1986 — 2011 |
Warren, Stephen T. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Molecular Cloning of the Fragile X Site
Fragile X syndrome is a frequent cause of mental retardation that is inherited as an X-linked dominant with reduced penetrance. The mutational change in nearly all affected patients is the unstable expansion of a CGC trinucleotide repeat in the 5' untranslated region of the FMRI gene. This repeat is normally polymorphic in length and content, exhibiting a mode of 30 cryptic repeats in the normal population, but the triplet is found in excess of approximately 230 repeats in affected patients, often approaching 1,000 copies. Male, and most female, carriers have a FMRI premutation with an intermediate number of repeats, between about 60 and 200 triplets. In most penetrant males with full mutation alleles containing >230 repeats, the FMRI gene is abnormally methylated and late replicating. In such a state, the lengthy CGG repeat is believed to constitute the chromosomal fragile site. As a consequence, the FMRI gene is transcriptionally repressed in full mutation patients and the absence of the encoded protein, FMRP, a selective RNA-binding protein, is responsible for the clinical phenotype. Much of the understanding of this previously quite puzzling disorder emerged in the past 4 years, in part due to research supported under this award. Proposed below is a research program to continue our studies, initiated over a decade ago, to more fully understand this syndrome. We plan three broad specific aims. We will characterize the FMRI repeat in order to more fully understand molecular influences over its stability and evolution. We will continue our characterization of the FMR protein, absent in fragile X syndrome, with the hope that understanding its normal function will give insight into the pathophysiology of fragile X syndrome and human cognition. Finally, we will continue development of clinically useful diagnostic tools for this syndrome, in particular development of ELISA methods to rapidly and accurately quantitate FMRP. We will measure FMRP in women with the full fragile X mutation, who exhibit incomplete penetrance and extremely broad expressivity. Thus, the goal of this proposal is to capitalize upon the successful positional cloning of the FMRI gene and now use it as a molecular reagent to explore the mechanisms and consequences of the remarkable trinucleotide repeat expansion at the fragile X site.
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1 |
1990 — 1992 |
Warren, Stephen T. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Genetic Analysis of Xq28
The terminal band of the human X chromosome long arm, Xq28, is estimated to be <10,000 kb. Although small in size, over 20 loci have been mapped to this region, 13 of whom have alleles that lead to genetic diseases of which little or nothing is understood at the molecular level, such as Emery- Dreifuss muscular dystrophy and an X-linked form of manic-depressive illness. A somatic cell genetic approach has been developed which allows for the isolation of Xq28 within a hamster cell line, as the sole human DNA present, permitting rapid saturational cloning of this small region of the human genome. For these reasons, Xq28 is an ideal region of the human genome for in-depth molecular analysis. Somatic cell hybrids, isolated from fusions between hamster cells deficient in both HGPRT and G6PD activities and human cells derived from fragile X syndrome males, will be used to select clones that have lost all of the human X chromosome except for Xq28. this will be accomplished by inducing, in the hybrid cells, chromosome breakage at the fragile X site (Xq27.3) with thymidine stress and identifying those cells which have lost HGPRT (which maps proximal to the fragile site) but retained G6PD (which maps to Xq28). A strategy for isolating such hybrids is based upon selection against HGPRT with 6- thioguanine and subsequent enrichment for G6PD-positive cells by oxidative stress. Multiple independent hybrids will be isolated which appear to contain only human Xq28 and they will be subjected to careful and complete characterization to verify the presence of the unrearranged authentic human chromosomal band. Cosmid libraries of hybrid cells will be prepared and clones containing human inserts identified and isolated to provide a panel of cosmids of sufficient number to saturate Xq28. This cosmid panel will be screened for those that detect new polymorphic loci. Loci which detect relatively frequent plymorphisms will be placed upon the genetic and physical maps of Xq28. A genetic map, utilizing known and newly identified loci, will be constructed to approach 1 cM resolution. These loci will also be placed upon a physical map of this region, using pulsed filed gel electrophoresis, to allow for the correlation of the two maps. Such a composite map, as well as the resource of cosmids which saturate Xq28, should prove valuable for the identification and isolation of candidate genes for the genetic disorders which map to Xq28 as well as provide the substrates necessary for a future contig and sequence analysis of Xq28.
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1 |
1997 — 2002 |
Warren, Stephen T. |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
X Linked Disorders
cell line; cell bank /registry; cell transformation; sex linked trait; Epstein Barr virus; lymphoblast; human genetic material tag;
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1 |
1997 |
Warren, Stephen T. |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Genetic Repository
This protocol provides the facility and services necessary to collect, process and store lymphoblasts and/or DNA from index cases or family blood samples in the GCRC Molecular Cell Biology Laboratory. When an investigator encounters a patient with a rare genetic disorder at Emory Clinic, the Advisory Committee has approved an outpatient visit for blood drawing and subsequent genetic repository. No ancillaries were paid.
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1 |
1997 — 2002 |
Warren, Stephen T. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Model Systems For the Study of Fragile X Syndrome
Functional analysis of FMRP is hampered due to a lack of functional assays. In this project we propose the development of two distinct assays for FMRP function. The first system is based upon our recent discovery that FMRP can transform NIH 3T3 cells. This is consistent with the biochemical attributes of FMRP as another translation factor, eIF-4E, has previously been shown to cause transformation. This system will be developed as an assay for FMRP function. We will determine if RNA-binding and/or nucleocytoplasmic shuttling is required for transformation. We will seek to understand how excess FMRP causes transformation as this may lead to more general insight into function. As additional attributes of FMRP become known, we will test them in this system as well. The second system is based upon the fmr1 knockout mouse which exhibits cognitive deficit. In order to answer fundamental questions regarding fragile X syndrome and to provide a more experimentally useful murine knockout model, we will replace, in ES cells, the normal mouse fmr1 promoter with the tetracycline-response element promoter without other wise modifying the murine gene. Simultaneously, we will insert the rtetR/VP16 fusion transcription factor, under the control of the normal Fmr1 promoter, into the X-linked HPRT locus to achieve single copy integration. In these and derivative cell lines, addition of the tetracycline derivative, doxycycline, will result in turning the Fmr1 gene on. Mice will be developed from these ES cells, resulting in animals in which both temporal and quantitative control over FMRP expression can be controlled by doxycycline exposure. We will then determine if FMRP expression is essential during development or if later expression of FMRP can influence the cognitive deficit. Such data is of fundamental importance in the consideration of therapeutic interventions. Developing, testing, and utilizing these model system should allow considerable analysis and understanding of FMRP function and the consequences of its absence.
