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• Sequencing data for CLL patients

  Single-cell RNA-sequencing and other genome-wide approaches were applied to a cohort of CLL patients receiving Venetoclax treatment to study mechanisms of resistance.

  Study EGAS00001005815

• Neuroblastoma Evolution

  Here, we quantify the somatic evolution of neuroblastomas by deep (80x) whole-genome sequencing, molecular clock analysis and population-genetic modeling in a comprehensive cohort (Hipo_K09R) covering all subtypes.

  Study EGAS00001006533

• IFNL4 Organoid Transcriptome Profiles

  RNAseq of liver organoids with a dG genotype (B20, nt115, U15) and with a TT genotype (nt5, U16, U19) was performed, which was used to study the impact of IFNλ4 on the cellular response to Sendai viral infection.

  Dataset EGAD00001007820

• sn-RNAseq profiling of the impact of a cytokine storm model in human cardiac organoids

  sn-RNAseq profiling of the impact of a cytokine storm model in human cardiac organoids

  Dataset EGAD00001007533

• Exome sequencing of 3 blood samples from tall man and his parents

  Exome sequencing was carried out in a tall male (height 3.5 SDS) and his parents (3 samples). The data was sequences on a Illumina Hiseq2000 and the library was prepared with Agilent SureSelect V4.

  Dataset EGAD00001007767

• FACS-based purification and paired-end RNA sequencing

  We performed a prospective investigation in Sézary syndrome by the application of a standardized multiparameter flow cytometry, FACS-cell sorting, and RNA-sequencing for an in-depth immunophenotypic and transcriptional profiling of Sézary cells.

  Dataset EGAD00001007687

• In this study single cell RNA-Seq data was used to train a deconvolution algorithm. The algorithm was validated on paired bulk RNA-Seq profiles.

  In this study single cell RNA-Seq data was used to train a deconvolution algorithm. The algorithm was validated on paired bulk RNA-Seq profiles.

  Dataset EGAD00001009688

• Transcriptomics sequencing 4 samples from the same KMT2A-rearranged Acute Lymphoblastic Leukemia patient

  Dataset contains four samples taken from a neonate with congenital KMT2A-rearranged Acute Lymphoblastic Leukemia patient (CHI-0391) with rare IKZF1 gene fusions. Sequencing was carried out using mRNA-seq sequencing on a Illumina NextSeq 500 machine

  Dataset EGAD00001009974

• WGS

  Purified DNA from PDX samples were subjected to WGS. Libraries were performed using the TruSeq DNA PCR-Free kit (Illumina) starting with 1μg of input DNA and performed following manufacturer's instructions. Libraries were sequenced on a NovaSeq 6000 (2x151 bp) instrument (Illumina). A mean coverage of 30.4x was obtained.

  Dataset EGAD00001010309

• Whole Exome Sequencing of a Melanoma Patient with Acquired Resistance to MEK plus CDK4/6 Inhibition

  Longitudinal biopsies from a melanoma patient who initially responded to MEK plus CDK4/6 inhibitor therapy were whole exome sequenced to identify potential resistance mutations. The biopsies included normal tissue, pre-treatment, on-treatment, and several post-resistance timepoints.

  Dataset EGAD00001003989

• Exome sequencing files for "A single mutant clone populates the pancreatic ductal system to generate coexisting neoplastic lesions"

  Files from whole exome sequencing of eight tumors from eight pancreatic cancer patients along with matched PanIN precursor lesion(s) and a matched normal tissue.

  Dataset EGAD00001004044

• BRIDGE SPEED April 2016

  Whole genome sequencing CRAM files for four samples from the BRIDGE Consortium (SPEED project) with pathogenic variants in a gene associated with a movement disorder.

  Dataset EGAD00001002070

• Carcinoid study - WGS dataset

  Fernandez-Cuesta et al., 2014, Nature Communication, Whole genome sequencing was performed using a read length of 2x100 bp for all samples. On average, 110 Gb of sequence were produced per sample, aiming a mean coverage of 30x for both tumour and matched normal.

