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• Leptomeningeal melanocytic tumour

  This is the first whole exome sequencing analysis of a primary meningeal melanocytic tumour (MMT) alongside the patients germline. Here we report the CRAM files from the tumour and germline.

  Dataset EGAD00001003750

• Transcriptomic profiling of human small intestine macrophage and DC subsets

  Using low input SMART-seq protocol, the whole transcriptome of human small intestine macrophage subtypes is characterized.

  Dataset EGAD00001003581

• HEMOGLOBIN HAPLOTYPES IN ABIDJAN

  This is a prospective study with 100 participants. The enzymatic digestion profiles after conventional PCR allowed the identification of different haplotypes of hemoglobin in Abidjan.

  Dataset EGAD00001008546

• danMAC5

  Three whole genome sequecing of three independent cohorts. The three cohorts derives from projects including samples of inviduals with Danish origin. Data is deviden into males and female and compiled.

  Dataset EGAD00001009756

• Whole Exome Sequences from Eivissan and Menorcan Individuals

  We analyzed Exome sequences of present day Eivissan and Menorcan individuals in order to expand on the knowledge about their demographic history and its functional consequences.

  Study EGAS50000000428

• Immune Profiles Study

  This study assesses glioma patient blood methylation longitudinally beginning pre-surgery through other clinically important timepoints. Progression and survival are studied in relation to methylation derived immunologic profiles and other characteristics. For this study, patients scheduled for surgery at University of California San Francisco (UCSF) for a possible newly diagnosed glioma (grades 2-4) or recurrent grade 2/3 glioma were consented and enrolled. Patients had blood collected pre-surgery and, if the pathology results confirm a glioma, every few weeks or months during their treatment (up to 30 total timepoints). Blood immunomethylomic profiles were measured at these timepoints to assess associations with glioma patient outcomes, clinical measures, other known prognostic markers, and imaging characteristics.

  Study phs002998

• Sequencing data of tumor tissue obtained from GANNET53 study patients

  The GANNET53 clinical trial evaulated novel treatment options for ovarian cancer patients with platinum-resistant relapse. Archival fresh-frozen paraffin embedded tissue was available from 131 of the 133 enrolled patients. NGS sequencing aimed at assessing the mutational spectrum of key ovarian cancer genes (with a focus on TP53), and their relevance for therapy resistance. From available FFPE samples, DNA was extracted and NGS sequenced using the SureSeq™ Ovarian Cancer Panel and the NGS Library Preparation kit covering all exons of 7 key ovarian cancer genes BRCA1, BRCA2,TP53, PTEN, ATM, ATR, NF1 for single nucleotide variants (SNV) and indels. Finally, sequence data from 118 individual FFPE tumor tissue samples were generated.

  Study EGAS50000000935

• iNHL WXS Data Commitee

  The iNHL WXS Data Commitee is responsible for managing access to datasets submitted to the European Genome-phenome Archive (EGA). Our committee ensures that access requests are evaluated in compliance with ethical guidelines, regulatory requirements, and the conditions specified by data submitters. Researchers requesting access to these datasets must provide a clear and valid scientific purpose, demonstrate affiliation with a recognized institution, and agree to the terms of use outlined in the Data Access Agreement. The iNHL WXS Data Commitee works to uphold data privacy and security while facilitating responsible data sharing to advance scientific discovery. For further information on our policies or the application process, please contact Hauke Busch (hauke.busch@uni-luebeck.de).

  Dac EGAC50000000488

• Data access policy

  Investigators who download restricted data from this dataset should: - Not attempt to identify individual human research participants from whom the data were obtained. - Acknowledge in all oral or written presentations, disclosures, or publications the specific dataset(s) or applicable accession number(s) and the repositories through which the investigator accessed any data. Any user requesting access to this data must apply for authorization, which is granted by the Data Access Committee (DAC). The DAC will review and approve or disapprove all requests from the research community for data access. Decisions to grant access are made based on whether the request conforms to the specifications of the Research Ethics Committee approval and program specific requirements or procedures (if any).

  Dac EGAC50000000504

• The British Autozygosity Populations BioResource (2018-06-06)

  This data set contains whole exome sequences of individuals with self-stated parental relatedness from the East London Genes & Health cohort. Rare frequency functional variants in these healthy individuals will be studied with respect to the genetic health of the participants and loss-of-function analysis of human genes. 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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-06-06.

