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• 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

• National Institute of Mental Health (NIMH) Duke Cognition Cohort

  The overall goal is to identify genetic variants influencing normal variation between humans, with a focus on cognitive and neurosensory traits. Because of the focus of funding agencies on disease, very few studies of the genetics of non-disease traits have been performed. The genetic variation underlying the vast majority of differences between humans therefore remains not only undiscovered, but also unexplored. We have assessed >1,200 healthy volunteers for >70 diverse, non-disease phenotypes, with a focus on cognitive and neurosensory traits that are understudied and seem to have a strong biological basis. Our study includes measurements of face recognition, night vision, cognitive performance, auditory pitch discrimination, contagious yawn susceptibility, time perception, sense of direction, taste preferences, personality, sexual behaviors, sleep habits, acne, headache locations, synesthesia, and teeth sensitivity. This method is very different from the focus of most studies on collecting cohorts of patients with disease and controls with minimal phenotypic information. Because we phenotype the same healthy volunteers for multiple highly variable yet heritable traits, we can perform genetic analyses on a large number of phenotypes by just investing once in sequencing the DNA of these participants. An additional >2,000 participants in our cohort have been measured just for cognitive performance instead of for the more extensive phenotyping. Most of the genetic studies in this cohort have been about cognitive perfromance. The number of participants with genetic data generated who have undergone the more extensive phenotyping is limited. Our studies of the more novel traits like contagious yawning have therefore focused more on correlations between different phenotypes until we have a sufficient sample size to truly attempt to make genetic discoveries. . The dataset also includes two small challenge studies. In one study, the cognitive performance of 150 healthy volunteers was measured before and after an acute dose of the antiepileptic drug topiramate. In the other study, the cognitive performance of 13 healthy volunteers was measured before and after 24 hours of sleep deprivation.

  Study phs001406

• Identification of Somatic Changes in Tumors from Fanconi Anemia Patients

  This study focused on the identification of genomic signatures present in tumors from Fanconi anemia patients. Fanconi anemia is a rare hereditary disease caused by defects in DNA interstrand crosslink repair. The primary patient phenotypes are bone marrow failure and cancer predisposition. We concentrated on squamous cell carcinomas and used whole genome Illumina sequencing (22 tumor samples and 12 normal samples) , whole exome sequencing (37 tumor samples and 33 normal samples), PacBio long-read whole-genome (nine tumor and four normal samples),10X linked-read whole-genome sequencing, 10x single-cell/nuclei 3’ RNA sequencing (three tumor samples), 10x Visium spatial transcriptomics (one tumor sample), EPIC 850K methylation array (six samples), and bulk RNAseq (six tumor samples) to identify somatic changes present in tumors. The study aimed to identify changes that drive tumorigenesis in Fanconi anemia, give insight into the early development and aggressive nature of these tumors, and suggest therapeutic avenues for these patients. Another goal was to compare the genomic changes identified in tumors from Fanconi anemia patients with sporadic head and neck cancers. This study demonstrated that the tumors from Fanconi anemia individuals are generally not driven by HPV. Instead, they acquire mutations in the p53 tumor suppressor. The main characteristic of the tumors is the presence of a high number of structural variants in the form of small deletions, unbalanced translocations, and fold-back inversions, which often form complex rearrangements. These rearrangements result in amplifications and deletions of a multitude of oncogenes and tumor suppressors, respectively. The study also shows that lack of the Fanconi anemia DNA repair pathway leads to an epithelial-to-mesenchymal transition in a mouse model and in human samples that may influence the behavior of tumors in Fanconi anemia. Finally, comparing genomic changes in Fanconi anemia and sporadic tumors of the head and neck, we propose that the structural variants present in sporadic cancer result in a functional deficiency of the Fanconi anemia DNA repair pathway.

  Study phs002652

• Bacterial Vaginosis, Cervical Immune Cells and HIV Susceptibility

  This was a cross-sectional study to characterize cervical immune cell composition and activation status in the presence versus absence of bacterial vaginosis (BV) using bulk messenger RNA sequencing (mRNA-Seq). Women enrolled in a longitudinal, open cohort study and engaged in a sex work in Mombasa, Kenya, were eligible. On the day of enrollment, participants self-collected vaginal swabs for generation of Gram-stained slide. The slides were scored from 0-10 using the method of Nugent and Hillier; in this system, women with scores of 0-3 are considered to have normal vaginal flora, those with scores of 4-6 are considered to have intermediate flora, and those with scores of 7-10 are considered to have BV. For this study, only women with normal flora (Nugent scores 0-3) or BV (Nugent scores 7-10) were eligible. Participants underwent speculum-assisted pelvic examination and collection of cervical biopsy specimens using Tischler forceps. Biopsies were placed immediately in ice cold medium and transferred to the laboratory where they were weighed and transferred to freezing medium (10% DMSO + fetal bovine serum) and cooled slowly overnight. Samples were shipped from Kenya to the United States in liquid nitrogen dry shippers, collagenase digested into single cell suspensions, and sorted on a FACS aria to enrich for a population of live, CD45+ cells. Sorted samples (N=17 with BV and N=13 without BV) were immediately lysed and processed using the Takara SMART-Seq v4 Ultra Low Input RNA Kit for sequencing. Library generation was completed using the manufacturer's instructions and sequencing performed on an Illumina NextSeq500 platform using Illumina NextSeq 500/550 High Output v2.5 (150 Cycles). The FASTQ files generated and BV status (N=9 with BV and N=12 without BV that passed quality control) of the donor sample will be available on dbGaP. We identified over 1000 differentially expressed genes between women with versus without BV at an adjusted p-value of <0.05 (listed under "gene names" below).