  Dataset EGAD00001000813

• BLUEPRINT: A human variation panel of genetic influences on epigenomes and transcriptomes in three immune cells (WGS)

  BLUEPRINT: A human variation panel of genetic influences on epigenomes and transcriptomes in three immune cells (WGS)

  Dataset EGAD00001002663

• Osteoporotic Fractures in Men (MrOS)

  The Osteoporotic Fractures in Men Study (MrOS) is a multi-center prospective, longitudinal, observational study of risk factors for vertebral and all non-vertebral fractures in older men, and of the sequelae of fractures in men. The original specific aims of the study include: (1) to define the skeletal determinants of fracture risk in older men, (2) to define lifestyle and medical factors related to fracture risk, (3) to establish the contribution of fall frequency to fracture risk in older men, (4) to determine to what extent androgen and estrogen concentrations influence fracture risk, (5) to examine the effects of fractures on quality of life, (6) to identify sex differences in the predictors and outcomes of fracture, (7) to collect and store serum, urine and DNA for future analyses as directed by emerging evidence in the fields of aging and skeletal health, and (8) define the extent to which bone mass/fracture risk and prostate diseases are linked. The MrOS study population consists of 5,994 community dwelling, ambulatory men aged 65 years or older from six communities in the United States (Birmingham, AL; Minneapolis, MN; Palo Alto, CA; Monongahela Valley near Pittsburgh, PA; Portland, OR; and San Diego, CA). Inclusion criteria were designed to provide a study cohort that is representative of the broad population of older men. The inclusion criteria were: (1) ability to walk without the assistance of another, (2) absence of bilateral hip replacements, (3) ability to provide self-reported data, (4) residence near a clinical site for the duration of the study, (5) absence of a medical condition that (in the judgment of the investigator) would result in imminent death, and (6) ability to understand and sign an informed consent. To qualify as an enrollee, the participant had to provide written informed consent, complete the self-administered questionnaire (SAQ), attend the clinic visit, and complete at least the anthropometric, DEXA, and vertebral X-ray procedures. There were no other exclusion criteria. The baseline examination was completed over a 25-month period from March 2000 to April 2002. Participants completed questionnaires regarding medical history, medications, physical activity, diet, alcohol intake, and cigarette smoking. Objective measures of anthropometric, neuromuscular, vision, strength, and cognitive variables were obtained at a clinic visit. Skeletal assessments included DEXA, calcaneal ultrasound, and vertebral radiographs. Vertebral and proximal femoral QCT was performed on a subset (65%) of participants. Serum, urine, and whole blood specimens were collected. During the study period, participants complete a tri-annual questionnaire every four months that obtains information concerning the occurrence of incident falls and fractures. Follow-up is over 99% complete. All reported fractures are confirmed using physician review of radiology reports or study radiologist review of x-rays. All deaths are also centrally adjudicated using death certificates and recent hospitalization records. In additional to the baseline study visit and tri-annual questionnaires, all surviving active participants were invited to follow-up visits and questionnaires. A second comprehensive clinic visit was completed between March 2005 and May 2006 or about 4.5 years after baseline. Most baseline measures, including vertebral radiographs, were repeated at the second visit. A third comprehensive clinic visit was completed between March 2007 and March 2009 or about 7.0 years after baseline. Many baseline measures were repeated at the third visit. A measure of energy expenditure was also obtained utilizing an accelerometer based armband device. Surviving participants have also completed two extensive mailed questionnaires designed to updated information obtained at clinic visits. The first questionnaire was mailed between baseline and visit 2 between July 2002 and March 2004. The second questionnaire was mailed after the third questionnaire between March 2009 and February 2011. The MrOS Sleep Study, an ancillary study of the parent MrOS cohort, was conducted between December 2003 and March 2005 and recruited 3,135 MrOS participants for a comprehensive sleep assessment. Men were screened for nightly use of mechanical devices during sleep including pressure mask for sleep apnea (CPAP or BiPAP), mouthpiece for snoring or sleep apnea, or oxygen therapy and were generally excluded. The sleep visit included objective measures of sleep using actigraphy and polysomnography. Other measures at the sleep visit include neuropsychiatric measures, performance measures, health related questionnaires, routine exam measures previously completed at MrOS clinic visits and a urine and serum specimen collection. During the sleep study period, participants complete a tri-annual questionnaire every four months that contains information about incident cardiovascular events. All reported events are centrally adjudicated utilizing hospital records, study ECGs and other supporting documentation. The Hip Osteoarthritis study, another ancillary study of the parent MrOS cohort, was completed at the second clinic visit between March 2005 and May 2006. Participants were asked for consent for a hip x-ray and osteoarthritis measurements were obtained from these x-rays. DNA was extracted from baseline whole blood samples for use in genetic research. Consent for use of DNA was obtained through written consent. Raw GWAS data is housed at the study's coordinating center and not released as part of the dbGAP release. The raw data can be requested from the study's coordinating center. Only QC cleaned Plink files are available on dbGAP.