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1 |
1997 — 1998 |
Warren, Stephen T. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Program of Investigation Into Fragile X Syndrome
Fragile X syndrome is a leading cause of mental retardation in humans. The molecular basis of fragile X syndrome is the expansion of a trinucleotide repeat within the FMR1 gene, leading to the absence of the encoded protein, FMRP. Although there has been a spectacular increase in the understanding of this disorder in recent years, it is now time for a well focused, multidisciplinary group effort to further elucidate the molecular basis of fragile X syndrome. Seven interrelated and collaborative project at Emory University School of Medicine are proposed. These projects dramatically expand the scope of contemporary fragile X syndrome research and specifically address issues crucial for future investigation and intervention. Clues to the mechanism(s) of repeat expansion will be sought and exploited. The consequence of repeat expansion, the transcriptional suppression of FMR1, will be investigated to understand the mechanism leading to the absence of FMRP. Understanding the biochemistry of FMRP will be highlighted with studies aimed at understanding the structural determinants of FMRP:RNA interaction, including the role of FMRP isoforms; the role of FMRP on protein translation and the consequence of its absence on neuronal protein synthesis; the localization of FMRP in mammalian brain, particularly within neuronal somatal-dendritic compartments, and the consequence of its absence on dendritic complexity and dendritic spine morphology. Model systems are proposed to further drive these studies to greater levels of understanding. A model system will be developed in yeast investigating yeast genes whose products are of similar structure to FMRP and the result of vertebrate FMRP expression within yeast will be investigated. A mammalian cellular system to assess FMRP function will be developed based upon the ability of excess FMRP to transform 3T3 cells in culture. Finally, a new generation of Fmr1 knockout mice will be developed in which FMRP expression can be temporally and quantitatively controlled, both pre- and postnatally, by drug exposure. Fundamental questions relating to future therapeutic strategies will be directly addressed. It is anticipated that this proposed investigation into fragile X syndrome by a highly interactive and multidisciplinary team of proven collaborative abilities will result in a synergistic increase in knowledge of this important disorder and a broader understanding of a common form of mental retardation.
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1 |
1997 |
Warren, Stephen T. |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Emery-Dreifuss Muscular Dystrophy
No research subjects are admitted to the GCRC under this protocol. It utilizes the Molecular Cell Biology Laboratory only. The Lab Supervisor transforms and stores immortal Epstein-Barr virus lymphoblast cell lines from patient samples sent directly to the Lab. The cell lines then serve as a permanent DNA/RNA resource, as well as an in vitro model system for the molecular genetics investigations.
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1 |
1999 — 2005 |
Warren, Stephen T. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
A Program of Investigation Into Fragile X Syndrome
DESCRIPTION (provided by applicant): Fragile X syndrome is a leading cause of mental retardation. The molecular basis of fragile X syndrome is the expansion of a trinucleotide repeat within the FMR1 gene, resulting in the absence of the encoded protein, FMRP. Although there has been a spectacular increase in the understanding of this disorder in recent years, much remains to be learned. To capitalize upon this trajectory of understanding, a well focused, multidisciplinary group effort to further elucidate the molecular basis of fragile X syndrome was initiated in September of 1997 with the funding of this program project composed of seven projects and one core. This revised proposal, in response to the formal review following three years of funded research, reflects a tighter, more thematic program of five interrelated and collaborative projects and one core at Emory University School of Medicine. These projects dramatically expand the scope of contemporary fragile X syndrome research and specifically address issues crucial for future investigation and intervention. A central program theme of FMRP expression and function cover the five broad, multidisciplinary projects. Project II will seek to understand the mechanistic details of chromatin changes leading to the transcriptional suppression of FMR1, the disease-causing consequence of full repeat expansion. Project I aims determine the biochemical and clinical consequences of smaller intermediate and premutation alleles that are found in 5% of the population. Projects V seeks to understand the biochemistry of FMRP with structure/function studies that are key in our continued understanding of the consequences of the absence of FMRP or a more subtle reduction of FMRP levels, studied in the prior two projects. Project III develops model systems where genetically modified mice and cell lines are produced where FMRP expression can be temporally and quantitatively controlled, both pre- and postnatally as well as in vitro. Along with the other projects, these novel biological resources will be used to explore new aspects of the pathophysiology of fragile X syndrome. This program of investigation into fragile X syndrome, by a highly interactive and multidisciplinary team with proven collaborative abilities, represents one of the largest research centers on this disorder in the world and aims to further our continued understanding of this important and common form of mental retardation.
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1 |
2001 |
Warren, Stephen T. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Developing a Center For Autism Research
DESCRIPTION (Provided by applicant): This application will develop the Autism Research Center at Emory University. The application will integrate basic science and clinical research programs, establish cores in genetics and phenotyping, and create the organization for a center. The ultimate goal is to use the resources from this application to apply for a Center for Excellence in Autism Research. The program is built on a strong clinical base that has been developed over the past 10 years at Emory University. Both mouse and non-human primate models will be developed to study the neurobiology and genetics of deficits in social behavior.
