1/2 Schizophrenia Heterogeneity and Toxoplasma Exposure

描述（由申请人提供）：精神分裂症（SZ）在病因学上无疑是异质性的，其风险来自遗传和非遗传因素。在病因学上更同质的群体的识别对于发展我们对与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来研究SZ的病因，将个体暴露于弓形虫（弓形虫）的数据纳入我们现有的SZ易感性全基因组关联分析（GWAS）中，弓形虫是一个得到充分支持的SZ危险因素。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。假设将在一项针对目前在约翰霍普金斯大学就读的德系犹太人（AJ）个体的病例对照研究中进行检验。研究对象包括：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病例均有父母，总N = 1,084）和3)AJ筛查对照组（N = 356）。目前存在大量关于这些个体的临床和生物学数据，包括用于评估弓形虫IgG抗体滴度的血浆样本。除了开创性的探索性分析外，还将测试几个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是否有临床差异。具体而言，我们计划探索弓形虫血清学暴露指数和我们在精神症状领域的广泛数据，以确定特定症状领域是否区分伴有弓形虫感染的SZ与不伴有弓形虫感染的SZ。我们计划确定弓形虫暴露在SZ先知者的母亲中，以探讨妊娠感染可能是弓形虫与SZ风险之间的一个因素。我们将利用现有的GWAS数据对SZ患者和筛选的对照组进行研究，以验证SZ与弓形虫感染和神经免疫反应相关通路的遗传变异相关的假设。我们将进一步研究弓形虫暴露背景下25个SZ位置或功能候选基因的作用，并确定这些基因是否在弓形虫感染与SZ风险之间起作用调节作用。我们将在全基因组的基础上探索弓形虫感染与SZ之间的关系，并利用基于途径的生物信息学将这些数据置于病理生理背景下。

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.