  Study phs000373

• A Natural History Study of CMT1B, CMT2A, CMT4A and CMT4C

  Charcot Marie Tooth disease (CMT) is an umbrella term that covers any inherited peripheral neuropathy. People with CMT have a problem with the nerves that go to the feet and hands that cause muscle and sensation loss, as well as difficulty with balance. There are at least forty genes that, when mutated, cause CMT. The purpose of this study is to look at the natural history of CMT to see how it changes over time. Particular emphasis will be put on studying people with CMT1B, CMT2A, CMT4A, and CMT4C, though all people with CMT are encouraged to participate. Participants are invited back on a yearly basis to determine how the changes are occurring. Objectives: Determine the natural history and genotype-phenotype correlations of disease-causing mutations in CMT1B, CMT2A, CMT4A and CMT4C as well as other forms of CMT Determine the capability of the newly developed CMTPeds score and the Minimal Dataset to measure impairment and perform longitudinal measurements in patients with multiple forms of CMT over a ten-year window This is a longitudinal study of individuals with CMT. Study participants will be invited to be re-evaluated every year. Evaluations will consist of neurological histories and examinations, selected nerve conduction studies (NCS) as well as completion of assorted clinical outcome measures including the CMTNS, Minimal Dataset, and Peds CMT Scale. Selected CMT patients and controls will also receive glabrous skin biopsies.

  Study phs001419

• A New Pipeline to Predict and Confirm Tumor Neoantigens Predicts Better Response to Checkpoint Blockade

  Mutations that drive oncogenesis in cancer can generate neoantigens that may be recognized by the immune system. Identification of these neoantigens remains challenging due to the complexity of the major histocompatibility complex (MHC) antigen and T-cell receptor interaction. Here we describe the development of a systematic approach to efficiently identify and validate immunogenic neoantigens. Whole exome sequencing of tissue from a melanoma patient was used to identify nonsynonymous mutations, followed by MHC binding prediction and identification of tumor clonal architecture. The top 18 putative class I neoantigens were selected for immunogenicity testing via a novel in vitro pipeline in HLA-A201 healthy donor blood. Naive CD8 T cells from donors were stimulated with allogeneic dendritic cells pulsed with peptide pools and then with individual peptides. The presence of antigen-specific T cells was determined via functional assays. We identified one putative neoantigen that expanded T cells specific to the mutant form of the peptide and validated this pipeline in a subset of patients with bladder tumors treated with durvalumab (N = 5). Within this cohort, the top predicted neoantigens from all patients were immunogenic in vitro. Finally, we looked at overall survival in the whole durvalumab-treated bladder cohort (N = 37) by stratifying patients by tertile measure of tumor mutation burden (TMB) or neoantigen load. Patients with higher neoantigen and TMB load tended to show better overall survival.