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1 |
2007 — 2011 |
Warren, Stephen T. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Schizophrenia Susceptibility by Copy Number Variation in the Ashkenazim
[unreadable] DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a severe psychiatric disorder with a strong genetic susceptibility. Heritability is estimated to be 70-90% for SZ. Intense efforts using both linkage and association studies to identify susceptibility loci thus far have met only limited success. Recently it has been appreciated that widespread copy number variation (CNV), in the form of duplications and deletions, frequently occurs in the human genome and is a largely unsurveyed source of individual genetic variation. CNV may be an unrecognized source of SZ genetic susceptibility and potentially a confounding influence on prior genetic studies. We propose here to survey the entire nonrepetitive human genome, using arrays with oligonucleotide markers at an average spacing of 1.5 kb, in 1,000 unrelated Ashkenazi Jewish SZ cases and controls as well as in parents of 300 of the SZ cases. Using this population isolate to limit genetic heterogeneity, we will identify large (>100 kb) and small (-15 - 100 kb) CNV, both frequent (> 1%) and rare (< 1%). We will confirm selected CNV from each of these four classes by quantitative TaqMan PCR. We will characterize breakpoints by long-range PCR followed by DNA sequencing or by FISH to metaphase chromosomes. Using prior high-density SNP genotyping in four genomic regions in these samples, we will investigate linkage disequilibrium patterns between individual CNVs and flanking SNPs. We will compare the CNV of the 300 trios to confirm genetic transmission and, along with the remaining 200 SZ cases and 500 controls, we will code CNV loci. CNVs with overlapping breakpoints will be initially coded as alleles of one locus but will also be evaluated as distinct loci as well. We expect to identify ~1,700 nonredundant CNVs in this study and we will publicly release this data within one month of its generation. These data will be evaluated by joint analysis of trios, cases, and controls for statistically significant evidence of association of one or more CNV loci with SZ. This study will result in a detailed examination of CNV in the Ashkenazim, providing one of the first large-scale evaluations of CNV in humans, and identify CNV loci that may influence SZ susceptibility. Schizophrenia (SZ) is a severe psychiatric disorder that is caused, at least in part, by variation in the DNA of patients' genomes. A new class of variation is the deletion or duplications of stretches of DNA. Using arrays that can scan the human genome for this "copy number variation", we will examine 1,000 unrelated Ashkenazi Jewish cases and controls as well as in 600 SZ parents. Although SZ is not found at an elevated frequency in individuals of AJ decent, the relative isolation of this population will reduce genome complexity, easing analysis. This study will not only be one of the first large-scale examinations of this type of variation in humans but may also identify variants that may influence whether or not an individual will suffer from SZ. [unreadable] [unreadable] [unreadable] [unreadable]
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1 |
2008 — 2009 |
Warren, Stephen T. |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
A Chemical Library Screen For Potential Fragile X Therapeutica @ Baylor College of Medicine
4-Isoxazolepropanoic acid, alpha-amino-2,3-dihydro-5-methyl-3-oxo-; AMPA; AMPA Receptors; Alleles; Allelomorphs; Ammon Horn; Animal Model; Animal Models and Related Studies; Animals; Assay; Award; Behavior; Bioassay; Biologic Assays; Biological Assay; Biological Function; Biological Models; Biological Process; Blood - brain barrier anatomy; Blood-Brain Barrier; CGG repeat; Chemical Structure; Chemicals; Clinical Trials, Therapy; Cognition; Common Rat Strains; Cornu Ammonis; Courtship; Development; Disease; Disorder; Dose; Drosophila; Drosophila genus; Drug Compounding; Drug Evaluation, Preclinical; Drug Preparation; Drug Screening; Drugs; Escalante syndrome; Evaluation Studies, Drug, Pre-Clinical; Evaluation Studies, Drug, Preclinical; FMR1; FMR1 Gene; FMRP; FXTAS; Faculty; Flies; Fmr1 gene,; Fmr1,; Fragile X; Fragile X Mental Retardation 1 Gene; Fragile X Syndrome; Fragile X premutation-associated tremor ataxia syndrome; Fruit Fly, Drosophila; Funding; Future; Glutamates; Hemato-Encephalic Barrier; Hippocampus; Hippocampus (Brain); Hyperactive behavior; Hyperactivity; Hyperactivity, Motor; Hyperkinesia; Hyperkinesis; Hyperkinetic Movements; Investigators; Knockout Mice; L-Glutamate; Laboratories; Lead; Length; Libraries; Lobe; Mammals, Rats; Martin-Bell Syndrome; Martin-Bell-Renpenning syndrome; Mediating; Medication; Mice, Knock-out; Mice, Knockout; Model System; Modeling; Models, Biologic; Molecular; Mushroom Bodies; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nerve Cells; Nerve Degeneration; Nerve Unit; Neural Cell; Neurocyte; Neuron Degeneration; Neurons; Null Mouse; Ovarian Failure, Premature; Pathway interactions; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Phenotype; Preclinical Drug Evaluation; Premature Ovarian Failure; Proteins; Rat; Rattus; Receptors, AMPA; Renpenning syndrome 2; Research Personnel; Researchers; Screening procedure; Synapses; Synaptic; Testing; Therapeutic; Therapeutic Trials; Therapy Clinical Trials; Time; Toxic effect; Toxicities; United States National Institutes of Health; Variant; Variation; Work; X-linked mental deficiency-megalotestes syndrome; X-linked mental retardation with fragile X syndrome; X-linked mental retardation-fragile site 1 syndrome; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; audiogenic seizure; autism-fragile X (AFRAX) syndrome; autism-fragile X syndrome; base; disease/disorder; drug development; drug/agent; fly; fra(X) syndrome; fra(X)(28) syndrome; fra(X)(q27) syndrome; fra(X)(q27-28) syndrome; fragile X associated tremor ataxia syndrome; fragile X mental retardation 1; fragile X-associated tremor/ataxia syndrome; fragile X-mental retardation syndrome; fragile Xq syndrome; fragile site mental retardation 1; fragile x [{C0016667}]; fragile x syndromes; fruit fly; gene product; heavy metal Pb; heavy metal lead; hippocampal; in vivo; insight; interest; macro-orchidism-marker X (MOMX) syndrome; macro-orchidism-marker X syndrome; mar(X) syndrome; marker X syndrome; member; mental retardation-macroorchidism syndrome; model organism; neural degeneration; neurodegeneration; neuronal; neuronal degeneration; novel; pathway; psychopharmacologic; psychopharmacological; receptor internalization; screening; screenings; small molecule; small molecule libraries; success; trafficking
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0.943 |
2008 — 2011 |
Warren, Stephen T. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Bipolar I Susceptibility by Copy Number Variation in An Isolated Population
DESCRIPTION (provided by applicant): Bipolar I disorder (BPI) is a severe psychiatric disorder with a strong genetic influence on susceptibility. Heritability, the proportion of phenotypic variation in a population that is attributable to genetic variation, is estimated to be >90%. However, intense efforts using both linkage and association studies to identify susceptibility loci thus far have met only limited success. Recently it has been appreciated that widespread copy number variation (CNV), in the form of duplications and deletions, frequently occurs in the human genome and may be a major contributor to individual genetic variation. However, CNV has not been sampled in typical genetic studies, and may therefore be an unrecognized source of BPI genetic susceptibility and potentially a confounding influence on prior investigations of disease. We propose here to characterize CNV in 366 case-parent BPI trios plus an additional 162 BPI cases, all of Ashkenazi Jewish descent. We will survey the entire nonrepetitive human genome, at an average density of 1.1 kb, using 2.1 million feature oligonucleotide arrays and a competitive genomic hybridization protocol, reliably detecting CNV 8kb and larger. For common (>1% frequency) CNV, the data will be evaluated for distorted transmission of CNV to affected BPI offspring. Additionally, presence of excess rare (<1%) CNV in BPI linkage regions as well as in or near previously identified candidate gene regions will be evaluated by comparison of 510 independent BPI cases and 500 Ashkenazi controls previously assessed for genome-wide CNV. Significant CNV loci will be validated with an alternate technology, breakpoints will be resolved with PCR and/or quantitative genotyping strategies, and variants will be carefully scrutinized for their proximity to genes or evolutionarily conserved sequences. We further propose to explore association in a joint dataset of the 366 BPI trios and 162 BPI cases discussed here, plus 500 schizophrenia (SZ) patients (including 300 SZ trios) and 500 controls, all of Ashkenazi Jewish descent, in whom CNV detection is already proceeding. It has been suggested that BPI and schizophrenia may not represent distinct entities, but instead are varying manifestations of a similar biological lesion. This is supported by the substantial overlap between these disorders, in both clinical presentation and genomic loci identified by linkage and association. Our joint dataset, the largest of its kind from an inbred population, has the potential to test the assertion that BPI and SZ are part of a continuum of psychiatric illness, and reveal CNV that predispose to psychiatric illness. PUBLIC HEALTH RELEVANCE: Bipolar I disorder is a severe psychiatric illness that affects ~1% of the general population, but causes of this disorder remain unknown. We propose to investigate whether deletions or duplications in the human genome are related to bipolar I susceptibility;these variants may harbor important clues about the genes, and ultimately the biological process, involved in the development of Bipolar I disorder.
