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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

• DNA methylation database for gynecological cancer detection, classification and assay development

  MeD-seq data (fastq files) from gynecological cancers and associated healthy tissues. In total 292 fastq files generated by MeD-seq are deposited consisting of: healthy tissues (vulva n=11, cervix n=15, endometrium n=13, fallopian tube n=18 and ovary n=13), precursor lesions of cancer (vulva n=23 and cervix n=46) and cancer (vulva n=21, cervix n=45, endometrium n=26, fallopian tube n=8 and ovary n=33)

  Dataset EGAD50000000611

• Mitochondrial DNA sequencing of human iPSC, parental cells, and iPSC derived cardiomyocytes

  Dataset contains whole mitochondrial DNA sequencing data in fastq format (Illumina MiSeq paired-end) of 62 samples, in total. Those samples include sequencing data of the endothelial cell populations of 10 different donors and of 26 early-passage iPSC clones derived thereof. Moreover, the dataset contains the data of 7 of those iPSC clones sequenced additionally in passage 30 and 50, each. Lastly, 4 iPSC clones were sequenced during directed cardiomyocyte differentiation, each at day 0, 5, and 15 of differentiation.

  Dataset EGAD00001008021

• Regulatory T cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors

  Tregs were sorted as CD4+CD25+CD127- cells from peripheral blood of patients with advanced metastatic melanoma, stage III(B-D)-IV, who were receiving treatment with anti-PD1 (n =26); and patients with kidney, non-small cell lung, liver and bladder cancer who were receiving treatment with anti-PD1. RNA was extracted and polyA libraries were prepared using the Illumina Truseq sample preparation kit v.2. Single-end sequencing was performed on NextSeq500.

  Dataset EGAD00001006415

• BLUEPRINT release August 2016, ChIP-Seq for band form neutrophil, on genome GRCh38

  ChIP-Seq data for 4 band form neutrophil sample(s). 26 run(s), 23 experiment(s), 23 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002454

• Childhood Cancer Data Initiative (CCDI): Molecular Characterization Initiative

  The National Cancer Institute's (NCI) Childhood Cancer Data Initiative (CCDI) focuses on the critical need to collect, analyze, and share data to address the burden of cancer in children, adolescents, and young adults (AYAs). The Molecular Characterization Initiative (MCI) will further the CCDI's goals by providing access to better diagnostic tests for pediatric and AYA patients. The molecular characterizations of solid tumors, soft tissue sarcomas, and rare diseases are performed in a CLIA-certified setting as results may be used to screen for and/or confirm clinical trial eligibility, direct treatment, or otherwise contribute to the conduct of the trial. The following molecular characterization assays were performed:Tumor/Normal Whole Exome sequencing Methylation arraysArcher fusion panel Deidentified clinical reportsNote: New data will be added periodically, please check the CCDI Hub Explore site for updates.

  Study phs002790

• High coverage target resequencing of coding and regulatory regions of 38 Parkinson disease genes associated either to the Mendelian or the sporadic forms of the disease

  Coding sequences and putative regulatory sequences (retrieved from Ensembl and including up to 2500 bp of promoter sequence upstream the transcription start site) were re-sequenced to a mean depth of 49X on 38 genes associated to Parkinson's disease (RAB25, NUCKS1, RAB7L1, GBA, SYT11, ACMSD, STK39, MCCC1, STBD1, GAK, DGKQ, BST1, SCARB2, HLA-DRB5, GPNMB, FGF20, ITGA8, HIP1R, STX1B, SETD1A, SREBF1, MED13, RAI1, MAPT, RIT2, GIGYF2, HTRA2, EIF4G1, SNCA, LRRK2, VPS35, PINK1, DJ1, ATP13A2, UCHL1, PARK2, FBXO7, and PLA2G6). Sequencing was performed on 249 Parkinson's idiopathic cases and 145 unrelated controls of Spanish origin. All sequencing data was generated with an Illumina Hiseq2000 instrument after enrichment with a custom NimbleGen array. Raw reads were mapped to human reference genome hg19/GRCh37 using BWA aligner.

  Study EGAS00001000973

• 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

• MYO5B mutations in Pheochromocytoma/Paraganglioma promote cancer progression

  Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status.Immunohistochemistry and mRNA expression analysis in 30 primary PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic tumor cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmatic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a PGL case harboring a MYO5B:p.G1611S mutation. Mutation analysis of additional PPGL tumors revealed additional, and hence recurrent, mutations in the paralog MYO5A. Three missense mutations in MYO5B were functionally studied using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293 cell line). Functional analysis of the mutants verified a significant increased proliferation rate in all MYO5B mutated clones (p.L587P, p.G1611S, and p.R1641C). The two somatically derived mutations p.L587P and p.G1611S were also found to increase the migration rate, and all three mutants affected intracellular transport by increased transferrin uptake. Downstream expression analysis of MYO5B mutants demonstrated a transcriptional activation of genes involved in glucose metabolism, proliferation, homeostasis, and migration. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved the malignant progression of PPGL tumors.

  Study EGAS00001003991

• De Novo Mutation Rates at the Single-Mutation Resolution in the Human Genome

  We developed a method to measure the origination rates of target mutations of choice and applied it to the HbS and nearby mutations in the human beta-globin (HBB) gene, as well as to the equivalent mutations in the nearly identical delta-globin (HBD) gene in sperm cells from African and European donors. Specifically, after extracting DNA from the sperm of the donors, each sample is enriched for the HbS mutation and nearby mutations by the restriction enzyme Bsu36I, which cleaves the wild-type (WT) sequence CCTGAGG at positions 16–22 of HBB and the homologous positions of HBD while leaving the HbS mutant and other mutants in these positions intact. Next, unique barcodes are attached to the DNA fragments from these Bsu36I-treated samples in order to reduce error by consensus sequencing of copies originating from the same original fragment. To determine how many target WT sequences have been removed (scanned) by Bsu36I digestion and hence to be able to calculate the de novo mutation rate, we run a second reaction in parallel for each donor. This reaction involves the same steps as the former reaction except for digestion by Bsu36I (Bsu36I-untreated). Spiking into the Bsu36I-treated and untreated samples known amounts of mock HBB-like DNA molecules that are fully resistant to Bsu36I digestion allows to calculate in the sequence analysis stage the Bsu36I-enrichment score based on the change in their frequency between the two treatments, which in turn is used to calculate the number of scanned WT sequences. Our results show significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than Europeans in the HBB region studied. Finally, the rate of the 20A>T mutation, called the “HbS mutation” when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations, and no instances were observed in the European HBB ROI or in the European or African HBD ROI.12 consented subjects; samples from two subjects were pooled

  Study phs002391