  Study phs002269

• Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA)

  The Resource for Genetic Epidemiology Research on Aging (GERA) Cohort was created by a RC2 "Grand Opportunity" grant that was awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics (AG036607; Schaefer/Risch, PIs). The RC2 project enabled genome-wide SNP genotyping (GWAS) to be conducted on a cohort of over 100,000 adults who are members of the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), and participating in its RPGEH. The purpose of the RPGEH is to facilitate research on the genetic and environmental factors that affect health and disease by linking together clinical data from electronic health records, survey data on demographic and behavioral factors, and environmental data from various sources, with genetic data derived from biospecimens collected from participants. At the time of the award of the RC2 project in late 2009, the RPGEH had established a cohort of about 140,000 individuals who had answered a detailed survey, provided saliva samples for extraction of DNA, and given broad consent for the use of their data in studies of health and disease. To maximize the diversity of the resulting sample, the GERA cohort was formed by including all racial and ethnic minority participants with saliva samples (N = 20,925; 19%); the remaining participants were drawn sequentially and randomly from white non-Hispanic participants (89,341; 81%). A total of 110,266 participant samples were included to ensure that at least 100,000 were successfully assayed. The resulting GERA cohort is 42% male, 58% female, and ranges in age from 18 to over 100 years old with an average age of 63 years at the time of the RPGEH survey (2007). The sample is ethnically diverse, generally well-educated with above average income. Approximately 69% of the participants are married or living with a partner. Length of membership in KPNC averages 23.5 years. UCSF and RPGEH investigators worked with the genomics company Affymetrix to design four custom microarrays for genotyping each of the four major race-ethnicity groups included in the GERA Cohort, described in detail in Hoffmann et al., 2011a and 2011b. Following genotyping and quality control procedures, and after removal of invalid, discordant, or withdrawn samples, about 103,000 participants were successfully genotyped. The resulting genotypic data were linked to survey data and data abstracted from the electronic medical records. As described below, all RPGEH participants were mailed new consent forms with explicit discussion of the placement of data in the NIH-maintained dbGaP. About 77% of participants returned completed consent forms, resulting in a final sample size of 78,486 participants in the GERA Cohort with data for deposit into dbGaP. Origins of the RPGEH GERA Cohort The goal in creating the RPGEH GERA cohort was to create a large, multiethnic, and comprehensive population-based resource for research into the genetic and environmental basis of common age-related diseases and their treatment, and factors influencing healthy aging and longevity. The GERA Cohort consists of a diverse cohort of more than 100,000 adults who are members of the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), and participating in its Research Program on Genes, Environment and Health (RPGEH). KPNC is an integrated health care delivery system with a population of about 3.3 million people in northern California. The membership of KPNC is representative of the general population in the 14 county area in which facilities are located, although the membership is underrepresented for the extremes of income at both ends of the spectrum. The RPGEH utilizes the longitudinal electronic health records (EHR) of KPNC to obtain clinical, laboratory, imaging and pharmacy information on all cohort members, to which personal demographic, behavioral and health characteristics have been added through member surveys. The GERA Cohort comprises a subsample of the RPGEH participant cohort, and was created through the RC2 award from the NIA, NIMH, and NIH Common Fund as described above. GERA Study Design The GERA Cohort is a subsample, as described above, of the longitudinal cohort enrolled in the Kaiser Permanente RPGEH. The RPGEH cohort includes about 400,000 survey participants of whom about 200,000 have provided broad consent and a sample of saliva or blood for use in studies of genetic and environmental factors in health and disease. The GERA Cohort was developed from a mailed survey sent to all adult members of KPNC who had been members for two years or more in 2007. All survey respondents were contacted and asked to complete a consent form; those who completed consent forms were asked to provide a saliva sample. Additional male participants were added to the RPGEH through inclusion of the Northern California sample of the California Men's Health Study (CMHS) cohort of about 40,000 men from KPNC, ages 45-69 years old at