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1 |
2009 — 2013 |
Warren, Stephen T. |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training Program in Human Disease Genetics
DESCRIPTION (provided by applicant): Although the Human Genome Project has led to unprecedented advances in our understanding of human genetics, the dearth of genetics professionals in the United States means that we will be limited in our ability to translate this information to human health. The Training Program in Human Disease Genetics will produce a new generation of genetics professionals who are up to this task by providing a broad exposure to the expertise that is important for modern human genetics research. The program is designed for pre- and postdoctoral trainees in the Department of Human Genetics at Emory University School of Medicine, and will take advantage of the remarkable cadre of research and clinical faculty in the department. The interests of the participating faculty range from statistical methodologies in human genetics, to high-throughput genomic resequencing, to animal models, including nonhuman primates, to studying human genetic disease, and finally to genetic epidemiology. This multidisciplinary approach to the same problem - how does genetic variation cause disease?- will provide trainees with a broad view of research in human disease genetics and will place them at the forefront of research on human genetic variation. In addition to didactic training, instruction in scientific communication, and deep participation in a research project, the trainees will also have the opportunity to explore the translational applications of their research - both in terms of clinical genetic testing as well as treatment for genetic disease - as they work closely with the Medical Genetics team in the department. Upon completion of the program, the trainees will be competitive candidates for research careers in human genetics or for careers in medical genetic diagnostic and testing laboratories. As the data on human genetic variation from the Human Genome Project are being collected at a rate that exceeds our ability to understand its meaning, these trainees will be at the leading edge of research in human disease genetics. RELEVANCE: Over the past several years, there has been a tremendous explosion in our ability to detect human genetic variation of many types. However, we do not fully understand the significance of this variation. It is crucial that we train human geneticists who can take a multi-pronged approach to studying human genetic variation and that they consistently keep in focus the translational applications of their work.
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1 |
2009 — 2010 |
Warren, Stephen T. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Epigenetic Marks as Peripheral Biomarkers of Autism
DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) are a common phenotype with a complex etiology. While a rare single gene or genomic interval may be sufficient to lead to ASD, most patients likely owe their disease to a combination of both genetic and environmental variation. One area that bridges genetic and environmental influences is epigenetic variation. Seeking evidence for epigenetic variation specific to ASD, we screened 49 ASD males and their unaffected fathers for methylation status of 1,505 CpG dinucleotides corresponding to 807 genes. Using 33 pairs as a training set and 16 pairs as a validation set, we statistically identified 116 differentially methylated loci (DML) that gave the highest predictive power to classify ASD boys from their fathers. Using these DML, we screened, in a blinded fashion, DNA isolated from whole blood in an additional 29 ASD son/unaffected father pairs and correctly classified ~80% of the ASD affected individuals. We validated a subset of these loci using bisulfite sequencing and ruled out age-dependent effects. To follow-up on this extraordinary observation, we propose here to conduct a comprehensive genome-wide methylation analysis that will interrogate 27,578 CpG dinucleotides associated with more than 14,000 genes in DNA isolated from whole blood in 300 ASD Simons Simplex 4-person families (father, mother and discordant male sib pair). Using this data, we will then construct a smaller custom set of DML and screen an additional 900 ASD probands and their families. This analysis will directly test our provocative preliminary data and potentially identify DML that could compromise a peripheral biomarker assay for ASD. PUBLIC HEALTH RELEVANCE: Autism is a common disorder whose causes are poorly understood. Both genetic and environmental influences are thought to act together causing autism. Epigenetics is an area that bridges genetic and environmental influencing and commonly is studied by examining dynamic methylation changes to the DNA. We have screened a total of 78 autistic boys and their fathers by this method in 807 genes and find 116 methylation changes that together can correctly identify nearly 80% of the affected boys from their fathers. We propose to confirm these exciting data in a much larger set of genes in 1,200 autistic boys and their families, including unaffected brothers. These data not only could provide new insight into the causes of autism but could also result in a screening test for autism. )
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1 |
2012 — 2015 |
Caspary, Tamara J. Warren, Stephen T. Weinshenker, David (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Characterization of the Schizophrenia-Associated 3q29 Deletion in Mouse
DESCRIPTION (provided by applicant): Project Summary/Abstract Recent exciting progress in schizophrenia genetics has revealed genomic copy number changes with large susceptibility for disease. Large (~1Mb), heterozygous, typically de novo copy number changes on chromosomes 1q21, 15q11, 15q13, 16p11, 22q11, and most recently a deletion on chromosome 3q29 are all enriched in SZ patients relative to controls. Interestingly, these copy number changes are also enriched in autism and intellectual disability cohorts. However, these discoveries have been unaccompanied by identification of the specific gene responsible for the phenotype(s). At Emory we have established an interdisciplinary team that consists of the labs of Stephen Warren, Tamara Caspary and David Weinshenker, and our initial goal is to recapitulate the human 3q29 interval by creating mouse models of the deletion and reciprocal duplication, and ascertaining the behavioral consequences on multiple mouse strain backgrounds using a comprehensive battery of tests. Ascertaining the full behavioral spectrum in alternate genomic contexts will allow us to elicit differences that are predicated on mouse strain background, recapitulating the variable phenotypes observed in humans. For the microdeletion, we further propose to create a series of smaller overlapping deletions in the two strains with the most robust phenotypes. In this way we will establish the minimal deletion (and therefore minimal genes) required for a behavioral phenotype. This approach will enable us to 1) create models of the 3q29 deletion and duplication syndromes, 2) discern whether disruption of an individual gene or combination of genes are responsible for the SZ, ID and autism-like features exhibited by deletion patients or if distinct genes are responsible for the different phenotypes and 3) identify the causative gene(s) which will, in turn, provide a molecular handle through which these neuropsychiatric conditions can be better understood and treated. Using these mouse models combined with behavioral testing, we expect to identify the gene responsible for the 3q29 deletion phenotype, a major candidate gene for schizophrenia, intellectual disability, and autism. Thus this grant will develop a valuable mouse model and provide a molecular handle of the genetic pathways that the community requires to advance psychiatric genetic research.
