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• A Genome-Wide Association Study of Peripheral Arterial Disease

  The Electronic Medical Record Phenotypes and Community-engaged Genomic Association Study aims to identify genetic variants mediating susceptibility to peripheral arterial disease (PAD). The study leverages a biorepository of blood samples of 1688 PAD cases and 1649 controls, and the electronic medical record (EMR) to annotate the biorepository. PAD cases were identified from the vascular laboratory database as having an ankle brachial index (ABI) <0.9 at rest or after exercise or having non-compressible vessels. Controls were without prior history of atherosclerotic vascular disease and when tested, no evidence of ischemia on a stress test. Phenotypes and environmental exposures including age, ethnicity, demographic and anthropometric data are derived from the Mayo Electronic Medical Record (EMR). Comorbidities were determined using algorithms for diabetes and hypertension based on ICD-9 codes and medication use. Relevant laboratory data, including lipid levels, fasting blood sugar and serum creatinine at index date or within a 1-year window of the index date were extracted. Medication classes at index date were identified using Mayo's Natural Language Processing-based system with RxNorm codification and NDF-RT terminologies mapping. Smoking status was confirmed by natural language processing of clinical notes. Genotyping of ~600,000 SNPs across the genome is being conducted at the Broad Institute using the Illumina 660W platform. Statistical analyses will be conducted to identify genetic variants associated with susceptibility to PAD.

  Study phs000203

• Transformation of Dysplasia in Barrett's Esophagus

  Complex chromosomal alterations are a hallmark of advanced cancers but rarely seen in normal tissue. The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations that can drive their transformation through focal oncogenic amplifications. However, the etiology and evolution dynamics of these alterations are poorly understood. Here we study chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) by multi-regional whole-genome sequencing analysis of BE samples with dysplasia and microscopic EAC foci. Through haplotype-specific copy-number analysis of BE genome evolution, we identified distinct patterns of episodic copy-number evolution consistent with the outcomes of abnormal mitosis and dicentric chromosome breakage. While abnormal mitosis, including whole-genome duplication, accounts for most chromosome or arm-level copy-number changes, segmental copy-number alterations display signatures of multi-generational evolution of unstable dicentric chromosomes. Continuous evolution of dicentric chromosomes through breakage-fusion-bridge cycles and chromothripsis rapidly increases genomic complexity and diversity among BE cells, culminating in the generation of distinct focal amplifications. These mutational processes enable multiple subclones within small dysplastic areas to undergo parallel transformation to cancer following acquisition of distinct oncogenic amplifications. Our results demonstrate how chromosomal instability drives clonal diversification in precancer evolution and promotes tumorigenesis in primary human samples.

  Study phs002706

• An Advanced Molecular Medicine Case Report of a Rare Human Tumor Using Genomics, Pathomics, and Radiomics

  The associated data of this study is derived from a single female patient with pulmonary sclerosing pneumocytoma (PSP). The aim of this study is to provide the most comprehensive, multi-modality sequencing study of a single case of PSP to-date. To this end, the following sequencing experiments were performed: i) RNA-Seq of the primary tumor and adjacent normal tissues (6 replicates for each tissue type), which was intended to analyze RNA-Seq fusions, gene expression, expression mutations, ii) low-pass DNA whole genome sequencing (WGS) from primary tumor tissue and germline, which was intended to analyze copy number aberrations, and iii) DNA targeted panel sequencing of lung cancer associated genes, using primary tumor tissue and germline from white blood cells, which was intended to analyze somatic mutations. Principal findings: i) the PSP hallmark mutation AKT1 (p.E17K) was detected within both the DNA and RNA, and ii) the TP53 signaling pathway was found to be statistically significant by three different pathway analysis tools of analyzing gene expression and pathway ramifications. Among proteins within the TP53 signaling pathway, the p53 inhibitor encoded by MDM2 was found to be overexpressed (by differential gene expression analysis). The original sequencing data (i.e., FastQ files) from each of the aforementioned samples will be accessible through dbGaP.

  Study phs003154

• OncoArray: Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)

  The Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) was one of five projects funded in 2010 as part of the NCI's Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (http://epi.grants.cancer.gov/gameon/). FOCI represents a collective effort that builds upon the strengths and history of collaboration inherent in the Ovarian Cancer Association Consortium (OCAC), a multidisciplinary group comprised of epidemiologists, genetic epidemiologists, statistical geneticists, molecular and cell biologists and clinicians that was formed in 2005. The other four funded GAME-ON projects were: the ColoRectal TransdisciplinaryStudy (CORECT), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE), and Transdisciplinary Research in Cancer of the Lung (TRICL). As part of our aim to discover, expand, and replicate ovarian cancer susceptibility loci, the GAME-ON projects and other consortia formed the OncoArray network (http://epi.grants.cancer.gov/oncoarray/) to develop and genotype a new custom genotyping array in large numbers of cancer cases and controls (over 400,000 samples) across multiple cancer types. The FOCI data includes over 50,000 ovarian cancer cases and controls genotyped with the Oncoarray at the Center for Inherited Disease Research (CIDR). Genotype calling and quality control procedures were performed under a standardized protocol across the Oncoarray consortium, and over 490,000 SNPs passed QC and are included under this dbGaP submission.

