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• eMERGE: Genetics of Complex Pediatric Disorders from the Center for Applied Genomics

  The Center for Applied Genomics (CAG) is a specialized Center of Emphasis at the Children's Hospital of Philadelphia (CHOP) with the primary goal of translating basic research findings to medical innovations. The mission of CAG is to develop new and better ways to diagnose and treat children affected by rare and complex medical disorders. We aim to discover genetic causes for the most prevalent diseases of childhood including asthma, autism, diabetes, epilepsy, obesity, schizophrenia, pediatric cancer, and a range of rare diseases. Ultimately, our objective is to generate new diagnostic tests and to guide physicians to the most appropriate therapies. The CAG is one of the world's largest genetics research programs in pediatrics, and the only center at a pediatric hospital to have established a large-scale biobank of genotyped samples. The electronic Medical Records and Genomics (eMERGE) Network is a consortium of 9 clinical sites with EMR linked DNA biobanks, including Northwestern University and its NUgene biobank, funded by the NHGRI (National Human Genome Research Institute) to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 100,000 individuals using EMR-derived phenotypes and DNA from linked biorepositories. Using electronic phenotyping methods, the consortium has been and is using DNA samples from all participating sites to explore the genetic determinants of approximately 80 phenotypes, including both diseases and traits, for which the electronic phenotyping algorithms have or are being published on PheKB.org.

  Study phs001165

• Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Victorian Collaborative AuTism Study (CATS): Family and Community Study of the Genetics of Autism Spectrum Disorder

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs002044

• 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'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

• Transposable Elements in FTLD-TDP and ALS-TDP

  Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease involving the rapid and progressive loss of motor neurons. While a number of inherited mutations have been identified as causing ALS, the vast majority of cases are sporadic with no family history of disease. This has led to the model that ALS may be a complex syndrome with an unknown number of causal molecular pathways. However, nearly all ALS patient tissues display aggregates of the RNA binding protein TDP-43 (TARDBP/TAR DNA-binding protein), and mutations in the gene encoding this protein are known to cause ALS. We show that one of the normal functions of TDP-43 is to bind and regulate retrotransposons, repetitive sequences in the genome that are normally silent, due in part to the function of TDP-43. Furthermore, we demonstrate that many ALS patients with TDP-43 pathology also display de-silencing of retrotransposon RNAs, consistent with a loss of normal TDP-43 function. Those ALS patients that exhibit high levels of retrotransposon expression form a distinct subset of ALS subjects that also show other correlated alterations to the transcriptome. Using unsupervised machine learning algorithms, we identified three distinct molecular subtypes from the whole genomes and transcriptomes of a large cohort of 148 ALS patient samples. The retrotransposon re-activated subset formed 20% of ALS samples; two additional groups displayed signatures of oxidative stress (61%), and glial dysfunction (19%), respectively. Together these results demonstrate that retrotransposon re-activation is common in a subset of ALS patients with TDP-43 pathology.

  Study phs001889

• Single Chromatin Fiber Profiling in the Human Brain

  We developed a human postmortem brain-applicable ‘Fiber-seq' protocol for genome-scale, PCR-free single molecule sequencing of on average 8-10kb long chromatin fibers, to map nucleosome positioning and nucleosome-depleted regions which include, for example, active promoters and enhancers. We generated two Fiber-seq reference sets, one from sorted non-neuronal NeuN- prefrontal cortex (PFC) nuclei from a 32 year old female donor, with total of 11,143,795 reads/fibers, and median of 30-fold genomic coverage. The other reference set was generated on sorted prefrontal NeuN+ neurons, from two 24 year old brain donors (1 female/1 male), with a combined total read/fiber count of 4,749,556 and median of 20-fold genomic coverage. Each of the peaks in the Fiber-seq libraries seq signal correlated with the ATAC peak levels in the neuronal and non-neuronal ATAC-seq libraries, respectively (promoters, clusters 1, 3; NeuN+, r = 0.574; NeuN-, r=0.683, PHowever, Fiber-seq detected 19,978 highly significant peaks which, while showing some non-significant/near-background ATAC-Seq alignments, lacked a corresponding site-specific enrichment in conventional short-read ATAC- and ChIP-seq datasets. However, 60% of these peaks were in repetitive DNA elements. Therefore, long read single chromatin fiber sequencing, which exceed the base pair length of conventional short-read libraries by two orders of magnitude, could capture many actively regulated repeat elements at the site of specific gene loci, that otherwise would remain unmappable by conventional ATAC-, and histone- ChiP-seq.