  Study phs002329

• NextGen Consortium: The iPSCORE (iPSC Collection for Omic Research) Resource for Studying the Impact of Genetic Variation on Molecular and Physiological Phenotypes - Whole Genome Sequence

  The iPSC Collection for Omic Research (iPSCORE) Resource was created as part of the Next-Gen Consortium funded by NHLBI. The overarching purpose of the resource is to provide a large collection of human induced pluripotent stem cells (iPSCs) for use in studying the impact of genetic variation on molecular and physiological phenotypes. The resource has been used in a number of studies in the Dr. Kelly A. Frazer's Lab examining both the characteristics of human iPSCs and a variety of iPSC-derived cell types including cardiovascular progenitor cells (iPSC-CVPCs), pancreatic precursor cells (iPSC-PPCs), and retina pigment epithelium cells (iPSC-RPEs). We have shown that the iPSCs, CVPCs, and PPCs are suitable surrogate models to identify genetic factors active in early developmental processes because they exhibit fetal-like molecular properties.A total of 273 individuals have participated in the study, of which 222 have had iPSCs generated from fibroblasts. Of the 273 individuals, 181 are part of 55 families that include 24 monozygotic twin pairs and 5 dizygotic twin pairs, allowing for the incorporation of familial relationships into genetic analyses.Germline DNA has been sequenced from blood or fibroblast samples for all 273 individuals (available through dbGaP phs001325) and other genomic data (RNA-seq, DNA methylation, genotype arrays, ATAC-seq, H3K27ac ChIP-seq, HiC-seq) have been generated from the 222 iPSCs as well as derived cell types (available through dbGaP phs000924).QTL analyses were conducted for multiple omics data types and summary statistics are available through dbGaP phs0001325.Important note: Of the 273 individuals, 268 are consented for general research use and 5 are consented for cardiac research only.For detailed information about iPSCORE Collection including samples, methods used to generate the data, and how to access the datasets visit the Frazer lab website.The 222 well characterized iPSC lines that constitute the iPSCORE resource are available, please contact Dr. Kelly A. Frazer (kafrazer@health.ucsd.edu) if you are interested in obtaining the collection.

  Study phs001325

• Clinical and Genetic Evaluation of Individuals with Undiagnosed Disorders through the Undiagnosed Diseases Network (UDN)

  The National Human Genome Research Institute and the NIH Clinical Center established the intramural Undiagnosed Diseases Program (UDP) in 2008 to make progress in uncovering, understanding, and treating rare disorders. Based on the success of the UDP, the NIH Common Fund established the Undiagnosed Diseases Network (UDN) in FY 2013 (Phase I, 9/16/2015-8/31/2018) to achieve this type of cross-disciplinary approach to disease diagnosis in academic medical centers around the United States. The NIH Common Fund expanded the network in 2018 (Phase II, 9/1/2018-6/20/2023) to increase the availability of diagnostic services, foster opportunities for collaboration between laboratory and clinical investigators, provide resulting data and protocols to the broader community, and assess development of a sustainable national resource after Common Fund support ends. The UDN transitioned from Common Fund in 2023. The National Institute of Neurological Disorders and Stroke (NINDS) will oversee the Network in Phase III, which launched in July 2023, with help from 17 different NIH Institutes and Centers along with the NIH Office of the Director. With help from patients, family members, patient advocacy groups, a Data Management and Coordinating Center (DMCC), several Clinical Sites, and other stakeholders, the NIH envisions the UDN evolving into a larger, diverse, and self-sustained network that fosters scientific discovery and provides expert diagnostic services for undiagnosed patients across the nation. The overarching goals of the UDN in Phase III include: Continuing the proven success of the UDN in improving the clinical evaluation of difficult-to-diagnose patients using a collaborative team approach and investigating and validating promising new diagnostic technologies. Facilitating research into the etiology of undiagnosed diseases by collecting and sharing standardized, high-quality clinical and laboratory data including genotyping, phenotyping, and documentation of environmental exposures. Promoting a broader integrated and collaborative community across multiple Clinical Sites and among laboratory and clinical investigators prepared to investigate the genetic, pathophysiologic, cell biologic, and molecular mechanisms underpinning these difficult-to-diagnose conditions.

