1/2 Schizophrenia Heterogeneity and Toxoplasma Exposure

描述(申请人提供)：精神分裂症(SZ)在病因上无疑是异质性的，既有遗传因素也有非遗传因素造成的风险。识别病因学上更同质性的群体对于发展我们对与SZ病因学相关的多种病理生理途径的认识是重要的。在这项研究中，我们将从一个新的角度研究SZ的病因，将个人暴露于弓形虫(Toxo)的数据纳入我们现有的SZ易感性的全基因组关联分析(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。假说将在一项病例对照研究中进行验证，研究对象是目前在约翰·霍普金斯大学学习的德裔犹太人(AJ)。研究对象包括：1)AJ-SZ(N=537)和BP(N=452)病例；2)AJ-SZ和BP患者的父母(254例SZ和288例BP，共1,084例)和3)AJ筛查对照(N=356)。目前存在大量关于这些人的临床和生物学数据，包括允许评估弓形虫抗体滴度的血浆样本。除了突破性的探索性分析外，还将测试几个新颖的、在统计上站得住脚的假设。我们将确定接触过弓形虫的深圳人与没有接触过弓形虫的深圳人在临床上是否有所不同。具体地说，我们计划探索弓形虫血清暴露指数和我们在精神症状领域的广泛数据，以确定特定的症状领域是否将伴有弓形虫感染的SZ与不是弓形虫感染因素的SZ区分开来。我们计划在SZ先证者的母亲中确定弓形虫暴露，以探索妊娠感染可能是连接Toxo与SZ风险的一个因素的概念。我们将使用我们现有的关于SZ患者和筛选的对照受试者的Gwas数据来检验SZ与弓形虫感染和神经免疫反应相关途径中的遗传变异有关的假设。我们将进一步研究SZ的25个位置或功能候选基因在弓形虫暴露的背景下的作用，并确定这些基因是否在弓形虫感染和SZ风险之间的联系中作为效应修饰物。我们将在全基因组的基础上探索弓形虫感染和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学背景下。 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。以前的研究表明，与未诊断为精神分裂症的人相比，被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，我们将专注于德系犹太人后裔的个体，他们是一个相对同质的群体，并测试几个研究问题，这些问题涉及弓形虫暴露与精神分裂症风险之间的关系，以及它在双相情感障碍中的可能作用。

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.