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1 |
2013 — 2016 |
Warren, Stephen T. |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
2/5 International Consortium On Brain and Behavior in 22q11.2 Deletion Syndrome
DESCRIPTION (provided by applicant): The International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome (22q11DS) is a collaborative RO1 of 22 institutions, with one genomic and four phenotyping leading sites. The collaboration combines genomic with neuropsychiatric and neurobehavioral paradigms to advance the understanding of the pathogenesis of schizophrenia (SZ) and related phenotypes. The Consortium provides the largest available sample to date of 1000 genetically and phenotypically characterized individuals with 22q11DS. There is a substantial risk for developing SZ in adolescents and young adults with 22q11DS (~25-30%), with illness presentation and course similar to SZ in the general population (~1%). Consortium sites have established collaborations with extensive experience in applying integrative genomic and brain-behavior strategies to study 22q11DS and SZ across the lifespan. We will examine neuropsychiatric features through an integrated consensus focusing on SZ and emergence of psychosis. Neurobehavioral measures will be investigated across domains, establishing their relation to psychosis (Specific Aim 1). We will conduct whole genome sequencing (WGS) on 600 individuals with 22q11DS to uncover genetic variation that may contribute to the heterogeneity of neuropsychiatric and neurobehavioral phenotypes of SZ and psychosis. The convergence of phenotypic and genomic measures in adult and pediatric populations will permit examination of shared genetic variants that influence the expression of SZ and early psychosis. We will perform WGS on 300 adults using phenotypic extremes: 150 22q11DS individuals with SZ and 150 22q11DS individuals without psychotic symptoms, as well as 300 pediatric participants with 22q11DS phenotyped by cognitive decline and psychosis proneness. This will be followed by association analysis on all common SNPs and CNVs in the entire sample. The discovered genomic variation will be followed in non-deleted SZ GWAS (Specific Aim 2). As diverse approaches and instruments are applied in assessing neuropsychiatric and neurobehavioral phenotypes in 22q11DS, the Consortium can advance the field by developing and piloting common measures that tap major dimensions of psychopathology and brain function. This will enhance the integration of phenotypic and genomic data, lay the foundation for a systematic approach internationally and provide a framework for longitudinal studies. This approach will cohere with RDoC and integration of genomic and neuroscience paradigms (Specific Aim 3). The resource built by the international Consortium will be a platform for data sharing as tools created, specimens collected and high fidelity data are placed in the public domain (Specific Aim 4). The proposed project will be an unprecedented international initiative to examine a common deletion associated with SZ and elucidate its genomic and behavioral substrates. Beyond the potential for yielding a better understanding of a severe manifestation of 22q11DS, the results will help identify pathways leading to SZ in the general population in a way that will inform novel treatments.
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1 |
2014 — 2019 |
Warren, Stephen T. |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Modifiers of Fmr1-Associated Disorders: Application of High Throughput Technologi
DESCRIPTION (provided by applicant): The goals of our Center, Modifiers of FMR1-associated disorders: application of high throughput technologies, are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1- associated conditions. Project A will focus on the variable expression of epilepsy among boys with Fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of Fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the permutation (PM), with a lifetime prevalence of 30% among males. Project C focuses Fragile X association primary ovarian insufficiency (FXPOI), which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistemic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use the Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. The research we propose in our Center is highly innovative, using cutting-edge technologies, to answer fundamental questions related to Fragile X-related disorders. All Center investigators are part of Emory University, an institution with possibly the largest group of independent faculty working on Fragile X-related disorders and with nearly a 30-year history of contributions to the field. Moreover, an added synergy and excitement within this Center is driven by the common theme among all the projects, ensuring a highly interactive and productive research environment.
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1 |
2014 — 2019 |
Warren, Stephen T. |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Recruitment Core
The goals of our Center, Modifiers of FMR1-associated disorders: application of high throughput technologies, are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1 associated conditions. Project A will focus on the variable expression of epilepsy among boys with fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the premutation (PM), with a lifetime prevalence of 30% among males. Project C focuses fragile X association primary ovarian insufficiency (FXPOl), which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistatic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. Specifically, the Recruitment Core will: 1) identify project-eligible probands from fragile X families; 2) screen for initial eligibility, obtain consent, and collect samples; and 3) obtain pedigree histories to investigate clustering of phenotypes.
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1 |
2014 — 2019 |
Warren, Stephen T. |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Genomics and Analytical Resource Core Section
The goals of our Center, Modifiers of FMR1-associated disorders: application of high throughput technologies, are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1-associated conditions. Project A will focus on the variable expression of epilepsy among boys with fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the premutation (PM), with a lifetime prevalence of 30% among males. Project C focuses fragile X association primary ovarian insufficiency (FXPOl) which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistatic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use the Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. This core will provide a common computational and analytical infrastructure for all projects, leading to natural economies and synergies including: 1) decreased costs due to larger sample sizes per experiment, 2) common equipment use, 3) increased quality control because all experiments use the same protocol, and 4) reduced errors in interpretation of results because of common analytical approaches. This final resource of 600 sequenced genomes of those with FMRI mutations will be available for future analyses by those in scientific community.