  Study phs001232

• NHLBI TOPMed: Lung Tissue Research Consortium (LTRC)

  Chronic obstructive pulmonary disease (COPD), a disease state characterized by airflow limitation that is not fully reversible, is the third leading cause of death in the U.S. COPD is a heterogeneous syndrome, with affected individuals demonstrating marked differences in lung structure (emphysema vs. airway disease); physiology (airflow obstruction); and other clinical features (e.g., exacerbations, co-morbid illnesses). Multiple genomic regions influencing COPD susceptibility have been identified by genome-wide association studies (GWAS), and rare coding variants can also influence risk for COPD. However, only a small percentage of the estimated heritability for COPD risk can be explained by known genetic loci. Like most complex diseases, COPD is influenced by multiple genetic determinants (each with modest individual effects). Emerging evidence supports the paradigm that complex disease genetic determinants are part of a network of interacting genes and proteins; perturbations of this network can increase disease risk. To identify this network, multiple Omics data will need to be analyzed with methods to account for nonlinear relationships and interactions between key genes and proteins. Our overall hypothesis is that integrated network analysis of genetic, transcriptomic, proteomic, and epigenetic data from biospecimens ranging from lung tissue to nasal epithelial cells to blood in highly phenotyped subjects will provide insights into COPD pathogenesis and heterogeneity. We will leverage the well-phenotyped, NHLBI-funded Lung Tissue Research Consortium (LTRC) to address these questions. We will perform multi-omics analysis in 1548 lung tissue and blood samples from the LTRC. With these multi-omics data, we will utilize a systems biology approach to understand relationships between multiple genetic determinants and multiple types of Omics data. We will begin by performing single Omics analyses in COPD vs. control lung, nasal, and blood samples. Next, we will integrate single Omics data with genetic variants identified by WGS to assist in fine mapping genetic determinants of COPD. We will then perform integrated network analysis of COPD with genetic and multiple Omics data using correlation-based, gene regulatory, and Bayesian networks. Subjects were recruited from Mayo Clinic, Universities of Colorado, Michigan, and Pittsburgh, and Temple University.

  Study phs001662

• Diabetic Retinopathy Genomics Study (DRGen) - Genetic Biomarkers of Diabetic Retinopathy

  Using a well-defined, clinically supported phenotypic strategy, we seek to better understand the role of common and rare genetic variants in the progression of diabetic retinopathy (DR). Whole exome/whole genome sequencing (WES/WGS) was used to systematically search the human genome to detect DR susceptibility genes or genes that protect people from developing advanced DR. Clinical data and bio specimens were obtained from clinically defined DR phenotypes such as, (i) No/Mild NPDR (non-proliferative DR) with a subset of extreme phenotype, ii) Diabetic macular edema (DME) alone and iii) Proliferative diabetic retinopathy (PDR) alone. In this ongoing comprehensive genomic study, we wish to i) Identify potential common and rare variants that may influence the phenotypic differentiation of DR into DME or PDR, ii) Define genetic variants stratified based on the "extreme phenotype," and iii) Characterize genetic factors that determine the differential response to anti-VEGF drugs in DME patients. Definition of Diabetic Retinopathy and classification of groups Study 1. Proliferative diabetic retinopathy (PDR). Anybody showing evidence of retinal neovascularization on the disc (NVD) or elsewhere (NVE) with or without pre-retinal and vitreous hemorrhage will be considered PDR. We will include only those "active" PDR patients. The total number of consented subjects in this study is 182. Study 2. Isolated Phenotype: Varied response with anti-VEGF treatment is a significant limiting factor for better clinical outcomes. We quantify the response to anti-VEGF treatment based on visual acuity changes and anatomic features of DME assessed by optical coherence tomography (OCT). Depending on the response at one month following three monthly intravitreal anti-VEGF injections, we have observed two phenotypes: 1) Good responders: Participants were considered "good responders" if the anatomical outcome to anti-VEGF treatment resulted in a significant reduction of baseline central retinal thickness (CRT) &gt; 25% after three anti-VEGF injections. 2) Poor Responders: Participants were classified as "poor responders" if the outcome of anti-VEGF treatment resulted in a reduction of CRT &lt; 20% or in any increase in CRT after three monthly injections. The total number of consented subjects in this study is 17.

  Study phs002501

• UK10K NEURO IOP COLLIER

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Genetics and Psychosis (GAP) set consists of samples from subjects with schizophrenia, ascertained as a new-onset sample. This set is of UK origin, with data on cognition, brain imaging and other endophenotypes. The Maudsley twin series consists of probands ascertained from the Maudsley Twin Register, defined as patients of multiple birth who had suffered psychotic symptoms. This set is of UK origin, with data on cognition, brain imaging and other endophenotypes, with DNA available from an MZ or DZ affected or unaffected co-twin. The Maudsley family study (MFS) consists of over 250 families who have a history of schizophrenia or bipolar disorder Within the Maudsley Family Study, biological markers of psychosis include neuropsychological tests, Evoked Response Potentials Tests (ERPs), MRI scans, dermatoglyphics and eye tracking. Early risk factors for psychosis and clinical symptoms are also investigated. This set is of UK origin, with DNA available from both affected and unaffected relatives in many of the probands. For further information on this study please contact David Collier (david.collier@kcl.ac.uk).

  Study EGAS00001000121

• Germline elongator mutations in sonic hedgehog medulloblastoma

  Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHa subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

  Study EGAS00001004126