2/2 Schizophrenia Heterogeneity and Toxoplasma Exposure

2/2 精神分裂症异质性和弓形虫暴露

• 批准号: 8024600
• 负责人: BRADLEY D PEARCE
• 金额: $ 16.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/8024600
• 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

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）无疑在病因学上具有异质性，遗传和非遗传因素都会增加风险。识别病因学上更同质的群体对于发展我们对与 SZ 病因学相关的多种病理生理学途径的了解非常重要。在这项研究中，我们将从新的角度研究 SZ 病因，将个人接触弓形虫 (Toxo)（一种得到充分支持的 SZ 危险因素）的数据纳入我们现有的 SZ 易感性全基因组关联分析 (GWAS) 中。此外，我们还将能够探索弓形虫暴露与双相情感障碍 (BP) 风险之间的关系。这些假设将在一项针对德系犹太人 (AJ) 个体的病例对照研究中得到检验，这些个体目前正在约翰霍普金斯大学参加研究。主题包括以下内容： 1) AJ SZ (N = 537) 和 BP (N = 452) 病例； 2) AJ SZ 和 BP 病例的父母（254 例 SZ 病例和 288 例 BP 病例的父母均可提供；总数 N = 1,084）和 3）AJ 筛查对照（N = 356）。目前存在这些个体的大量临床和生物学数据，包括可用于评估 Toxo IgG 抗体滴度的血浆样本。除了突破性的探索性分析之外，还将测试一些新颖且统计上有力的假设。我们将确定接触过弓形虫的 SZ 个体与未接触过弓形虫的个体在临床上是否存在差异。具体来说，我们计划探索弓形虫血清学暴露指数和我们关于精神症状领域的广泛数据，以确定特定症状领域是否能够区分伴有弓形虫感染的精神分裂症和弓形虫不是影响因素的精神分裂症。我们计划确定 SZ 先证者母亲的弓形虫暴露情况，以探索妊娠期感染可能是将弓形虫与 SZ 风险联系起来的一个因素。我们将利用现有的 SZ 患者和筛选的对照受试者的 GWAS 数据来检验 SZ 与 Toxo 感染和神经免疫反应相关途径的遗传变异相关的假设。我们将进一步研究 25 个 SZ 位置或功能候选基因在 Toxo 暴露背景下的作用，并确定这些基因是否作为 Toxo 感染与 SZ 风险之间关系的效应调节剂。我们将在全基因组基础上探索 Toxo 感染与 SZ 之间的关系，并使用基于通路的生物信息学将这些数据置于病理生理学背景中。 公共卫生相关性：精神分裂症是一种慢性精神疾病，影响全球 1% 的人口，涉及生物和环境因素。先前的研究表明，被诊断为精神分裂症的人比未诊断为精神分裂症的人接触弓形虫（一种原生动物寄生虫）引起的感染的几率更高。在这项研究中，我们将重点关注德系犹太血统的个体，这是一个相对同质的人群，并测试一些关于弓形虫暴露与精神分裂症风险之间的关系及其在双相情感障碍中可能发挥的作用的研究问题。