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• Detection of rare mutations, copy number variation, and DNA methylation in the same template DNA molecules

  The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic and genetic alterations present in the DNA molecules can then be obtained from the original and copied strands, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung and colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics in the future.

  Study EGAS00001006839

• 3/7 Psychiatric Genomics Consortium: Finding Actionable Variation

  The goal of this study was to generate new therapeutic hypotheses by targeted sequencing of 161 genes most likely to harbor schizophrenia (SCZ) causal variants in multi-ancestry schizophrenia case-control cohorts. The gene panel was intended to contain putative SCZ risk genes, from within which, the majority of new discoveries from additional WES/WGS would come. To this end, we integrated current knowledge of the genetic architecture of SCZ (results from The Schizophrenia Exome Sequencing Meta-Analysis Consortium, or SCHEMA) and gene membership in gene sets that have been implicated in SCZ using a Bayesian framework. A total of 23,352 individuals selected to be non-overlapping with SCHEMA, as well as other previous and ongoing sequencing efforts in the field, were identified from over 20 individual study sites. Sequencing of the exonic regions of 161 prioritized genes was performed on the Ion Torrent platform in between June 2018 and April 2019. Sequencing plates were matched with respect to ancestry and case/control composition whenever possible. The average sequencing depth across all samples was 224x. Single sample calling was performed using Torrent Variant Caller v5.8.0, which is specially optimized to exploit the underlying flow signal information generated by the Ion Torrent sequencing. The schizophrenia case-control status was obtained from each original study site.

  Study phs003138

• Natural History, Pathogenesis and Outcome of Melorheostosis

  Melorheostosis is a rare osteosclerotic disease resulting in exuberant excessive bone growth with a characteristic radiographic appearance often described as "dripping candle wax". As a result of these bony formations, patients report mild to moderate pain that interferes with their routine activities. It is usually diagnosed on radiographs but bone biopsy may be performed to exclude other osteosclerotic diseases and/or osteosarcoma. Deformities, limb-length discrepancy, muscle atrophy, neurological deficit have been reported as complications. A subset of patients have somatic mutations in MAP2K1. The cause of this disease is not known in all patients, the natural history poorly described and there is no clearly-defined systemic therapy. We propose a prospective observational study to investigate the natural history and pathogenesis of the disease. Subjects will undergo standardized initial evaluation and medically indicated testing. Skin biopsies may be performed to test for known mutations related to melorheostosis, and if negative affected bone and/or skin may be sent for genetic testing for acquired somatic mutations in genes that control bone homeostasis. Enrolled subjects will be followed every two to three years for assessment of disease progression and receive clinically indicated testing and treatment. The study of this rare bone disease offers the potential to generate new insights, provide answers as well as generate new questions into the biology of the skeletal and mineral metabolism.

  Study phs001976

• Population Genetic Testing and SERPINA1 Sequencing Identifies Unidentified Alpha-1 Antitrypsin Deficiency Alleles and Gene-Environment Interaction with Hepatitis C Infection

  Design and aims: Data were available through an institutional effort to combine de-identified electronic health records (EHR) data with genomic information from a DNA biobank. The design of this work was a retrospective cohort study in which we investigated the rates of liver transplantation and hepatitis C infection as it relates to genotype risk for alpha-1 antitrypsin deficiency (AATD). We used regression analysis to look for relationships between these risks and outcomes. This led to further investigation of environmental exposures and phenotypes as it related to the underlying genotypic risk. Population information: The cohort consisted of 72,027 individuals of European ancestry for whom genotype and EHR data were available. Molecular technologies employed: Genome-wide genotyping was previously performed using the Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content (referred to as the Vanderbilt University Medical Center BioVU MEGAEX). Individuals' AATD-related alleles were inferred from the genotyping data. Principal findings of the study: Liver transplantation was associated with presence of the Z AATD allele and with hepatitis C infection. There was a significant interaction between AATD genotype groups and hepatitis C infection as it related to liver transplantation. Data available through dbGaP: Inferred AATD genotype status, sex, age, length of EHR in years, presence/absence of AATD clinical diagnosis, liver transplant status, and hepatitis C infection status.

  Study phs003297

• Characterizing the Neurobehavioral Phenotype(s) in MPS III (Pilot Study)

  Mucopolysaccharidosis III (MPSIII) syndrome is characterized by a severe cognitive decline ending in dementia and death. MPSIII is also associated with a range of abnormal and disruptive behaviors that can include, but go well beyond, childhood noncompliance and oppositionality. The purpose of this study is to conduct a cross-sectional investigation to identify the behavioral phenotype and its neural basis in MPSIII. An overall goal of this research is to develop easily administered, sensitive and specific neurobehavioral markers to characterize the behavioral phenotype(s) of MPSIII, track their progression, and to delineate their possible neural substrates. The study looks to develop develop a sensitive and specific behavioral rating of disease progression in MPS III which can be used for clinical outcome studies. The research objectives are: Develop a measure for the use of health professionals to use in tracking MPSIII phenotypes and disease progression. Test our model of MPSIII with objectively recorded behaviors in a well-defined experimental setting. Elucidate the neural bases of MPSIII by correlating behavioral profiles with changes in brain structures through quantitative neuroimaging. Determine the relationship between the loss of cognitive functions and development of behavioral abnormalities in MPSIII. This is an observational pilot study that will enroll 45 individuals with MPS III Type A or B. Those participating in the study will be evaluated during a one-day assessment and chart review.