  Study phs003771

• Cancer Moonshot Biobank

  The National Cancer Institute initiated the Cancer Moonshot Biobank to accelerate research through the collection and distribution of biospecimens for key research efforts. The Biobank will engage with over one thousand cancer patients, being treated with standard-of-care therapies, for longitudinal biospecimen and data collection. Cancer patients will be enrolled into the study from a diverse participant population engaged at medical institutions throughout the U.S. The biospecimens will be distributed to qualified scientists to accelerate research progress. The Biobank program, working closely with Leidos Biomedical, Inc. (LBR), will partner with community hospitals and other medical institutions, designated as Biospecimen Source Sites (BSS), to engage and consent eligible participants and collect biospecimens and associated clinical data; work with a central Biospecimen Core Resource (BCR) to support biospecimen collection, processing and storage activities and perform pathology quality control; work with LBR's Molecular Characterization (MoCha) lab to perform clinical tumor molecular characterization assays and return results to patients and their physicians; and make the biospecimens and associated data available to researchers to accelerate cancer research progress. Return of clinical results, a dedicated Patient and Provider Engagement (PPE) website, electronic informed consent, local participant engagement projects, and an embedded ethical, legal and social issues sub-study will together support patient and provider engagement in the program. Cancer Moonshot Biobank imaging data is being made available in The Cancer Imaging Archive (TCIA) on a release schedule that is coordinated with the program releases of data to dbGaP. The imaging data can be found at the following link: Cancer Moonshot Biobank Imaging

  Study phs002192

• dbGaP Collection: Open Translational Science in Schizophrenia (OPTICS)

  Schizophrenia is a chronic, severe, disabling brain disorder that affects approximately 1% of the population worldwide. Epidemiologic studies have clearly demonstrated that genetics play a strong role in etiology, but the inheritance is very complex. Innovative analytic approaches and creative ways of combining disparate data sets will be necessary for making breakthroughs in identifying causal pathways and ultimately new drug targets. This dbGaP Collection consists of all genetic studies of schizophrenia available in dbGaP that have been consented for general research use. The goal is to facilitate identification of datasets with related scientific content in order to expedite the application process and ascertainment of datasets of interest for increased scientific discovery. The Open Translational Science in Schizophrenia (OPTICS) Project, was launched by Janssen Research & Development, LLC, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, with a group of leading research organizations including the National Institutes of Health, Yale University School of Medicine, Rutgers University and the Harvard T.H. Chan School of Public Health, to create a new forum for collaborative analysis of Janssen's schizophrenia clinical trial data and other publicly available data about schizophrenia with the goal of creating new models for conducting research. The OPTICS project is one part of a larger effort at Janssen and other Johnson & Johnson research companies to share clinical trials data to enhance public health and advance science and medicine. Qualified investigators and physicians may apply for access to anonymized clinical trials data from Janssen, for more information please visit https://sites.google.com/site/opticsschizophrenia/.

  Study phs000887

• Oncogenome of Kaposi Sarcoma

  Kaposi Sarcoma (KS) is an aggressive cancer caused by the Kaposi Sarcoma Herpesvirus (KSHV/HHV-8). Individuals with immunodeficiencies, exemplified by HIV, have an elevated risk of developing KS. However, understanding of the genetic factors contributing to KS progression is still limited. To explore potential genetic alterations in KS that could offer biological or therapeutic insights, whole exome sequencing was performed on 78 KS tumors and matching normal skin samples from 59 adults with KS (46 with HIV-associated KS and 13 with HIV-negative KS) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. Results showed a very low mutational burden in all samples except one (median = 11 mutations), which is the smallest number of mutations found across all 33 cancer types in The Cancer Genome Atlas (TCGA). No recurrent mutations were identified. Mutational signatures included impaired DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from a single clone. The number of genome copy alterations per genome was higher in tumors from individuals without HIV and those with advanced-stage disease. This suggests that lesions that take longer to develop may accumulate more alterations, although the overall number of alterations remains low compared to other cancers. These findings suggest that KS pathogenesis differs from other cancers, with KSHV viral infection and the expression of viral oncogenes being the primary drivers of carcinogenesis, rather than clonal oncogenic transformation arising from genetic alterations of cancer-related cellular genes.

  Study phs003897

• Frequent post-treatment monitoring of colorectal cancer using individualized ctDNA validated by multi-regional molecular profiling

  Purpose: Circulating tumor DNA (ctDNA) analysis has been proposed as an approach for prediction of post-treatment patient outcomes. However, whether a single platform will provide optimal information in all patients or alternatively a patient-specific monitoring approach based on assessment of mutations in the primary tumor from that patient remains an urgent question. Experimental Design: We conducted multiregional sequencing of 42 specimens of 14 colorectal tumors (Stage III and more) from 12 patients, including two double cancer cases, to identify the full spectrum of mutational heterogeneity and identify aberrations that could be used to develop personalized ctDNA assays. Results: ?Founder? mutations that occur in all regions of the sample were identified in 12/14 (85.7%) tumors. Subsequent phylogenetic analysis of each tumor showed that 12/14 tumors (85.7%) carried at least one ?truncal? mutation. Most founder and truncal mutations exhibited higher variant allele frequency (VAF) than ?non-founder? and ?branch? mutations. In addition, both founder and truncal mutations were more likely to be detected as ctDNA than non-founder and branch mutations. Synchronized ctDNA dynamics of multiple mutations suggested those mutations from the same clonal origin. For 10/12 patients (83.3%) with nearly 1,000 days of post-operative observation, the validity of frequent personalized ctDNA monitoring was confirmed in terms of early relapse prediction, treatment efficacy, and non-relapse corroboration. Conclusions: Personalized ctDNA monitoring based on aberrations with a high VAF in the primary tumor site should be explored in larger prospective clinical trials to determine the full clinical validity.

  Study JGAS000243