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• Structure of the Mucosal and Stool Microbiome in Lynch Syndrome

  The gut microbiota has been associated with colorectal cancer (CRC), but causal alterations preceding CRC have not been elucidated. To prospectively assess microbiome changes prior to colorectal neoplasia, we investigated samples from 100 Lynch syndrome patients using 16S rRNA gene sequencing of colon biopsies, coupled with metagenomic and metatranscriptomic sequencing of feces. Colectomy and CRC history represented the largest effects on microbiome profiles. A subset of Clostridiaceae were depleted in stool corresponding with baseline adenomas, while Desulfovibrio was enriched in both stool and mucosal biopsies. A classifier leveraging stool metatranscriptomes resulted in modest power to predict interval development of preneoplastic colonic adenoma. Predictive transcripts corresponded with a shift in flagellin contributors and oxidative metabolic microenvironment, potentially factors in local CRC pathogenesis. This suggests that the effectiveness of prospective microbiome monitoring for adenomas may be limited but supports the potential causality of these consistent, early microbial changes in colonic neoplasia.

  Study phs002343

• A catalog of the genetic causes of Hereditary Angioedema in the Canary Islands (Spain)

  Hereditary angioedema (HAE) is a rare disease where known causes involve C1 inhibitor dysfunction or dysregulation of the kinin cascade. The updated HAE management guidelines recommend performing genetic tests to reach a precise diagnosis. Unfortunately, genetic tests are still uncommon in the diagnosis routine. Here, we characterized for the first time the genetic causes of HAE in affected families from the Canary Islands (Spain). Whole-exome sequencing data was obtained from 41 affected patients and unaffected relatives from 29 unrelated families identified in the archipelago. The Hereditary Angioedema Database Annotation (HADA) tool was used for pathogenicity classification and causal variant prioritization among the genes known to cause HAE. Manual reclassification of prioritized variants was used in those families lacking known causal variants. We detected a total of eight different variants causing HAE in this patient series, affecting essentially SERPING1 and F12 genes, one of them being a novel SERPING1 variant (c.686-12A>G) with a predicted splicing effect which was reclassified as likely pathogenic in one family. Altogether, the diagnostic yield by assessing previously reported causal genes and considering variant reclassifications according to the American College of Medical Genetics guidelines reached 66.7% (95% Confidence Interval [CI]: 30.1-91.0) in families with more than one affected member and 10.0% (95% CI: 1.8-33.1) among cases without family information for the disease. Despite the genetic causes of many patients remain to be identified, our results reinforce the need of genetic tests as first-tier diagnostic tool in this disease, as recommended by the international WAO/EAACI guidelines for the management of HAE.

  Study EGAS00001006547

• Genome-wide Association Study of Myasthenia Gravis

  The purpose of this project was to conduct a genome-wide associate study to search for the genetic factors that predispose to myasthenia gravis. The rationale for this study lies in the fact that, although the immunological and physiological processes affecting the neuromuscular junctions of myasthenia gravis patients are well understood, the spectrum of genetic factors that predispose to myasthenia gravis and influence its disease manifestations are not well known. Identification of the myasthenia gravis-related genes will shed light on the fundamental cellular events underlying myasthenia gravis, and will provide focus for research aimed at developing therapies that alter the natural course of the disease. A consortium of fourteen institutions in North America collected DNA samples from 1028 people diagnosed with autoimmune myasthenia gravis. Relevant clinical data have been collected for each patient, including age of onset, severity of disease, response to drug therapy, personal and family history of other autoimmune diseases. Genotyping of the case cohort was performed in the Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD. Genotyping of the case cohort was performed using the HumanOmniExpress-12v1_C SNP array manufactured by Illumina Inc. For the control cohort, we downloaded genotype data from dbGAP (accession phs000196.v2.p1) for 1,998 US neurologically normal individuals. The control cohort had been previously genotyped at the Center for Inherited Disease Research at Johns Hopkins University on HumanOmni1-Quad version 1.0B beadchips (Illumina) as part of the NeuroGenetics Research Consortium GWAS of Parkinson's disease. Analyses were confined to the 677,673 autosomal SNPs that were common to both chips. Of the 1028 samples which were genotyped, 21 samples were excluded due to mismatched genders, 9 were excluded due to low genotype call rate, 5 samples were excluded as duplicates, and 25 samples were excluded as ethnic outliers. The remaining 972 samples were used in analysis.