  Study phs001882

• Mid-pass Whole-genome Sequencing in a Malagasy Cohort Uncovers Body Composition Associations

  The majority of human genomic research studies have been conducted in European-ancestry cohorts, reducing the likelihood of detecting potentially novel and globally impactful findings. Here, we present mid-pass whole-genome sequencing data and a genome-wide association study in a cohort of 264 self-reported Malagasy individuals from three locations on the island of Madagascar. We describe genetic variation in this Malagasy cohort, providing insight into the shared and unique patterns of genetic variation across the island. We observe phenotypic variation by location, and find high rates of hypertension particularly in the Southern Highlands sampling site as well as elevated self-reported malaria prevalence in the West Coast site relative to other sites. After filtering to a subset of 214 minimally-related individuals, we find a number of genetic associations with body composition traits, including many variants that are only observed in African populations or populations with admixed African ancestry from the 1000 Genomes Project. This study highlights the importance of including diverse populations in genomic research for the potential to gain novel insights, even with small cohort sizes. This project was conducted in partnership and consultation with local stakeholders in Madagascar and serves as an example of genomic research that prioritizes community engagement and that has potential impacts on our understanding of human health and disease.

  Study EGAS50000000496

• Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions

  Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genomic data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180-200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5' flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23-31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process.

  Study EGAS50000000481

• Germline Genetics of Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

  Myelodysplastic syndromes (MDS) are part of a heterogeneous and overlapping group of clonal diseases that arise in the hematopoietic stem or progenitor cells and also include acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and the hybrid MDS/MPN entities. Individuals with MDS have a high risk of progressing to leukemia, with approximately 30% expected to develop AML. This study evaluates genetic susceptibility to myeloid malignancy using data from population-based case control studies of myelodysplastic syndromes and acute myeloid leukemia in adults (ages 18-85 years) and pediatric MDS cases with banked samples at the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult cases were identified through the Minnesota Cancer Reporting System and controls were recruited from the State Driver's License/Identification Card list. DNA samples were collected via mouthwash collection kits (AML cases and controls) or Oragene saliva collection kits (adult MDS cases and controls). Pediatric MDS samples were banked at CIBMTR prior to receipt of a transplant and DNA was extracted from isolated T cells or whole blood samples. Genotyping data were generated using the Illumina Global Diversity array and quality control and genotype calling was conducted using established best practices. Our primary analyses investigated the contribution of genetic variation to MDS risk and evaluated the role of the killer cell immunoglobulin receptors (KIR) on incidence and survival.

  Study phs002962

• DLK1 Distinguishes Subsets of NF1-Associated Malignant Peripheral Nerve Sheath Tumors with Divergent Molecular Signatures

  Study Design and Aims We aimed to investigate the molecular mechanisms underlying the malignant transformation of pre-existing neurofibromas (PNST) to malignant peripheral nerve sheath tumors (MPNST) in individuals with neurofibromatosis type 1 (NF1). Our primary focus was on the role of DLK1 in this transformation process and its potential as a biomarker for diagnosis, risk assessment, and therapeutic stratification. Population InformationThis study consisted of a case set of peripheral nerve sheath tumor specimens, including plexiform neurofibromas, atypical neurofibromas, and MPNSTs, acquired under IRB approval at our institution. The majority of the subjects had neurofibromatosis type 1. Principal Findings DLK1 Overexpression: The study found that DLK1 is significantly increased in MPNST compared to non-malignant neurofibromas.Early Marker: DLK1 overexpression may precede histological changes indicative of malignancy.Serum Levels: Higher serum levels of DLK1 were observed in both mice and humans with MPNST.Molecular Stratification: Divergent levels of DLK1 expression identified distinct MPNST subsets with unique molecular characteristics and potential therapeutic targets.Clinical Implications: Overexpression of DLK1 was associated with the reactivation of embryonic signatures, an immunosuppressive microenvironment, and poorer overall survival in NF1-MPNST patients. Data Availability Whole exome sequencing, bulk RNA sequencing, and single-cell RNA sequencing data from this study will be made available through the database of Genotypes and Phenotypes (dbGaP) to support further research and validation studies.

  Study phs003835

• NIH RECOVER: A Multi-Site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection

  The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in decedents who die more than 60 days after initial onset or after hospital discharge, whether in-hospital or out-of-hospital at time of death, and who meet the working definition of PASC as defined by the recent World Health Organization publication given in Section 5.4. The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of decedents who died between15-60 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003768

• Genetic and Hormonal Contributions to Gene Expression in Immune Cells

  The origins of sex differences in human disease are elusive, in part because of difficulties in separating the effects of sex hormones and sex chromosomes. To isolate the effects of testosterone, estradiol, and sex chromosome complement (XX or XY) in humans, we implemented a four-state, cross-sectional study design of trans- and cisgender individuals, the former receiving exogenous testosterone or estradiol for at least a year as part of their gender-affirming medical care. This study design allowed us to compare four combinations of sex hormones and sex chromosomes in humans: XX individuals treated with exogenous testosterone (n=21), XY individuals treated with exogenous estradiol (n=13), untreated XX individuals (n=20), and untreated XY individuals (n=15). We chose to focus on the human immune system because it displays an impressively broad range of sex-differential biology. We collected blood samples from each individual and isolated PBMCs the same day. We performed 10X Genomics 3' single-cell RNA-sequencing (scRNA-seq) on PBMCs from the 69 individuals. We generated 150-bp paired end reads from a total of 358,426 cells (with an average of 48,007 reads/cell) and identified 18 distinct immune cell types. We found that testosterone, estradiol, and sex chromosome complement have unique, non-overlapping effects on PBMC cell abundances and gene expression.

  Study phs003860