the time of the CMHS survey in 2002-2003. The CMHS participants contributed about 15,400 saliva samples to the RPGEH and were eligible for inclusion in the GERA Cohort. CMHS participants were included according to the same sampling design as for the RPGEH cohort as a whole. Specifically, all minority participants were selected for inclusion in order to maximize representation of minorities in the GERA Cohort, and Non-Hispanic White participants were selected at random to complete the sample of 110,266 GERA Cohort participants. GERA Genotypic Data High-density genotyping was conducted at UCSF using custom designed Affymetrix Axiom arrays, as described in Hoffmann et al. (2011a; 2011b). To maximize genome-wide coverage of common and less common variants, four specific arrays were designed for individuals of Non-Hispanic White (EUR), East Asian (EAS), African-American (AFR), and Latino (LAT) race/ethnicity. There was broad overlap among the SNPs on the arrays, which were designed using a hybrid greedy imputation algorithm (Hoffmann et al., 2011b) applied to genotype information validated by Affymetrix from the 1000 Genomes Project. However, in order to capture low frequency variants specific to particular race-ethnicity groups, SNP content varies between arrays. A more detailed description of the process of genotyping and results is included in Genotyping of DNA Samples. Description of the analyses of population structure and development of principal components for adjustment of population structure is included in Population Structure Analysis. GERA Phenotypic Data RPGEH and CMHS Survey Data. The sources of data on demographic and behavioral factors deposited in dbGaP for the GERA Cohort are the RPGEH and CMHS surveys. Data on common demographic factors such as gender, race/ethnicity, marital status, and education and on behavioral factors such as smoking, alcohol consumption, and body mass index, have been cleaned, edited, reconciled between the two surveys, and compiled into summary indices, where appropriate, for deposition into dbGaP. A more complete description of the survey variables is included in Survey Variables Documentation. Please note that the terms of use of the GERA Cohort Data, as specified in the Data Use Certification (DUC), prohibit the use of survey variables as outcomes in analyses. For example, a genome-wide association study (GWAS) of education or smoking is not permitted as specified by the DUC. Only health conditions can be used as outcome variables in analyses. Health Conditions derived from Kaiser Permanente Electronic Medical Records. Data on the occurrence of health conditions in participants in the GERA Cohort have been derived from summarizing ICD-9 coded diagnoses in Kaiser Permanente's electronic medical records. An algorithm that aggregates specific ICD-9 codes into appropriate diagnostic groups for selected conditions is applied to outpatient and inpatient databases; see Disease and Conditions Definitions Documentation for details. The criterion for including a condition as "present" for a participant is the occurrence of two or more diagnoses within a diagnostic category occurring on separate days. Two or more is used as the criterion in order to reduce false positives due to mistakes or rule-out diagnoses. When compared with validated disease registries, the criterion of 2+ diagnoses yields high specificity and good sensitivity. ICD-9 codes in the electronic records are specified in several ways. For outpatient visits occurring during the period 1995 to 2006, diagnoses were assigned by the treating physician who endorsed specific diagnoses on an optically scanned list that varied by specialty. Beginning in 2006 with the advent of an integrated, fully electronic medical record, outpatient diagnoses are made by physicians/ providers using a pull down menu. Discharge diagnoses from inpatient stays are specified by physicians and coded by specially trained coders. Databases of ICD-9 codes for diagnoses assigned at outpatient visits, or as one of the discharge diagnoses following inpatient stays, are complete and available for all KPNC members dating back to 1995. Although the average length of KPNC membership among GERA cohort members is 23.5 years in 2007, not all have been members since 1995, so the history for some conditions, such as those that are not chronic or recurrent, may not be complete for all cohort members. The year of first membership in KPNC is included as a variable in the list of survey variables, enabling investigators to estimate the number of years of observation of each Cohort member. RPGEH Access and Collaborations Website and Procedures The RPGEH maintains a web portal for inquiries and applications for collaboration and access to data. The url is: https://rpgehportal.kaiser.org/. RPGEH has an application process and an Access Review Committee that reviews applications for collaboration and use. For more details, please contact RPGEH through the website.

