1/2 Schizophrenia Heterogeneity and Toxoplasma Exposure

1/2 精神分裂症异质性和弓形虫暴露

基本信息

批准号：
8021507
负责人：
Dimitrios Avramopoulos
金额：
$ 37.71万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8021507
关键词：
Adult Affect Age Antibodies Ashkenazim Bioinformatics Biological Biological Assay Biological Factors Bipolar Disorder Candidate Disease Gene Case-Control Studies Characteristics Chronic Clinical Communities Copy Number Polymorphism Data Data Analyses Diagnosis Diet Disease Enrollment Environmental Risk Factor Epidemiology Etiology Exposure to Famines Frequencies Gene Frequency Genes Genetic Genetic Heterogeneity Genetic Polymorphism Genetic Variation Genome Heterogeneity Immunoglobulin G Individual Infection Investigation Knowledge Literature Mental disorders Meta-Analysis Mothers Odds Ratio Parasites Parents Paternal Age Pathway interactions Patients Plasma Population Predisposition Pregnancy Publishing Reporting Research Research Personnel Research Project Grants Risk Risk Factors Role Sampling Schizophrenia Serologic tests Serological Single Nucleotide Polymorphism Site Students Subgroup Symptoms Technology Testing Toxoplasma Toxoplasma gondii Toxoplasmosis Universities Variant Work base follower of religion Jewish genetic association genetic risk factor genetic variant genome wide association study genome-wide indexing non-genetic novel proband response season of birth sex

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is undoubtedly etiologically heterogeneous with contribution to risk from both genetic and non-genetic factors. The identification of etiologically more homogeneous groups is important to developing our knowledge about the multiple pathophysiological pathways that are associated with SZ etiology. In this study, we will examine SZ etiology from a new perspective by incorporating data on individual exposure to Toxoplasma gondii (Toxo), a well supported SZ risk factor, into our existing genome-wide association analysis (GWAS) of SZ susceptibility. In addition, we will also be able to explore the relationship between Toxo exposure and the risk for bipolar disorder (BP). Hypotheses will be tested in a case-control study of Ashkenazi Jewish (AJ) individuals who are currently enrolled in studies at the Johns Hopkins University. Subjects include the following: 1) AJ SZ (N = 537) and BP (N =452) cases; 2) parents of AJ SZ and BP cases (both parents are available for 254 SZ cases and 288 BP cases; total N = 1,084) and 3) AJ screened controls (N = 356). A wealth of clinical and biological data currently exists for these individuals, including plasma samples allowing for the assessment of Toxo IgG antibody titers. Several novel and statistically well-powered hypotheses will be tested in addition to groundbreaking exploratory analysis. We will determine if SZ individuals who have been exposed to Toxo differ clinically from those who have not. Specifically, we plan to explore Toxo serological exposure indices and our extensive data on psychiatric symptom domains to determine whether particular symptom domains distinguish SZ accompanied by Toxo infection versus SZ in which Toxo is not a factor. We plan to ascertain Toxo exposure in the mothers of SZ probands to explore the concept that gestational infection may be a factor connecting Toxo with SZ risk. We will use our existing GWAS data on the SZ patients and screened control subjects to test the hypothesis that SZ is associated with genetic variants in pathways related to Toxo infection and neuroimmune responses. We will further examine the role of 25 positional or functional candidate genes for SZ in the context of Toxo exposure, and determine whether these genes act as effect modifiers in the connection between Toxo infection and SZ risk. We will explore the relationships between Toxo infection and SZ on a whole genome basis, and place this data into pathophysiological context using pathway-based bioinformatics. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic psychiatric disorder that affects 1% of the population worldwide and involves both biological and environmental factors. Previous research has demonstrated that individuals diagnosed with schizophrenia have a higher rate of exposure to an infection caused by Toxoplasma gondii (a protozoan parasite) than individuals who are not diagnosed with schizophrenia. In this study, we will focus on individuals of Ashkenazi Jewish descent, a relatively homogeneous population and test several research questions regarding the relationship between toxoplasma exposure and the risk for schizophrenia but also its possible role in bipolar disorder.

描述（由申请人提供）：精神分裂症（SZ）无疑是病因异质的，对遗传和非遗传因素的风险有贡献。病因学群体的鉴定对于发展与SZ病因相关的多种病理生理途径的知识很重要。在这项研究中，我们将通过新的角度研究SZ病因，通过将有关弓形虫gondii（Toxo）的个人暴露的数据（一种受支持的SZ风险因素）纳入我们现有的全基因组易感性分析（GWAS）。此外，我们还将能够探索毒素暴露与双相情感障碍（BP）之间的关系。假设将在目前正在约翰·霍普金斯大学（Johns Hopkins University）学习的Ashkenazi犹太人（AJ）的病例对照研究中进行检验。受试者包括以下内容：1）AJ SZ（n = 537）和BP（n = 452）案例； 2）AJ SZ和BP病例的父母（父母都有254例SZ病例和288个BP病例；总n = 1,084）和3）AJ筛选对照（n = 356）。目前，这些个体存在大量临床和生物学数据，包括允许评估毒素IgG抗体滴度的血浆样品。除了开创性的探索性分析外，还将测试几种新颖和统计上能力的假设。我们将确定暴露于毒Toxo的SZ个人是否在临床上与没有的人有所不同。具体而言，我们计划探索毒素血清学暴露指数和我们有关精神病症状领域的广泛数据，以确定特定症状结构域是否区分了SZ伴随着毒素感染的SZ与SZ与毒性不是因素的SZ。我们计划确定SZ Proband的母亲中的毒素暴露，以探讨妊娠感染可能是将Toxo与SZ风险联系起来的因素。我们将使用有关SZ患者的现有GWAS数据并筛选对照对象，以检验以下假设：SZ与与毒Toxo感染和神经免疫反应有关的途径中的遗传变异有关。我们将进一步研究在毒品暴露的背景下，25个位置或功能性候选基因在SZ中的作用，并确定这些基因在毒素感染与SZ风险之间的联系中是否充当效应修饰符。我们将在整个基因组基础上探索毒素感染与SZ之间的关系，并使用基于途径的生物信息学将这些数据置于病理生理环境中。公共卫生相关性：精神分裂症是一种慢性精神疾病，影响了全球1％的人口，并且涉及生物学和环境因素。先前的研究表明，与未被诊断出患有精神分裂症的人相比，被诊断为精神分裂症的个体暴露于弓形虫引起的感染率更高。在这项研究中，我们将专注于Ashkenazi犹太血统的个体，这是一个相对均匀的人群，并测试了有关毒素暴露与精神分裂症风险之间关系的几个研究问题，但在双相情感障碍中也可能作用。