  Dataset EGAD00001004150

• Whole genome sequence of third generation family member (SFHS)

  Previously we performed deep WGS on 6 parents and 13 children from 3 large families from the Scottish Family Health Study to identify de novo mutations. This prelim is cover the additional sequencing of one grandchild from one of these three families. The inclusion of a third generation individual will provide additional experimental validation for the de novo mutations found in the initial trio. As in the previous study, the DNA will be WGS to a depth of approximately 25X to achieve this purpose.These data can only be used for the investigation of the genetic causes of the reported clinical phenotypes in these patients

  Dataset EGAD00001001454

• Whole Genome Sequences of 18th century African descended individuals from Charleston, South Carolina.

  This study presents Whole Genome Sequencing results from the Anson Street African Burial Ground Project, which is a community-based initiative aimed at understanding the histories of 37 Ancestors in Charleston, South Carolina. Here we report fastq files for all 37 Ancestors. DNA was extracted at the University of Tennessee-Knoxville following Dabney et al. 2013, and dual index libraries prepared using a modified NEBNext Ultra II kit with partial USER enzyme digestion. Libraries were then enriched for human genomic DNA (MyBaits) and sequenced on Illumina Platforms.

  Dataset EGAD00001009643

• COMPARE study: participants typed during UK Biobank version 2 array development phase

  The COMPARE study enrolled 29,066 British blood between donors between February 2016 and March 2017, the study aim is to find the optimum technology for haemoglobin screening (ISRCTN 90871183). All participants were at the time of recruitment active blood donors. The 4,796 participants in this dataset have consented to join the NIHR BioResource. Genotyping data was produced using the Thermo Fisher Scientific Axiom Genotyping platform. The UK Biobank version 2 array design was used, content on this array has been added to allow for accurate DNA based identification of human blood group antigens.

  Dataset EGAD00001005023

• Subset of EGAS00001005112 (The INFORM Precision Medicine Study for High-Risk Pediatric Malignancies, 17 exomes) which is used in EGAS00001005243 (Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B)

  Part of the project: The INFORM Precision Medicine Study for High-Risk Pediatric Malignancies resulted in the publication of this study: Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B. This dataset contains the subset of 17 patient exome sequencing data.

  Dataset EGAD00001007864

• Peripheral Blood Transcriptome Analysis of ALS Patients

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders which overlap in their clinical presentation, pathology, and genetic origin. An over-representation of autoimmune disorders exists in both ALS and FTD, but this remains an unexplained epidemiologic observation. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene (GeneID:203228) are the most common cause of familial ALS and FTD (C9-ALS/FTD), leading to both repeat containing RNA and dipeptide accumulation coupled with decreased C9orf72 protein expression in brain and peripheral blood cells. Here we show that loss of C9orf72 in myeloid cells is sufficient to recapitulate the age dependent lymphoid hypertrophy and autoinflammation seen in complete C9orf72-/- mice. Dendritic cells isolated from C9orf72-/- mice showed marked early activation of the type I interferon response, and C9orf72-/- myeloid cells were primarily hyperresponsive to activators of stimulator of interferon gene (STING1 GeneID:340061), a key regulator of the innate immune response to cytosolic DNA. STING degradation through the autolysosomal pathway was diminished in C9orf72-/- mice myeloid cells, and blocking STING suppressed hyperactive type I interferon responses in C9orf72-/- myeloid cells and splenomegaly and inflammation in C9orf72-/- mice. Additionally, mice lacking one or both copies of C9orf72 were more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in C9-ALS/FTD patients. Finally, we found that blood derived macrophages, peripheral blood monocytes, and brain tissue from C9-ALS/FTD patients all showed a hyperactive type I interferon signature compared to sporadic ALS/FTD subjects. Collectively, our results indicate that C9-ALS/FTD patients have an altered immunophenotype due to loss of C9orf72 regulation of STING mediated type I interferon activation.

  Study phs002055

• Luminal breast epithelial cells from wildtype and BRCA mutation carriers harbor copy number alterations commonly associated with breast cancer

  Cancer-associated mutations have been documented in normal tissues, but the prevalence and nature of somatic copy number alterations and their role in tumor initiation and evolution is not well understood. Here, using single cell DNA sequencing, we describe the landscape of CNA variants in >48,000 breast epithelial cells from women with normal or high risk of developing breast cancer. Individual cells with one or two of a specific subset of CNAs (e.g. 1q gain and 16q, 22q, 7q, and 10q loss) are detectable in almost all breast tissues and, in those from BRCA1 or BRCA2 mutations carriers, occurs prior to loss of heterozygosity (LOH) of the wildtype alleles. These CNAs, which are among the most common associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, are enriched almost exclusively in luminal cells and are generally absent from basal myoepithelial cells. Allele-specific analysis of the enriched CNAs reveals that each allele was independently altered, demonstrating convergent evolution of these CNAs in an individual breast. Tissues from BRCA1 or BRCA2 mutation carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53, LOH of BRCA1 or BRCA2, and multiple breast cancer-associated CNAs in addition to one or more of the common CNAs in 1q, 10q or 16q. Notably, cells with intermediate levels of CNAs were not detected, arguing against a stepwise gradual accumulation of CNAs. Overall, our findings demonstrate that chromosomal alterations in normal breast epithelium including from high risk women, link early stage CNAs to clonally expanded tumor genomes .