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1 |
2014 — 2019 |
Warren, Stephen T. |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Genetic Modifiers of Seizure Disorders in Fragile X Syndrome
The goals of our Center, Modifiers of FMR1-associated disorders: application of high throughput technologies, are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1-associated conditions by searching for modifying loci by whole genome sequencing (WGS) of 200 subjects in each of the three projects. Project A will focus on the variable expression of epilepsy among boys with fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the premutation (PM). Project C, the topic of this project proposal, focuses fragile X association primary ovarian insufficiency (FXPOl) which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. Project A will focus on FXS-associated comorbid conditions, targeting epilepsy. Epilepsy often occurs with intellectual disability and/or autism spectrum disorder (ASD) and many believe there may be shared susceptibility loci, although few have been identified. Since FXS increases the risk of epilepsy and ASD, the loss of FMRP may be considered a shared susceptibility locus but insufficient alone to trigger either comorbid conditions. Hence finding epistatic variants influencing epilepsy in FXS may identify shared modifiers between epilepsy and ASD. Epilepsy was also chosen as it is a precisely defined diagnosis and, unlike ASD for example, we can anticipate and therefore recognize at least one class of potential modifying loci based upon genes identified as leading to inherited seizure disorders, such as subunits of voltage-gated or ligand-gated ion channels. Therefore unraveling epilepsy-related modifying loci in FXS will not only significantly contribute to our understanding of FXS pathophysiology but may well uncover novel neurobiological interactions between FMRP loss and variation elsewhere in the genome.
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1 |
2014 — 2019 |
Warren, Stephen T. |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Genetic Modifiers of Fxtas Severity
The goals of our Center, Modifiers of FMR1-associated disorders: application of high throughput technologies, are targeted to the RFA research area to Advance the understanding ofthe pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMRI - associated conditions by searching for modifying loci by whole genome sequencing (WGS) of 200 subjects in each of the three projects. Project A will focus on the variable expression of epilepsy among boys with fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the premutation (PM). Project C, the topic of this project proposal, focuses fragile X association primary ovarian insufficiency (FXPOl), which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Other PM carriers have a normal reproductive life span. Our goal is to identify and understand the extent of the epistatic effects of modifying genes on these three Mendelian disorders. We will recruit FMRI repeat mutation carriers from the tails of the phenotype distribution and compare their genetic variant profiles obtained from WGS. Specifically for this proposed project, we will obtain WGS on the cohort of 200 fragile X premutation carriers (100 male premutation cases with onset of FXTAS symptoms before age 65 and 100 male premutation controls with minimal symptoms of FXTAS after age 70, matched by repeat length to cases). Prioritized candidate genes from WGS will be validated and then functionally assessed using high throughput phenotype assays in Drosophila. This project will equally use shared Center cores: Recruitment Core B and the Genomics and Analytical Core C. We anticipate that identified modifying genes of FXPOl will provide insight into interventions for women ovarian insufficiency.
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1 |
2014 — 2019 |
Warren, Stephen T. |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Genetic Modifiers of Fxpoi Severity
The goals of our Center, 'Modifiers of FMR1-associated disorders: application of high throughput technologies, are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1-associated conditions by searching for modifying loci by whole genome sequencing (WGS) of 200 subjects in each of the three projects. Project A will focus on the variable expression of epilepsy among boys with fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the premutation (PM), with a lifetime prevalence of 30% among males. Project C, the topic of this project proposal, focuses fragile X association primary ovarian insufficiency (FXPOl) which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Other PM carriers have a normal reproductive life span. Our goal is to identify and understand the extent of the epistatic effects of modifying genes on these three Mendelian disorders. We will recruit FMR1 repeat mutation carriers from the tails of the phenotype distribution and compare their genetic variant profiles obtained from WGS. Specifically for this project, women who experience cessation of menses for at least four months prior to age 35 will be defined as case probands and women who experience menopause after age 50 and have no indication of infertility will be defined as control probands. Prioritized candidate genes from WGS will be validated and then functionally assessed using high throughput phenotype assays in Drosophila. This project will equally use shared Center cores: Recruitment Core B and the Genomics and Analytical Core C. We anticipate that identified modifying genes of FXPOl will provide insight into interventions for women ovarian insufficiency. We have established a collaboration with ReproGen Consortium, a group that has brought together genetic data on age at menopause from many well-defined cohorts, including data on greater than 50,000 women. They will be able to interrogate their meta-data to further determine the value of our identified variants for future studies.
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1 |
2014 — 2017 |
Jin, Peng Warren, Stephen T. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Tet-Mediated Epigenetic Modulation in Autism
DESCRIPTION (provided by applicant): Autism is comprised of a clinically heterogeneous group of disorders, collectively termed autism spectrum disorders (ASD), which share common features of impaired social relationship, impaired language and communication, and limited range of interests and behavior. Although monogenic disorders collectively only account for a minority of autism cases (10-15%), the molecular alterations in these disorders could reveal common pathogenic pathways shared by ASDs. Cytosine methylation serves as a critical epigenetic mark by modifying DNA-protein interactions that influence transcriptional states and cellular identity. 5-methylcytosine (5mC) has generally been viewed as a stable covalent modification to DNA; however, the fact that 5-mC can be enzymatically modified to 5-hydroxymethylcytosine (5hmC) by Tet family proteins through Fe(II) alpha-KG- dependent hydroxylation gives a new perspective on the previously observed plasticity in 5mC-dependent regulatory processes. Epigenetic plasticity in DNA methylation-related regulatory processes influences activity- dependent gene regulation and learning and memory in the central nervous system (CNS). Hydroxylation of 5mC to 5hmC presents a particularly intriguing epigenetic regulatory paradigm in the mammalian brain, where its dynamic regulation is critical. To unravel the biology of 5hmC, we have developed approaches to map genome-wide 5hmC distribution. Using these technologies, we generated genome-wide maps of 5hmC during brain development, providing a detailed epigenomic view of regulated 5hmC in CNS. Our analyses suggest a highly dynamic regulation of 5hmC during neurodevelopment. More specifically, we have identified both stable and dynamic DhMRs (Differential 5-hydroxymethylated regions) during neurodevelopment. Surprisingly DhMRs are highly enriched in the genes that have been implicated in autism. We have also found that the loss of Mecp2 leads to the specific reduction of 5hmC signals at dynamic DhMRs of cerebellum. More intriguingly, we have recently found that the loss of Fmr1, responsible for fragile X syndrome, could alter the 5hmC signals at dynamic DhMRs in mice as well. These data suggest that 5hmC-mediated epigenetic regulation may broadly impact brain development, and its dysregulation could contribute to autism. In this proposal, we will determine whether there is consistent alteration of 5hmC modification at dynamic DhMRs among mouse models of ASD-linked monogenic disorders, and determine the functional role(s) of Tet-mediated epigenetic modulation in ASD-linked monogenic disorders.
