1/2 Schizophrenia Heterogeneity and Toxoplasma Exposure

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，遗传和非遗传因素均会导致风险。确定病因学上更同质的群体是重要的，发展我们的知识，与SZ病因学相关的多种病理生理途径。在这项研究中，我们将从一个新的角度研究SZ病因学，将个人暴露于弓形虫（Toxo），一个得到充分支持的SZ危险因素，到我们现有的SZ易感性的全基因组关联分析（GWAS）。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。假设将在一项病例对照研究中进行测试，该研究的对象是目前在约翰霍普金斯大学参加研究的德系犹太人（AJ）。主题包括：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病例的父母均可用;总N = 1，084）和3）AJ筛选对照（N = 356）。目前存在大量的临床和生物学数据，包括血浆样本，允许评估弓形虫IgG抗体滴度。除了突破性的探索性分析外，还将测试几个新的和统计学上具有良好功效的假设。我们将确定是否SZ个人谁已经暴露于弓形虫与那些谁没有在临床上不同。具体而言，我们计划探讨弓形虫血清学暴露指数和我们的广泛的数据，精神症状域，以确定是否特定的症状域区分SZ伴随弓形虫感染与SZ中，弓形虫不是一个因素。我们计划确定SZ先证者母亲的弓形虫暴露，以探讨妊娠期感染可能是弓形虫与SZ风险相关的因素。我们将使用我们现有的GWAS数据对SZ患者和筛选的对照受试者进行测试的假设，SZ与遗传变异的途径相关的弓形虫感染和神经免疫反应。我们将进一步研究25个位置或功能的候选基因的作用，SZ的背景下，弓形虫暴露，并确定这些基因是否作为效应修饰剂之间的连接弓形虫感染和SZ的风险。我们将探索弓形虫感染和SZ之间的关系，在全基因组的基础上，并将这些数据到病理生理背景下使用基于路径的生物信息学。 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个体比未被诊断为精神分裂症的个体暴露于弓形虫（一种原生动物寄生虫）引起的感染的比率更高。在这项研究中，我们将专注于个人的德系犹太血统，一个相对同质的人口和测试几个研究问题，弓形虫暴露和精神分裂症的风险之间的关系，也可能在双相情感障碍的作用。

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.