  Study phs001330

• Etiological Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes: A Natural History Study

  Background: A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders. Mutations in IBMFS genes are relevant to carcinogenesis in sporadic cancers. Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer. These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer. Carriers of IBMFS gene mutations are at increased risk of cancer. The prototype disorder is Fanconi Anemia (FA); other IBMFS will also be studied. Objectives: To determine the types and incidence of specific cancers in patients with an IBMFS. To investigate the relevance of IBMFS gene mutations in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers. To identify risk factors for IBMFS-related cancers in addition to the primary germline mutations. To determine the risk of cancer in IBMFS carriers. Design: Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance. Primary endpoints are all cancers, solid tumors, and cancers specific to each type of IBMFS. Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

  Study phs001481

• NHLBI TOPMed: Novel Risk Factors for the Development of Atrial Fibrillation in Women

  The Women's Genome Health Study (WGHS) is a prospective cohort comprised of over 25,000 initially healthy female health professionals enrolled in the Women's Health Study, which began in 1992-1994. All participants in WGHS provided baseline blood samples and extensive survey data. Women who reported atrial fibrillation during the course of the study were asked to report diagnoses of AF at baseline, 48 months, and then annually thereafter. Participants enrolled in the continued observational follow-up who reported an incident AF event on at least one yearly questionnaire were sent an additional questionnaire to confirm the episode and to collect additional information. They were also asked for permission to review their medical records, particularly available ECGs, rhythm strips, 24-hour ECGs, and information on cardiac structure and function. For all deceased participants who reported AF during the trial and extended follow-up period, family members were contacted to obtain consent and additional relevant information. An end-point committee of physicians reviewed medical records for reported events according to predefined criteria. An incident AF event was confirmed if there was ECG evidence of AF or if a medical report clearly indicated a personal history of AF. The earliest date in the medical records when documentation was believed to have occurred was set as the date of onset of AF.

  Study phs001040

• Identification of Cancer Predisposition Genes in Breast Cancer Families

  Breast cancer has a significant genetic component. The strongest epidemiologic risk factor is family history of the disease. Familial studies have identified a number of genes contributing to increased risk. Of these, the highly penetrant BRCA1 and BRCA2 genes account for the majority of families in whom disease-causal mutations have been identified. However, mutations in other genes have been associated with predisposition to breast or breast and ovarian cancer including (CHEK2, ATM, PALB2, RAD51C, RAD51D). Together these genes account for less than 20% of excess familial breast cancer risk and do not explain ~50% of high-risk families referred for genetic testing. This significant gap in our understanding of the genetic basis of breast cancer poses a significant barrier to our ability to identify women at increased risk, who would benefit greatly from appropriate clinical management. To identify additional breast cancer predisposition genes whole exome sequencing of familial high-risk breast cancer patients was undertaken. DNA samples from 50 pairs of breast cancer patients from high-risk breast cancer families with no pathogenic mutations in the BRCA1 or BRCA2 breast cancer predisposition genes were subjected to whole exome sequencing. The goal was to select candidate predisposition genes for further validation studies based on sharing of putative protein inactivating mutations among both members of each family and/or the frequency of inactivating mutations among the 50 families.

  Study phs000480

• ApoA-1 and Atherosclerosis in Psoriasis

  Apolipoprotein A-1 is a protein localized to high-density lipoprotein that functions to remove cholesterol from tissues for transport back to the liver. Psoriasis is a systemic inflammatory disease associated with poor high-density lipoprotein function and accelerated non-calcified burden by coronary computed tomographic angiography. In this study, 310 psoriasis patients from The Psoriasis, Atherosclerosis, and Cardiometabolic Disease Initiative (PACI) were studied at baseline to determine if levels of circulating apolipoprotein A-1 predict early onset coronary artery disease in inflammatory conditions. Of the 310 participants, 124 were followed for four years to determine if apolipoprotein A-1 predicts non-calcified coronary burden over time. The primary outcome of this study was non-calcified coronary burden by coronary computed tomography angiography. To assess non-calcified coronary burden, participants underwent coronary computed tomography angiography using the same scanner (320-detector row Aquilion ONE ViSION, Toshiba, Japan). For ApoA-1 quantification, fasting blood draw was performed the same day as the coronary computed tomography angiography. The 400MHz proton Vantera Clinical Analyzer was used to quantify Plasma apolipoprotein A-1. The study determined that low levels of apolipoprotein A-1 are associated with increased coronary artery burden and that this relationship persists over time. The data are available through dbGaP and the dataset includes all variables reported in the manuscript.

  Study phs003231

• Brain Cell Type-Specific Enhancer-Promoter Connectivity Maps and Disease Risk Association

  These studies map the epigenetic landscape of microglia, neurons, astrocytes and oligodendrocytes. The initial study compared acutely isolated microglia to cultured microglia from the same donors, to identify changes that occur when microglia are removed from the brain microenvironment. In collaboration with the Rady Children's Hospital, we obtained brain tissue samples from pediatric patients representing putative normal tissue resected to gain access to brain tumors as well as tissue resected to remove epileptic foci. We assayed microglia isolated from these samples using RNA-seq, ATAC-seq and ChIP-seq for PU.1, H3K4me2, and H3K27ac. For patients from whom a sufficient cell number was obtained, we additionally cultured their microglia for up to 7 days and subjected these to the same suite of assays. In a follow-up study, we obtained brain tissue from a comparable cohort of pediatric epilepsy patients from Rady Children's Hospital. We isolated nuclei from microglia, neurons, astrocytes and oligodendrocytes, and assayed for ATAC-seq, ChIP-seq for H3K4me3, and H3K27ac, and PLAC-seq (Proximity Ligated ChIP-seq). We isolated microglia from human fetal and postnatal sample and assayed for bulk RNA-seq, bulk ATAC-seq, bulk H3K27ac ChIP-seq, single-cell RNA-seq (scRNA-seq) and single-cell ATAC-seq. For these studies, human microglia are defined by signature genes/proteins, such as P2RY12, SALL1, and CX3CR1.

  Study phs001373