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1 |
2014 — 2019 |
Warren, Stephen T. |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Administrative Core
The goals of our Center, Modifiers of FRM1-associated disorders: application of high throughput technologies', are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FRM1-associated conditions. Project A will focus on the variable expression of epilepsy among boys with fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the premutation (PM), with a lifetime prevalence of 30% among males. Project C focuses fragile X association primary ovarian insufficiency (FXPOl) which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistatic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use the Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. The aims of the Administrative Core are to: 1) provide leadership and a center structure within which investigators can integrate their ideas, expertise and results, 2) facilitate communication and reporting of results to the scientific community, 3) facilitate research tasks by providing guidance in regulatory processes, budgeting, ordering and preparation of manuscripts and presentations, 4) facilitate data and resource sharing, and 5) provide coordinated research opportunities for students and postdoctoral fellows to engage them in fragile X-related conditions.
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1 |
2014 — 2017 |
Mulle, Jennifer Gladys Warren, Stephen T. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
1/2 Targeted Sequencing and Functional Evaluation of Mutations in Schizophrenia
DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a severe psychiatric disorder that affects 1% of the population worldwide and has a strong genetic influence on susceptibility. Recent genetic investigations of SZ, such as genome-wide association studies (GWAS) and structural genomic studies have made remarkable progress but leave a substantial part of the genetic risk unexplained, suggesting alternative models should be explored. We have designed a targeted sequencing experiment, by selecting coding and regulatory sequence in genomic intervals with high prior evidence for involvement in SZ. Our targets come from (i) genes that reside within SZ- associated copy number variant (CNV) intervals, or (ii) genes that show extreme transcriptional departures in SZ, for a total of ~600kb of sequence. We propose sequencing sample from the Molecular Genetics of SZ (MGS) collection and extracting sequence from the Genomic Psychiatry Cohort (GPC), resulting in a large, combined European ancestry (EA) discovery sample of 3,181 SZ cases and 3,500 matched controls. By limiting our target to a region that is small but likely enriched for SZ associated low frequency variants, we both lower the statistical threshold required for significance, and economically allow for a large sample size, giving us maximal power to identify new associations for SZ. We will then examine top hits for replication in the remaining GPC EA sample of 4,100 SZ cases and screened 5,400 controls. In addition, we propose adding another dimension of information, by functional evaluation of our most promising candidates. To accomplish this goal, in subsequent initial, exploratory work, we will generate and phenotypically characterize induced pluripotent stem cell (iPSC)-differentiated neurons from patients harboring associated mutations and from controls. If successful, our study will identify genes, putative mutations, and a mechanism of action by which those mutations contribute to SZ pathology. In this way we expect to refine our understanding of SZ and advance new, focused hypotheses to be tested. All data and biological materials will be rapidly shared through the designated NIMH repository (www.nimhgenetics.org) and dbGaP (dbgap.ncbi.nlm.nih.gov).
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1 |
2018 |
Caspary, Tamara J Mulle, Jennifer Gladys Warren, Stephen T. Weinshenker, David (co-PI) [⬀] |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Genetic and Molecular Drivers of the Schizophrenia-Associated 3q29 Deletion
3q29 deletion syndrome is caused by a recurrent, typically de novo 1.6 Mb heterozygous deletion that is associated with a range of neuropsychiatric phenotypes, including mild to moderate intellectual disability, autism, anxiety, and a 40-fold increased risk for schizophrenia. The high risk conferred by this deletion for neuropsychiatric phenotypes, coupled with its relatively low complexity (22 genes in the deletion interval), make it ideal for molecular dissection. Our team at Emory University has created the first mouse model of 3q29 deletion syndrome, and we show behavioral deficits consistent with compromised neurodevelopment. This model is therefore an excellent tool for interrogating the precise genetic and molecular mechanisms underlying 3q29 deletion syndrome. We propose using this model to a) identify the range of behaviors and other phenotypic manifestations with the largest departure from wild type; b) systematically pare the interval down to the minimal genes responsible for behavioral phenotypes by creating sub-deletion mice and assessing behavior; and c) identify the genes and pathways that are the molecular drivers of 3q29 deletion syndrome by evaluating transcriptional and proteomic changes in 3 distinct brain regions in full deletion and sub-deletion mice. Data from this project will be compared to our companion NIH-funded project where we are investigating molecular signatures in cells from human patients (?Modeling the Human Neuronal Phenotype of the Schizophrenia-Associated 3q29 Deletion,? 1 R01 MH110701). Understanding the specific biological processes disrupted in 3q29 deletion syndrome may provide a molecular window into key neurodevelopmental processes relevant to neuropsychiatric phenotypes, and can serve as a scaffold for integrating other targets identified in genetic studies of schizophrenia, autism, and intellectual disability. All molecular data and mouse lines will be readily and rapidly shared through NIH-approved databases and repositories.