  Study EGAS00001007716

• Telomerase activation by genomic rearrangements in high-risk neuroblastoma

  Neuroblastoma is a malignant pediatric tumor of the sympathetic nervous system1. Roughly half of these tumors regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavorable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive2-4. We have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n=39; low-risk, n=17) and discovered recurrent genomic rearrangements affecting a chromosomal region (5p15.22) proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumor type1,2,5. In an extended case series (n=217), TERT rearrangements defined a subgroup of high-risk tumors with particularly poor outcome. Despite the large diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumors, TERT expression was also elevated in MYCN-amplified tumors, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.22 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodeling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cells bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodeling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the center of transformation in a large fraction of these tumors.

  Study EGAS00001001308

• DNA methylation-based prognostic subtypes of chordoma tumors in tissue

  Chordomas are rare malignant bone cancers of the skull-base and spine. Patient survival is variable and not reliably predicted using clinical factors or molecular features. This study identifies prognostic epigenetic chordoma subtypes that are detected noninvasively using plasma methylomes. Methylation profiles of 68 chordoma surgical samples were obtained between 1996 and 2018 across three international centers along with matched plasma methylomes where available. Consensus clustering identified two stable tissue clusters with a disease-specific survival difference that was independent of clinical factors in a multivariate Cox analysis (HR = 14.2, 95%CI: 2.1–94.8, P = 0.0063). Immune-related pathways with genes hypomethylated at promoters and increased immune cell abundance were observed in the poorperforming “Immune-infiltrated” subtype. Cell-to-cell interaction plus extracellular matrix pathway hypomethylation and higher tumor purity were observed in the better-performing “Cellular” subtype. The findings were validated in additional DNA methylation and RNA sequencing datasets as well as with immunohistochemical staining. Plasma methylomes distinguished chordomas from other clinical differential diagnoses by applying fifty chordoma-versusother binomial generalized linear models in random 20% testing sets (mean AUROC = 0.84, 95%CI: 0.52–1.00). Tissue-based and plasma-based methylation signals were highly correlated in both prognostic clusters. Additionally, leave-one-out models accurately classified all tumors into their correct cluster based on plasma methylation data. Here, we show the first identification of prognostic epigenetic chordoma subtypes and first use of plasma methylome based biomarkers to noninvasively diagnose and subtype chordomas. These results may transform patient management by allowing treatment aggressiveness to be balanced with patient risk according to prognosis.

  Study EGAS00001006406

• Acute Respiratory Distress Network (ARDSNet) Studies 01 and 03 Lower Versus Higher Tidal Volume, Ketoconazole Treatment and Lisofylline Treatment (ARMA/KARMA/LARMA) (ARDSNet-ARMA/KARMA/LARMA-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-ARMA/KARMA/LARMA include plasma, serum and urine. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The ARDS Network is a consortium of clinical centers and a coordinating center to design and test novel therapies for the treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The primary objective of the KARMA trial was to investigate the efficacy and safety of Ketoconazole and Respiratory Management in the treatment of ALI and ARDS. The Ketoconazole arm of the study was later stopped due to an inability to show efficacy. Participants continued to be randomized to the respiratory management arms of the study (ARMA), which compared two ventilator strategies: a tidal volume of 6 mL/kg versus 12 mL/kg. The LARMA phase of the study investigated the efficacy of Lisofylline and Respiratory Management. Background Participants suffering from ARDS are extremely ill, require mechanical ventilation and, despite improvements in medical care and technology, had a mortality rate as high as 50 percent. An excessive inflammatory response is characteristic of ALI of which ARDS represents the most severe end of the pathophysiologic spectrum. The inflammatory response includes increased numbers of neutrophils activated to produce cytokines, proteases, and reactive oxygen intermediates. Pulmonary injury may also be enhanced by alveolar and tissue macrophages as a producer of vasoactive substances, neutrophil chemoattractants, and procoagulant substances. Ketoconazole, a synthetic antifungal imidazole, also has anti-inflammatory activities and may inhibit neutrophil recruitment via several different pathways known to be involved in the development of ALI and ARDS. Lisofylline causes a marked decrease in the circulating levels of the major oxidizable species of free fatty acids and also inhibits proinflammatory intracellular signaling. Mechanical ventilation in participants with ALI and ARDS have traditionally used tidal volumes of 10 to 15 ml per kilogram of body weight. These large tidal volumes are often necessary to achieve normal partial pressure of arterial carbon dioxide and pH, but may induce inflammatory responses through disruption of pulmonary epithelium and endothelium. Mechanical ventilation at lower tidal volumes may reduce injurious lung stretch and decrease the inflammatory response. Participants The Ketoconazole and Lisofylline trials were designed as 2 x 2 factorials and included 220 participants in each trial. A total of 860 participants were randomized into the ventilator management trial. Participants enrolled in the Lisofylline or Ketoconozole studies had to be concurrently enrolled in the ventilator management study and were first randomized into a ventilator strategy and then to drug or placebo. Conclusions Ketoconazole was found to be safe but did not reduce mortality, duration of mechanical ventilation, or improve lung function. Lisofylline was also found to be safe and to have no beneficial effect for participants with ALI or ARDS. Ventilation at lower tidal volumes resulted in reduced mortality and an increase in the number of days without ventilator support. (PMIDs: 10789668, 11902249, 10793162).