  Study phs000674

• Discovering the Genetic Basis of Human Neuroblastoma: A Gabriella Miller Kids First Pediatric Research Program (Kids First) Project

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Children with disseminated neuroblastoma have a very high risk of treatment failure and death despite receiving intensified chemotherapy, radiation therapy and immunotherapy. The long-term goal of our research program is to ultimately improve neuroblastoma cure rates by first comprehensively defining the genetic basis of the disease. The central hypothesis to be tested here is that neuroblastoma arises largely due to the epistatic interaction of common and rare heritable DNA variation. Here we will perform a comprehensive whole genome sequencing of 563 quartets of neuroblastoma patient germline and diagnostic tumor DNAs and germline DNAs from both parents. The case series was recently collected through a Children's Oncology Group epidemiology clinical trial and is robustly annotated with complete demographic (age, sex, race, ethnicity), clinical (e.g. age at diagnosis, stage, risk group), epidemiologic (parental dietary and exposure questionnaire) and biological (e.g. tumor MYCN status and multiple other tumor genomic measures) co-variates. Subjects were consented for genetic research and DNA is immediately available for shipment for sequencing. We propose Illumina-based whole genome sequencing in the 593 "trio" germline samples (Aim 1; due to missing parent: 487 full neuroblastoma triads, 106 child-single parent dyads = 1673 whole genome sequences) and matched diagnostic tumor DNA (Aim 2; N=366) at 30x sequencing depth (N=2039 whole genome sequences). Also in Aim 2 we will perform whole exome (100x) and RNA sequencing on the 366 tumor DNA and 228 tumor RNA samples from this cohort. Finally, we propose a pilot study of structural variation using long-range sequencing in 10 non-overlapping tumor samples chosen based on potentially relevant chromosomal alterations discovered with conventional NGS. Thus, a total of 2277 individual samples and 2655 sequences will be generated. We will use our established analytic pipeline that is currently being used to study the germline genomes of all cases sequenced through the NCI supported Therapeutically Applicable Research to Generate Effective Treatments program. We plan a three-stage analytic approach, first focusing on classic de novo and inherited Mendelian damaging alterations. We will next integrate our extensive epigenomic data from human neuroblastoma cell lines and genome-wide association study data (N=5,703 neuroblastoma cases to date) to guide a comprehensive assessment of noncoding variants that influence tumor initiation with a recently established analytic pipeline. Finally, we will utilize the tumor DNA analyses to inform relevance via somatic gain or loss of function effects at the sequence and/or copy number levels. All data generated in this project will be immediately placed into the Genomic Data Commons (GDC) and we will compute within this environment by importing our analytic pipelines into the GDC. These data will be fully integrated into the Kids First Data Resource and freely shared with all academically qualified petitioners. This comprehensive data set derived from a large and richly phenotyped series of neuroblastoma DNA quartets will be integrated with existing germline and/or tumor genomic data from over 6,000 neuroblastoma subjects (but none with matched patient-parent germline sequencing data) to provide an unparalleled opportunity to comprehensively discover the genetic basis of neuroblastoma.

  Study phs001436

• Genetic Basis of Developmental Disabilities

  Developmental disabilities are birth defects that cause lifelong problems with how a body part or system works. Developmental disabilities include nervous system insults affecting how the brain, spinal cord and nervous system function; they cause intellectual disability, including Down syndrome and fragile X syndrome; and they also cause learning and behavioral disorders, such as autism spectrum disorders. At the Kennedy Krieger Institute, approximately 450 inpatients and 13,000 outpatients are seen per year (involving 114,000 visits). For most of these disorders, the underlying molecular cause has not been identified. Some, such as chromosomal disorders, have a strongly genetic basis while others, such as traumatic brain injury, are caused by environmental insults but are nonetheless influenced by the genetic background. The purpose of the present study is to identify chromosomal abnormalities underlying a variety of developmental disabilities. The approach is to obtain blood and saliva from children, and from one or both biological parents (and in some cases from siblings and/or additional relatives). Genomic DNA is purified and assayed on single nucleotide polymorphism (SNP) microarrays and/or by sequencing, including whole genome sequencing. These technologies provide high resolution information about chromosomal changes, and the information provided by the parental (and other relatives') DNA allows an interpretation of whether changes in a child are inherited or occur de novo. The study design includes multiple data analysis procedures to interpret the biological significance of findings of chromosomal changes relative to a child's parents, relative to children with similar diagnoses, relative to children with other chromosomal anomalies, and (in some cases) relative to the chromosomal status of siblings. We will further interpret the significance of the findings relative to the general (apparently normal) population by obtaining publicly available data from apparently normal individuals.

