Genetics of Anxiety Disorders

Summary

Principal Investigator: Joel Gelernter
Abstract: DESCRIPTION (provided by applicant): ABSTRACT Anxiety disorders are major causes of morbidity and in some cases, mortality, in the US population in general, and in the Veteran population, specifically. The goal of the proposed project is to identify genes influencing susceptibility for anxiety disorders, especially panic disorder (PD) and social phobia (SocP), and anxiety traits. In previous work we collected a set of anxiety disorder extended pedigrees ascertained through probands with PD, and completed genome wide linkage scans for several anxiety traits. Recently we focused on association paradigms, and identified RGS2 as a gene that can influence anxiety phenotypes, and CNTNAP2 as a gene that can affect selective mutism risk. We have also focused on posttraumatic stress disorder (PTSD), with several frequently-cited publications on GxE interaction and PTSD. In the past funding period, we were able to take advantage of a large sample of subjects recruited for NIH-funded substance dependence studies, in which we obtained comprehensive diagnostic information, including anxiety disorder diagnoses. We propose to continue our investigations in already-collected clinical material, and by continuing collection of a set of college-age subjects ascertained by Dr. Murray Stein (UCSD &San Diego VA) (presently, >1800 subjects). These are projects and collaborations of demonstrated productivity. Our prior efforts have left us with a good clinical resource for identifying anxiety disorder risk genes (1084 PD patients and 795 SocP patients, excluding subjects with those diagnoses in the San Diego sample).For this work we will employ control subjects already recruited via other NIH-funded projects: presently we have 1,020 screened European-American, and 832 screened African-American, control subjects. At VA Connecticut, we will collect 120 new SSADDA-ascertained DSM-IV PD and SocP subjects yearly, a total of 480 subjects - a recruitment rate consistent with what we have achieved previously. These subjects, together with PD and SocP subjects already ascertained and enumerated above, will leave us with an adequately-powered case-control sample. At UCSD, our collaborator will collect for each of the following 4 years: 150 students with range of anxiety-related traits measured, 20 patients with panic disorder, and 40 patients with SocP (i.e. 600 trait-anxiety subjects, 80 PD subjects, and 160 SocP subjects over the course of the project). This will leave us with a total of >2400 trait anxiety subjects. We have obtained preliminary SocP GWAS data based on a sample size of 250 affected (and a much larger set of unaffected). We propose to expand the social phobia GWAS by 300 additional subjects. This will still be a modest-sized sample, however, should provide interesting new leads, and provide the basis to permit genotyping of our full SocP sample (Years 1 and 2). In Years 3 and 4, we will accomplish exomic sequencing of 150 affected subjects (planning to compare these with at least 300 control subjects available elsewhere). We have completed exome sequencing for 20 PD samples, 12 selected from a single pedigree and 8 unrelated selected from 8 additional pedigrees. Our preliminary analysis of these data will prepare us for dealing with the large data set that will result from 150 additional subjects and data handling and analysis issues specific to next-gene sequencing. Finally, possibly-associated common variants (identified through GWAS) and rare variants (identified through exome sequencing) will be genotyped in the entire anxiety sample (categorical diagnoses and trait anxiety). This project has been highly productive to date, in its application of linkage and association paradigms to identify chromosomal regions likely to harbor genes influencing risk for anxiety disorders and for anxiety-related traits. Continuation of this work would build on the already-valuable sample collection and accumulation of knowledge and expertise on genetic analysis of anxiety disorders.
Funding Period: 2013-04-01 - 2017-03-31
more information: NIH RePORT

Research Grants

  1. RADIOLOGICAL PHYSICS CENTER
    David S Followill; Fiscal Year: 2013
  2. GENETICS OF OPIOID DEPENDENCE
    Joel Gelernter; Fiscal Year: 2013
  3. Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors
    Darell D Bigner; Fiscal Year: 2013
  4. Genomics of Lupus
    JOHN BARKER HARLEY; Fiscal Year: 2013
  5. Genetics of Alcohol Dependence in African-Americans
    Joel Gelernter; Fiscal Year: 2013
  6. Elucidating Loci Involved in Prostate Cancer Suceptibility
    Brian E Henderson; Fiscal Year: 2013
  7. Costimulatory Mechanisms of Autoimmunity (Composite)
    David A Hafler; Fiscal Year: 2013
  8. Rare Variants and Risk of Type 1 Diabetes
    Stephen S Rich; Fiscal Year: 2013
  9. 5/6 The Genetics of Endophenotypes and Schizophrenia
    DEBBY WEN TSUANG; Fiscal Year: 2013
  10. 6/6 - The Genetics of Endophenotypes and Schizophrenia
    Laura C Lazzeroni; Fiscal Year: 2013