  Study phs003734

• Benchmarking of ProSolo, a new probabilistic single nucleotide variant caller for single cell DNA sequencing data. This study provides the whole exome sequencing dataset used in this assessment.

  Benchmarking of ProSolo, a new probabilistic single nucleotide variant caller for single cell DNA sequencing data that provides control over the false discovery rate of different single cell events at genomic sites (e.g. alternative allele presence or allele dropout). Here, we provide the newly generated whole exome sequencing data used in assessing ProSolo's performance. It contains whole exome sequencing of: a patient with a constitutional mismatch repair defect (MSH6-) and their parents and siblings, a granulocyte bulk sample and 5 single granulocytes sequenced after whole genome amplification.

  Study EGAS00001004123

• Research of factors related to diagnosis, progression, prognosis and treatment of hepato-biliary-pancreatic malignancies

  Advanced cancers with metastasis and/or recurrence are usually resistant and refractory to treatment. In our studies, whole exome sequencing analysis, comprehensive epigenetic analysis and genome-wide expression analysis were performed using cancerous and non-cancerous tissues derived from multicentric cohort study of hepatocellular carcinoma (HCC). The aim of the studies is identification of the refractoriness-related deriver genes for application to novel molecular targeted therapy and preventive medicine. The studies are intended for refractory HCC. High frequency of the tumor recurrence even after curative resection is one of the major difficulties in the treatment of HCC. According to our previous studies, not the recurrence itself, but the recurrence pattern has critical effects on prognosis of the patient with HCC. Then, we analyzed the cancerous and non-cancerous tissues of primary HCC on the point of the recurrence patterns in accordance with or without Milan criteria. The materials were obtained from thirty three patients underwent curative hepatectomy for HCC at Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University Hospital. Written informed consent from these patients, as well as the institutional review board approved was obtained. The determination of the refractory HCC group (16 cases) was based on the point of the recurrence patterns in accordance with Milan criteria for the recurrent tumor (solitary <5cm, or up to 3 nodules <3 cm, without major vascular invasion or distant metastasis) that has been proposed as the useful criteria of the liver transplantation for HCC. The cellular DNA was extracted from the cancerous and non-cancerous tissues of primary HCC by the phenol-chloroform method. After SNP certification using Genome-Wide Human SNP Array 6.0 (Affymetrix), whole exome sequencing was performed at the Cancer Institute of JFCR, as the support infrastructure. Exome sequencing was performed using HiSeq 2000 (Illumina), and the obtained reads were mapped to the human reference genome (hg19) using BWA software. GATK software was used for local realignment base call recalibration. Single nucleotide variants (SNVs) and indels were analyzed by MuTect and SomaticIndelDetector, as well as visual confirmation by IGV software.

  Study JGAS000052

• GECCO: Detecting Common and Rare Genetic Loci and GxE Interactions in Colorectal Cancer