  Study phs000726

• Whole genome sequencing of retinoblastoma reveals the diversity of rearrangements disrupting RB1 and uncovers a treatment related mutational signature

  Background: The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable suggesting alternative pathways to malignancy. Methods: We applied comprehensive whole genome sequencing (WGS) and transcriptomics to sporadic retinoblastomas derived from twenty patients attending our clinic, contrasting these results to that obtained through customary clinical testing. We sought RB1 and other driver mutations, investigated mutation burden, mutational signatures and phylogenetic relatedness in one case of bilateral retinoblastoma. Results: At least one RB1 mutation was identified in all retinoblastomas. We confirmed RB1 mutations previously identified by clinical screening, identified three new RB1 mutations and provided clarity to the mechanism behind a further six mutations. Eight tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Potential driver mutations included mutations in BCOR (5/20) and amplification of MYCN (2/20) and MDM4 (1/20). We show that RB1 mutations are not mutually exclusive of MYCN amplifications, and further reveal that all tumours demonstrate increased MYCN expression suggesting a universal role in retinoblastoma tumorigenesis.  Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. In-keeping with previous WGS of paediatric cancers, the mutation burden in retinoblastomas was extremely low. Mutational signature analysis showed a predominance of signatures associated with cell division and an absence of ultraviolet-related DNA damage. In a tumour exposed to chemotherapy prior to enucleation, a profound platinum-related mutational signature was observed. Conclusions: WGS provides a complete picture of the genomic landscape of retinoblastomas, allowing the discovery of mutations otherwise undetected by conventional clinical screening approaches. The presence of at least one RB1 mutation in all retinoblastomas and the relative paucity of driver mutations in other genes suggests mutations beyond RB1, MYCN and BCOR are rare. Whilst most RB1 mutations are identifiable by clinical screening, the increased resolution and ability to detect otherwise elusive rearrangements of RB1 by WGS, confirming whether they are somatic or germline, has important repercussions on clinical management and advice on recurrence risks.

  Dataset EGAD00001006431

• XClone for analyzing somatic copy number alterations

  Somatic copy number alterations (CNAs) are major mutations that contribute to the development and progression of various cancers. Despite a few computational methods proposed to detect CNAs from single-cell transcriptomic data, the technical sparsity of such data makes it challenging to identify allele-specific CNAs, particularly in complex clonal structures. In this study, we present a statistical method, XClone, that strengthens the signals of read depth and allelic imbalance by effective smoothing on cell neighborhood and gene coordinate graphs to detect haplotype-aware CNAs from scRNA-seq data. By applying XClone to multiple datasets with challenging compositions, we demonstrated its ability to robustly detect different types of allele-specific CNAs and potentially indicate whole genome duplication, therefore enabling the discovery of corresponding subclones and the dissection of their phenotypic impacts.

  Study EGAS00001007854

• Heart Failure Network Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure (HFN IRONOUT-BioLINCC)

  ObjectivesTo test the hypothesis that, compared to placebo, oral iron repletion in heart failure patients with iron deficiency improves exercise capacity after 16 weeks of therapy.Background Iron deficiency affects approximately one half of patients with symptomatic heart failure. The presence of iron deficiency in patients with heart failure is associated with reduced functional capacity, poorer quality of life, and increased mortality. Despite growing recognition of the significance of iron deficiency, randomized multicenter trials exploring the utility of oral iron supplementation, a therapy that is inexpensive, readily available, and safe, have not been performed in patients with heart failure. Moreover, patient characteristics and biochemical profiles that may influence responsiveness to oral iron in patients with heart failure have not been defined. Results of intravenous iron repletion trials have been favorable, but regularly treating patients with intravenous iron products is expensive and poses logistical challenges for outpatients. Therefore, the HFN-IRONOUT study was initiated to investigate the efficacy of oral iron in patients with heart failure with reduced ejection fraction (HFrEF). ParticipantsA total of 225 participants were enrolled, 111 randomized to receive oral iron and 114 randomized to receive the placebo. Design The HFN-IRONOUT study was a phase 2, double-blind, placebo-controlled randomized clinical trial that enrolled participants at 23 sites in the United States. Participants were randomly assigned, in a 1:1 ratio, to receive either oral iron polysaccharide or placebo with the use of an automated web-based system. A permuted block randomization method (with 4 participants per block) was stratified by enrolling site and anemia status (defined as hemoglobin At baseline, 8 weeks, and 16 weeks participants underwent studies including history and physical examination, cardiopulmonary exercise testing (CPET), Kansas City Cardiomyopathy Questionnaire (KCCQ), and 6-minute walk test. CPETs were performed using a 10 Watt/minute incremental ramp protocol and breath-by-breath measures of oxygen uptake were uniformly analyzed by the CPET Core Lab. Participants also underwent phlebotomy for biomarkers. Iron studies, including iron, total iron binding capacity, and ferritin, were measured at baseline and after 16 weeks to determine the extent to which oral iron led to iron repletion. The primary end point was the change in peak oxygen uptake (peak VO2) after 16 weeks of therapy. Conclusions Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks.