  Study phs000337

• Genomic Analysis of Mycosis Fungoides and Sézary Syndrome Identifies Recurrent Alterations in TNFR2

  Mycosis Fungoides (MF) and Sézary Syndrome (Sz) comprise the majority of Cutaneous T-Cell Lymphoma (CTCL) cases and are characterized by clinical heterogeneity. This array of symptoms includes skin patches, plaques and tumors as well as blood involvement and erythroderma. Because the genetic basis of CTCL is still poorly understood, we performed whole-exome sequencing on 11 MF/Sz samples and their matched, normal control DNA. Upon analyzing this data, we distilled a list of an additional 494 genes to be sequenced at depth. The majority of these 494 genes were sequenced in the exons alone, however, for a small subset of these genes we sequenced the entire genomic locus in search of structural variation events. This 494 gene targeted resequencing effort was performed upon 72 patients with MF/Sz and their matched, normal control DNA. An additional 5 MF/Sz and matched, normal DNA samples underwent whole genome amplification (WGA) prior to library preparation, which appears to have introduced mutations into these samples, however we also include them here. We additionally include 10 MF/Sz samples without a matched, normal control samples, 1 of which underwent WGA. In addition to primary disease samples, we also performed targeted resequencing on 4 CTCL cell lines (HH, MyLa, SeAx and Hut78) as well as on H9 cells (a subclone of Hut78 cells) and Jurkat cells, a T-ALL derived cell line that was used as an experimental system for our work. In sum, this data deposition includes exome and/or targeted resequencing from 92 individuals with 192 samples submitted.

  Study phs000913

• Genetics of Neuropsychiatric and Neurodevelopmental Disorders

  Although schizophrenia is a highly heritable disease, relatively little progress had been made in securely identifying the genetic causes of this disorder, and most instances of schizophrenia in the general population remain unexplained. One avenue of explanation for the genetic basis of schizophrenia, however, has been effectively closed by recent research. Genome-wide association studies (GWAS) have now shown that common variation makes at most a modest contribution to the risk of schizophrenia. At the same time that the role of common variation has been circumscribed by GWAS, however, the analysis of copy number variants that are detectable on a genome-wide scale has revealed and replicated a number of very rare variants that associate with schizophrenia. These rare copy number variants that have been implicated in schizophrenia, however, have one striking feature in common: they are all risk factors for other brain related disorders beyond schizophrenia such as mental retardation, autism and epilepsy. These findings argue that genetic risk factors may confer a highly penetrant vulnerability to neuropsychiatric disorder, which is then further modified by interacting genetic or environmental factors to determine the ultimate manifestation. Most schizophrenia collections that are being studied today, however, have been selected precisely for their homogeneity: including only schizophrenia patients with no comorbidities, or schizophrenia patients with relatives who have schizophrenia but no other neuropsychiatric conditions. These selection criteria are inconsistent with what we now know about the bulk of the genetic differences that have been associated with disease. The central hypothesis of this project is that there are rare genetic variants that strongly elevate the risk of various neuropsychiatric diseases, and that these risk factors can be identified most readily in families segregating multiple neuropsychiatric conditions.

