probability of melanoma, with 7/8 of these cases showing negative/non-aberrant results with either fluorescent in-situ hybridization, PRAME and/or p16 immunostains. Furthermore, no evidence of malignant behavior based on the genomic model was seen in 4 conventional borderline tumors with more than 1 year follow-up. Conclusion: This genomic model can become a clinically useful ancillary tool that is highly specific for differentiating melanomas from nevi.

  Study EGAS50000000887

• Combined MEK and BCL-2/XL inhibition is effective in high-grade serous ovarian cancer patient-derived xenograft models and BIM levels are predictive of responsiveness

  Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, thus making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft (PDX) models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the pro-apoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/XL inhibitor (ABT-263) significantly reduced cell number, increased cell death and displayed synergy in vitro in most models. In vivo, the GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive models – those with high BIM at baseline that was increased with MEK inhibition and those with low basal Bim and high pERK levels. Models with low BIM and low pERK were non-responsive. Our findings demonstrate that combined MEK and BCL-2/XL inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.

  Study EGAS00001003427

• Circulating Tumor DNA in Checkpoint Inhibitor treated Lung Cancer

  BackgroundImmune checkpoint inhibitors (ICI) are increasingly used to treat non-small cell lung cancer (NSCLC) and there is a critical need for novel predictive/prognostic biomarkers. We evaluated whether dynamics of circulating tumor (ctDNA) can identify NSCLC patients who benefit from single agent ICI.MethodsCirculating cell-free DNA (cfDNA) from 177 patients was analyzed prior ICI and at first treatment evaluation using a Commercial 77-gene panel. We performed de novo mutation calling and corrected for variants related clonal hematopoiesis. ctDNA changes were evaluated as predictors of tumor response estimated with PET/diagnostic CT and survival.ResultsMutations were detected in 159 of 174 (91.4%) analyzable patients. Most responders presented decreasing ctDNA levels, while non-responders had mixed molecular responses. Patients with a &gt;50% molecular ctDNA decrease or no detectable ctDNA demonstrated improved PFS (5.9 versus 1.8 months; HR 0.49, 95%CI, 0.35-0.67, P &lt; .001), and OS (18.9 versus 9.9 months; HR 0.41, 95%CI, 0.30-0.57, P &lt; .001) compared to patients not achieving these endpoints. Clearance of mutations (and no detected ctDNA) had a similar effect (PFS HR 0.45, 95%CI, 0.32-0.61, P &lt; .001; OS 0.37,95%CI, 0.27-0.52, P &lt; .001) compared to patients having stable or additional mutations. After adjusting for clinical factors both &gt;50% ctDNA decrease (HR 0.4, 95% CI, 0.3-0.6, P &lt; .001) and clearance of mutations (HR 0.42, 95% CI, 0.3-0.6, P &lt; .001) remained independent predictors for PFS and OS.ConclusionsctDNA testing reveals significant prognostic albeit not predictive information in ICI treated advanced NSCLC. This relevant information can be obtained with a commercial easy-to-implement ctDNA test that will facilitate extensive testing.

  Study EGAS00001004847

• Characterization of DLBCL with a PMBL gene expression signature

  Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typicallyaffects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas withgene expression features of PMBL have been described in non-mediastinal sites, raising questions abouthow these tumors should be classified.Here, we investigated whether these "non-mediastinal PMBLs" are indeed PMBLs or instead represent adistinct group within DLBCL. From a cohort of 325 de novo DLBCL cases, we identified tumors frompatients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature(nm-PMBLsig-pos, n=16, 5%). The majority of these tumors expressed MAL and CD23 – proteins typicallyobserved in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig-pos cases revealedclose associations with DLBCL, and the majority displayed a germinal center B-cell-like cell-of-origin(GCB). In contrast to bf-PMBL, nm-PMBLsig-pos patients presented at an older age, did not show pleuraldisease, and bone/bone marrow involvement was observed in three cases. However, while clinicallydistinct from bf-PMBL, nm-PMBL-sig-pos tumors resembled bf-PMBL at the molecular level with upregulationof immune response, JAK-STAT, and NF-kB signatures. Mutational analysis revealed frequent somatic genemutations in SOCS1, IL4R, ITPKB and STAT6, as well as CD83 and BIRC3, with the latter genes beingsignificantly more frequently affected than in GCB-DLBCL and bf-PMBL.Our data establish nm-PMBLsig-pos lymphomas as a group of DLBCL with distinct phenotypic and geneticfeatures, and potential implications for gene expression- and mutation-based subtyping of aggressive Bcell lymphoma and related targeted therapies.

  Study EGAS00001005057