  COLON, Colorectal Cancer: Longitudinal Observational study on Nutritional and lifestyle factors that influence colorectal tumor recurrence, survival and quality of life: The COLON study is a multi-center prospective cohort study to assess the role of diet and other lifestyle factors in cancer recurrence and survival among incident colorectal cancer patients in the Netherlands. DACHS, Darmkrebs: Chancen der Verh&#252;tung durch Screening:This German study was initiated as a large population-based case-control study in 2003 in the Rhine-Neckar-Odenwald region (southwest region of Germany) to assess the potential of endoscopic screening for reduction of colorectal cancer risk and to investigate etiologic determinants of disease, particularly lifestyle/environmental factors and genetic factors. During an in-person interview, data were collected on demographics, medical history, family history of CRC, and various life-style factors, as were blood and mouthwash samples. EPIC, European Prospective Investigation into Cancer: EPIC is an on-going multicenter prospective cohort study designed to investigate the associations between diet, lifestyle, genetic and environmental factors and various types of cancer. HPFS, Health Professionals Follow-up Study: HPFS is a parallel prospective study to the NHS. The HPFS cohort comprised 51,529 men aged 40-75 who, in 1986, responded to a mailed questionnaire. Participants provided information on health related exposures, including current and past smoking history, age, weight, height, diet, physical activity, aspirin use, and family history of colorectal cancer. Colorectal cancer and other outcomes were reported by participants or next-of-kin and were followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical record review. Information was abstracted on histology and primary location. Follow-up evaluation has been excellent, with 94% of the men responding to date. NHS, Nurses&#39; Health Study: The NHS cohort began in 1976 when 121,700 married female registered nurses age 30-55 years returned the initial questionnaire that ascertained a variety of important health-related exposures [PMID:248266]. Since 1976, follow-up questionnaires have been mailed every 2 years. Colorectal cancer and other outcomes were reported by participants or next-of-kin and followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical-record review. Information was abstracted on histology and primary location. The rate of follow-up evaluation has been high: as a proportion of the total possible follow-up time, follow-up evaluation has been more than 92%. NQplus, Nutrition Questionnaires plus: NQplus is a longitudinal observational study on diet and health in the general Dutch population.

  Study phs001315

• An essential role for MYB in driving oncogenic EVI1 expression in enhancer-rearranged leukemias

  In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence motifs essential for EVI1 transcription. Using this approach, we pinpoint a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression while being dispensable for GATA2 expression from its endogenous locus. This element contains a DNA binding motif for the transcription factor MYB that heavily occupies this site specifically at the translocated allele. MYB knockout as well as peptidomimetic blockade of p300-dependent MYB function resulted in downregulation of EVI1 but not of GATA2. Targeting MYB or mutating its DNA-binding motif within the GATA2 enhancer resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven EVI1 transcription provides a potential entry point for therapy of inv(3)/t(3;3) AMLs.

  Study EGAS00001004839

• Age related Macular Degeneration (AMD) - Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: Association and Sequencing Studies

  Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with the disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Study 1: To identify genetic variants and haplotypes that are associated with AMD, we submitted and obtained usable genotyping data on 2185 patients and 1155 controls from the Center for Inherited Disease Research (CIDR). Study 2: To identify rare coding variants associated with a large increase in risk of AMD, 10 candidate loci spanning 57 genes were sequenced in 2,335 cases and 789 controls. Probes were designed to capture 96.5% of the coding sequence and 35% of total locus sequence, generating an average 123Mb of on-target sequence per individual at 127x average depth. Substudies: phs000182 AMD-MMAP Cohort Study: A Joint Genome-Wide Asscociation Study phs000246 Fuchs&#39; Corneal Dystrophy GWAS phs000457 MMAP Methylation in AMD phs000685 Age-Related Macular Degeneration Targeted Sequencing Study

  Study phs000684

• NHLBI GO-ESP: Family Studies (Mendelian Lipid Disorders)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. In this study, we seek to identify the genetic cause of two monogenic lipid disorders-severe hypercholesterolemia and familial hypoalphalipoproteinemia. Monogenic severe hypercholesterolemia is clinically characterized by elevated total and low-density lipoprotein (LDL) cholesterol levels in plasma. Elevated LDL-cholesterol levels lead to excessive deposition of cholesterol in arterial walls, which eventually results in accelerated atherosclerosis and premature cardiovascular disease (CVD). Monogenic hypercholesterolemia has a prevalence of approximately one in 500 individuals, making it one of the most common inherited disorders. To date, mutations in the LDL receptor (LDLR) ligand-binding domains of APOB and PCSK9 have been shown to cause hypercholesterolemia. While mutations in these genes can explain a large percentage of clinically diagnosed patients, the underlying molecular determinant in a substantial fraction of patients remains unknown. Familial hypoalphalipoproteinemia (low HDL-C) is defined by an HDL-C below the age- and sex- specific 10th percentile. ABCA1, LCAT, and APOA1 are known to cause familial hypoalphalipoproteinemia. We hypothesize that: (1) additional novel genes responsible for Mendelian forms of low HDL-C exist; and (2) the causal gene and mutation(s) in each family may be discovered with exome analysis of just a few affected individuals in each pedigree.

  Study phs000587