  Study phs000682

• NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish

  The Amish Complex Disease Research Program includes a set of large community-based studies focused largely on cardiometabolic health carried out in the Old Order Amish (OOA) community of Lancaster, Pennsylvania (http://medschool.umaryland.edu/endocrinology/amish/research-program.asp). The OOA population of Lancaster County, PA immigrated to the Colonies from Western Europe in the early 1700's. There are now over 30,000 OOA individuals in the Lancaster area, nearly all of whom can trace their ancestry back 12-14 generations to approximately 700 founders. Investigators at the University of Maryland School of Medicine have been studying the genetic determinants of cardiometabolic health in this population since 1993. To date, over 7,000 Amish adults have participated in one or more of our studies. Due to their ancestral history, the OOA may be enriched for rare variants that arose in the population from a single founder (or small number of founders) and propagated through genetic drift. Many of these variants have large effect sizes and identifying them can lead to new biological insights about health and disease. The parent study for this WGS project provides one (of multiple) examples. In our parent study, we identified through a genome-wide association analysis a haplotype that was highly enriched in the OOA that is associated with very high LDL-cholesterol levels. At the present time, the identity of the causative SNP - and even the implicated gene - is not known because the associated haplotype contains numerous genes, none of which are obvious lipid candidate genes. A major goal of the WGS that will be obtained through the NHLBI TOPMed Consortium will be to identify functional variants that underlie some of the large effect associations observed in this unique population.

  Study phs000956

• CIP: Differential Response to Hydroxyurea and Incidence of Stroke in Sickle Cell Disease

  Sickle cell disease (SCD) is a severe debilitating hematological disorder associated with a high degree of morbidity and mortality. There are approximately 200,000 babies born with sickle cell disease each year, with the disease predominately affecting individuals in Africa. The overall global burden of the disease is tremendous, with more than 100,000 patients currently in the US and further millions worldwide. The governing bodies of the World Health Organization have recently adopted a resolution to strengthen the response to sickle disease in all affected countries and there is a definite need for high quality sickle cell disease research that has the potential to improve the treatment and prognosis of patients with this devastating disease. The clinical manifestations of SCD arise from a complex pathophysiology that includes hemolysis, acute vaso-occlusion, endothelial dysfunction, inflammation, and chronic organ damage. While the individual clinical course of this disease is highly variable, many of the associated complications demonstrate some degree of heritability. Intensive research into identifying genetic modifiers that can affect the pathophysiology of SCD has been limited to date and there is an urgent need to improve of our knowledge the molecular mechanisms underlying the clinical complications of SCD. The Sickle cell CIP project is investigating complication of stroke and pharmacogenomics of hydroxyurea response in patients with sickle cell anemia. The major benefit of hydroxyurea comes from its ability to induce fetal hemoglobin (HbF) and higher HbF levels are associated with reduced morbidity and mortality in SCA patients. We will perform whole exome and whole genome sequencing of SCA patients in order to identify genome variants associated with incidences of stroke and HbF response to hydroxyurea.

  Study phs000691

• Heart and Vascular Health Study (HVH)

  Objectives The Heart and Vascular Health Study (HVH) is a case-control study of risk factors for the development of myocardial infarction (MI), stroke, venous thrombosis (VT), and atrial fibrillation (AF). The study setting is Group Health, an integrated health care delivery system in Washington State. Background The HVH originated in 1988 with the examination of risk factors for MI. Over the ensuing years, the study has been funded by a series of grants, which have added case subjects with stroke, VT, and AF, and used a common control group. Study aims have focused on the associations of medication use with cardiovascular events. Starting in 1997, the study aims expanded to include genetic associations with cardiovascular disease. Participants recruited in 2009 or later and who provided blood samples for genetic analysis were asked for consent to deposit genetic and phenotype data in dbGaP. Design As part of the HVH study, case subjects were identified by searching for ICD-9 codes consistent with MI, stroke, VT, or AF, and medical records were reviewed to confirm the diagnosis. Control subjects were identified at random from the Group Health enrollment and were matched to MI cases. All subjects have an index date. For cases, the index date was assigned as the date that the cardiovascular event (MI, stroke, VT, or AF) came to clinical attention. For controls, the index date was a random date within the range of the case index dates. For both cases and controls, information was collected from the inpatient and outpatient medical record, by telephone interview with consenting survivors, and from the Group Health pharmacy and laboratory databases. Consenting participants provided a blood specimen. Genetic Research Genetic factors underlying cardiovascular disease are studied using DNA isolated from the blood samples.

  Study phs001013