  Study phs003557

• eIMPACT Trial: Modernized Collaborative Care to Reduce the Excess CVD Risk of Older Depressed Patients

  Cardiovascular disease (CVD) is the #1 killer of American men and women, and its economic burden is substantial and on the rise. Adults with depression are at elevated risk of CVD events and poor CVD prognosis. Unfortunately, past clinical trials of depression treatments have not observed the anticipated cardiovascular benefits. A novel explanation for these null results is that the depression interventions in these trials, which all involved patients with preexisting CVD, were delivered too late in the natural history of CVD. Accordingly, the objective of this single-center, parallel-group, assessor-blinded randomized controlled trial was to determine whether successful depression treatment before, versus after, the onset of clinical CVD reduces CVD risk in depression. Primary care patients with depression and elevated CVD risk from a safety net healthcare system (N = 216, Mage = 59 years, 78% female, 50% Black, 46% with income <$10,000/year) were randomized 1:1 to 12 months of the eIMPACT intervention (a modernized collaborative stepped care program involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and psychiatrists). The primary outcome was endothelial dysfunction (brachial flow-mediated dilation) at 12 months, and the secondary outcomes were self-reported depressive symptoms (Hopkins Symptom Checklist-20), autonomic dysfunction (high-frequency heart rate variability), systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein), and platelet activation (β-thromboglobulin and platelet factor 4) at 12 months. The central hypothesis was that the eIMPACT intervention would improve endothelial dysfunction in depressed adults by decreasing depressive symptoms, autonomic dysfunction, systemic inflammation, and platelet activation. Primary results are posted to ClinicalTrials.gov at NCT02458690. The de-identified limited dataset available on BDC consists of only the individual phenotypic data needed to confirm this trial’s primary results – i.e., randomization status, primary and secondary outcome variables, and participant characteristics utilized in the hypothesis-testing models (age, sex, race, education, income, and systolic blood pressure). We also provide the SAS code to replicate the results of the hypothesis-testing models reported in Table 4 and Supplemental Tables 1-3 in the main outcomes paper (#2 in Selected Publications). Of note, the user will need to specify the file path for the dataset to run the SAS code. Instructions for requesting individual-level data are available on BDC at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BDC. For questions about availability, you may contact the BDC team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs003283

• Single Cell Genomic Analysis of Lymphoma

  Our study aimed to define the extent of heterogeneity between anatomically separated tumor manifestations in follicular lymphoma at single-cell resolution. We subjected single-cell suspensions derived from nodal, synchronously-acquired fine needle aspirations from two distinct tumor sites to high-throughput microfluidics-based single-cell RNA sequencing. By comparing the relative composition of the tumor subpopulations between the two tumor sites, we found that some patients can exhibit site-to-site differences. While the overall composition of the tumor microenvironment did not differ significantly between sites, we did detect a specific correlation between site-to-site tumor heterogeneity and T follicular helper cell abundance. Our study demonstrates the significant limitations of a solitary biopsy in defining the full scope of a patient's disease.