Detail Information

Research Grants30

  1. RADIOLOGICAL PHYSICS CENTER
    David S Followill; Fiscal Year: 2013
    ..Thus, the RPC's overall QA program impacts not only on clinical trial patients, but on the quality of all patients treated at the institution. ..
  2. GENETICS OF OPIOID DEPENDENCE
    Joel Gelernter; Fiscal Year: 2013
    ..This project has the potential to identify the next significant pool of OD genetic risk variants, thus advancing the field, with resulting improved understanding of biology, and consequent applications to public health. ..
  3. Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors
    Darell D Bigner; Fiscal Year: 2013
    ..abstract_text> ..
  4. Genomics of Lupus
    JOHN BARKER HARLEY; Fiscal Year: 2013
    ..The resulting level of understanding promises to establish the genetic etiology of lupus, spawn new diagnostics, prognostics, and therapeutics which provide therapeutic benefit to this and many related illnesses. ..
  5. Genetics of Alcohol Dependence in African-Americans
    Joel Gelernter; Fiscal Year: 2013
    ..Successful completion of this research would be expected to increase our understanding of alcohol dependence, and potentially to lead to early identification of susceptible individuals, and to new treatments. ..
  6. Elucidating Loci Involved in Prostate Cancer Suceptibility
    Brian E Henderson; Fiscal Year: 2013
    ..The overarching goal is to discover the pathways that drive prostate cancer pathogenesis and to assess their role in clinical decision making. ..
  7. Costimulatory Mechanisms of Autoimmunity (Composite)
    David A Hafler; Fiscal Year: 2013
    ....
  8. Rare Variants and Risk of Type 1 Diabetes
    Stephen S Rich; Fiscal Year: 2013
    ..These findings should lead to novel pathways of etiology and avenues for T1D prediction, prevention and therapy. ..
  9. 5/6 The Genetics of Endophenotypes and Schizophrenia
    DEBBY WEN TSUANG; Fiscal Year: 2013
    ..Once we understand the genetic architecture of these abnormalities, new medications that aim to improve the functioning and quality of life of schizophrenia patients can be developed. ..
  10. 6/6 - The Genetics of Endophenotypes and Schizophrenia
    Laura C Lazzeroni; Fiscal Year: 2013
    ..abstract_text> ..
  11. 4/5-The Genetics of Endophenotypes and Schizophrenia
    Raquel E Gur; Fiscal Year: 2013
    ..Once we understand the genetic architecture of these abnormalities, new medications that aim to improve the functioning and quality of life of schizophrenia patients can be developed. ..
  12. Exome Sequencing to Identify CVD Risk Variants in Hispanics &African Americans
    Carl D Langefeld; Fiscal Year: 2013
    ..abstract_text> ..
  13. Washington National Primate Research Center
    David M Anderson; Fiscal Year: 2013
    ..All lentivirus-infected primates are housed in ABSL2/3 containment facilities with appropriate biosafety procedures. The University of Washington, including the WaNPRC, is fully accredited by AAALAC International. ..
  14. Center for the Neurobiology of Addiction Treatment
    Steven R Childers; Fiscal Year: 2013
    ..These projects utilize several animal models and technologies uniquely developed by the Center investigators over the previous years of its funding history. ..
  15. Quantifying the impact of rare mutations on ADHD
    BENJAMIN MICHAEL NEALE; Fiscal Year: 2013
    ..New treatment targets are needed to develop better medications for treating ill patients and, perhaps, for preventing the disorder in susceptible people. ..
  16. Basic and Clinical Studies of Cystic Fibrosis
    Raymond A Frizzell; Fiscal Year: 2013
    ..The Core Center will operate a Pilot and Feasibility Program to bring new investigators into CF research. This Center emphasizes the translation of basic knowledge into applied therapeutics. ..
  17. Staphylococcal biofilm and disease
    Kenneth W Bayles; Fiscal Year: 2013
    ..Ultimately, these studies will pave the way for novel therapeutic approaches for the treatment of staphylococcal infections. ..