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1 |
2018 — 2021 |
Jin, Peng Warren, Stephen T. |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dynamic Rna Modifications in Human Brain Development and Autism
PROJECT SUMMARY Epigenetic regulation has been shown to play pivotal roles in neurodevelopmental and neuropsychiatric disorders. In addition to DNA and histone modifications, more than 150 post-transcriptionally modified ribonucleosides have been identified in various types of RNA. Furthermore, recent studies have suggested that post-transcriptional messenger RNA (mRNA) modifications are dynamically regulated and significantly impact the outcomes of gene expression. These dynamic RNA modifications represent a critical new realm for gene expression regulation in the form of ?RNA epigenetics? or ?Epitranscriptomics?. Among different RNA modifications, our published and unpublished works suggest that m6A, m3C and m1A are dynamic and could play important roles during neurodevelopment and, potentially, contribute to developmental pathology if dysregulated. Autism spectrum disorder (ASD) is a clinically heterogeneous group of developmental disorders frequently characterized by impaired social relationships, impaired language and communication, a limited range of interests and stereotypic behaviors. We have found that ASD-linked genes are subject to extensive RNA modifications during human brain development. We have further developed robust technologies and pipelines to ?quantitatively? profile/map these RNA specific modifications at the transcriptome-wide level in humans. In this proposed PsychENCODE study, we will use postmortem tissue and human induced pluripotent stem cell-derived organoids to systematically map three distinct mRNA/lncRNA modifications (m6A, m3C and m1A) during normal human brain development and identify any differential patterns between unaffected donors and patients with ASD. These datasets will provide a blueprint of how RNA marks impact the global transcriptome and we will annotate prominent modifications on key transcripts important for brain development and function. Our proposed work will identify and functionally annotate epitranscriptome marks critical to post- transcriptional gene expression regulation across human brain development and adulthood. A systematic analysis of these RNA modifications in the context of human brain development and ASD could provide new functional insights into critical nodes of vulnerability for dysregulated neural development.
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1 |
2019 |
Warren, Stephen T. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Polyglutamine Expansion Length Dependent Pathology
? DESCRIPTION (provided by applicant): There are at least nine inherited neurodegenerative disorders caused by the expansion of a polyglutamine (polyQ) domain in the respective disease proteins, including Huntington's disease (HD) and several spinocerebellar ataxia (SCA) disorders. Although all polyQ disease proteins are expressed throughout the brain and body, they selectively affect neurons and a few other types of cells in an age-dependent manner. In addition, different polyQ lengths cause different symptoms in juvenile and adult patients, indicating that polyQ repeats can induce cell-type specific and age-dependent pathology. Understanding how the expanded polyQ-containing proteins mediate the selective pathology is critical if we are to develop effective therapeutic strategies for treating these polyQ diseases. Although we know that protein context modulates the toxicity of polyQ expansion seen in polyQ diseases, the mechanism behind the repeat length dependent selective pathology remains unknown Protein context confers the selectivity of polyQ toxicity because it determines protein-protein interactions, half-life and stability, and subcellular localization. However, the length of polyQ also can modulate the selectivity of polyQ protein toxicity. The strong evidence is that in HD, polyQ repeats larger than 60 glutamines cause juvenile cases that show symptoms different from those in adult HD patients. Similarly, expansion of the polyQ tract (>42 glutamines) in TBP induces clinical symptoms in SCA17 patients. However, when polyQ repeats are more than 63Q, mutant TBP causes juvenile-onset SCA-17 cases with retarded growth, progressive clinical symptoms, and early death as well as marked muscle weakness, which are different from those in adult-onset SCA17 patients. We hypothesize that polyQ repeat length determines differential pathology via its effect on protein interactions in cell- or tissue-dependet manner. To test this hypothesis, we will use SCA17 mice that express mutant TBP containing different polyQ repeats in neuronal or muscles cells. SCA-17 is an excellent model for us to investigate the mechanism behind the differential pathology in polyQ disease as the function of TBP is well characterized. Specifically, in Aim 1 we will characterize the cell type-dependent pathology in SCA17 knock-in mice. In Aim 2 we will use SCA17 knock-in mice and AAV vectors expressing TBP containing different polyQ repeats to investigate polyQ repeat length-dependent pathology in neuronal and muscle cells. In Aim 3 we will explore the mechanisms underlying specific effects of polyQ lengths by examining the effects of different polyQ repeat lengths on the interactions of mutant TBP with transcription factors in neuronal and muscle cells. These studies will provide new insight into the differential pathology and phenotypes caused by different polyQ repeat lengths in juvenile and adult polyQ diseases.
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1 |
2021 |
Jin, Peng Warren, Stephen T. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Fmrp-Mediated Regulation in Human Brain Development and Therapeutic Advancement
Project Summary Fragile X syndrome (FXS) is an X-linked disorder of intellectual disability (ID) that is most commonly due to the expansion of a CGG-repeat in the 5?-untranslated region of the FMR1 gene. CGG expansion beyond 200 repeats leads to hypermethylation of the FMR1 promoter, resulting in the loss of FMR1 expression. FXS is thereby caused by the loss of functional fragile X mental retardation protein (FMRP). Over the course of nearly three decades of research since the discovery of the FMR1 gene, much has been learned about the function of FMRP and the consequence of its absence, primarily using mouse and fruit fly model systems. FMRP is a selective RNA-binding protein associated with messenger ribonucleoprotein mRNPs and/or stalled polyribosomes that appears to be involved in the regulation of local protein synthesis at synapses. The loss of FMRP leads to dysregulated translation of selective mRNAs. Substantial progress in characterizing the underlying disease mechanisms in animal models has led to highly successful preclinical studies of drugs modulating metabotropic glutamate and GABA receptors. However, follow-up clinical trials in humans have been largely unsuccessful, highlighting the imprecision of using the mouse model of FXS. Development of human iPSCs-derived monolayer culture (2D) and three-dimensional (3D) organoid culture systems, which recapitulate key features of human brain development, have provided a platform to model human development and disease, as well as to better screen for therapeutic drugs. Little is known of FMRP-mediated regulation of human brain development or the extent of its plasticity, which is essential to fully understand the pathophysiology of FXS. The overarching goal of this Center is to take a systematic approach to investigate how FMRP may regulate human brain development and circuit functions, and develop novel therapeutic approaches to treat FXS. Using our established human 2D and 3D model systems as well as mouse models, we will determine the role of FMRP in human brain function and systematically identify the functional mRNA targets of FMRP in human brain development and circuit functions. We will also use these iPSC models as translational tools to develop novel therapeutic approaches for FXS. The Center brings together an outstanding team of investigators with expertise in transcriptomic analyses, genome-wide translation profiling (translatomes), FMRP-RNA interactomes, single cell genomics, cell type-specific manipulations, dissection of activity- and circuit-dependent mechanisms, and high-throughput small molecule screening. Our coordinated effort will create scientific synergy and significantly advance our understanding of FMRP-mediated gene regulation in human brain development and circuit functions and enable novel therapeutic development for fragile X syndrome.
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2021 |
Warren, Stephen T. |
R33Activity Code Description: The R33 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the R21 mechanism. Although only R21 awardees are generally eligible to apply for R33 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under R33. |
Use of Crispr/Cas9 to Treat Huntington Disease |
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