  Study phs002188

• Neural Systems, Inhibitory Control, and Methamphetamine Dependence

  The Neural Systems, Inhibitory Control, and Methamphetamine Dependence study started in 2011 and is currently finishing data collection for its last participants. The study included methamphetamine abusing individuals and healthy control participants aged 18-55 years. Participants who qualified over the telephone were scheduled to visit the London Laboratory at the UCLA Semel Institute for Neuroscience and Human Behavior for the In-Person Screening Phase. The screening procedures, usually scheduled over two visits, determined if participants were eligible to complete the subsequent study visits. Both groups completed identical screening procedures, with the exception of more in-depth drug use questions for the methamphetamine users. After providing written consent, participants completed questionnaires about their mood, medical, psychiatric and drug use history, personality and life experiences. They also provided a urine sample to determine what drugs they recently used and a breath sample to determine the carbon monoxide levels in their system. The drug screen tested for recent methamphetamine, cocaine, opiates/opioids, benzodiazepines, THC and other amphetamines. Methamphetamine participants needed to test positive for methamphetamine at admission. If methamphetamine participants tested positive for any drugs other than methamphetamine or marijuana, and if healthy control participants tested positive for any drugs other than marijuana, they were excluded from the study. Additionally, the urine samples of female participants were tested for pregnancy; pregnant females were also excluded. If no exclusionary criteria were met during the first screening visit, participants completed a second screening visit to ensure they were mentally and physically healthy enough to participate. The second screening visit included a psychiatric diagnostic interview (DSM-IV (SCID-I) for first 500 participants and the MINI International Neuropsychiatric Interview M.I.N.I for the last 50 participants). Additionally, laboratory tests and procedures were completed by the UCLA General Clinical Research Center and interpreted by a study physician. Laboratory tests included vital signs (heart rate--BPM, blood pressure, and respirations), an electrocardiogram (ECG) to record the electrical activity of the heart, and an 18-cc blood sample to perform laboratory tests which included a complete chemistry and metabolic panel, hepatic panel, Hepatitis-C tests, and HIV test. The laboratory tests from this blood sample ensured that participants' liver and kidneys were functioning normally, and that their standard blood counts (red cell, white cell, and salts) were also normal. If a Hepatitis-C (HCV) or HIV test was positive, participants were not allowed to continue in the study and their results were reported to the California State Health Department. Participants deemed eligible to continue in the methamphetamine group participated on an outpatient basis or were admitted to the UCLA Medical Center to participate on an inpatient basis for up to 10 days. Typically, detectable levels of methamphetamine in urinalysis remain for 2-3 days, therefore inpatient days 0-3 served as a "washout period" and the methamphetamine abusing inpatient participants provided daily urine samples to test for recent drug use and pregnancy (female participants only). Outpatient participants were also required to remain abstinent from all drugs except nicotine and marijuana for at least 4 days prior to study sessions. Self-reported abstinence for outpatients was verified by urine toxicology and saliva screening at every visit to UCLA before completion of study procedures. Neurocognitive assessments, about three hours each, typically took place on two separate days. The purpose of the neurocognitive sessions were to assess participants' intellectual and neurocognitive functioning. On either the same day as the neurocognitive testing or on separate days, both methamphetamine abusers and healthy controls were administered a structural MRI to collect information on brain structure.

  Study phs001197

• Whole_genome_sequencing_of_100_DDD_trios_with_suspected_noncoding_causal_mutations

  We would like to whole-genome sequence 100 trios (300 individuals) from the DDD project in which we suspect the proband has a pathogenic noncoding mutation, to 30X coverage. These have been carefully selected to maximise the chances of finding pathogenic noncoding mutations. Specifically, we have selected probands who have no likely causal mutation within the coding region but who have a heterozygous loss-of-function mutation inherited from one parent in a known recessive developmental disorder gene, and whose phenotype is a good match for the typical phenotype caused by recessive variants in that gene. We suspect that these probands may have a heterozygous noncoding mutation on the other allele which reduces expression of the gene so that, together, these two mutations are effectively equivalent to a homozygous loss-of-function mutation. About a quarter of the probands have affected siblings and, if those siblings have been exome sequenced, we have checked that they are identical-by-descent in the region of the gene. We propose to search in the promoter region, intronic and annotated regulatory regions around these genes of interest for rare variants inherited from the other parent (i.e. not the one who transmitted the loss-of-function variant), or de novo variants. If we find such variants, and demonstrate an enrichment of this compound heterozygous LoF noncoding mechanism above that expected by chance, we intend to follow up specific candidates by RNAseq and potentially CRISPR/Cas9 experiments. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002452