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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
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Rubio, Mercedes
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Johns Hopkins University
Schools of Medicine
United States
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Hatzimanolis, Alex; Avramopoulos, Dimitrios; Arking, Dan E et al. (2018) Stress-Dependent Association Between Polygenic Risk for Schizophrenia and Schizotypal Traits in Young Army Recruits. Schizophr Bull 44:338-347
Parks, Samuel; Avramopoulos, Dimitrios; Mulle, Jennifer et al. (2018) HLA typing using genome wide data reveals susceptibility types for infections in a psychiatric disease enriched sample. Brain Behav Immun 70:203-213
Trampush, J W; Yang, M L Z; Yu, J et al. (2017) GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol Psychiatry 22:336-345
Lam, Max; Trampush, Joey W; Yu, Jin et al. (2017) Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. Cell Rep 21:2597-2613
Eckart, Nicole; Song, Qifeng; Yang, Rebecca et al. (2016) Functional Characterization of Schizophrenia-Associated Variation in CACNA1C. PLoS One 11:e0157086
Pham, X; Song, G; Lao, S et al. (2016) The DPYSL2 gene connects mTOR and schizophrenia. Transl Psychiatry 6:e933
Zeledón, Mariela; Eckart, Nicole; Taub, Margaret et al. (2015) Identification and functional studies of regulatory variants responsible for the association of NRG3 with a delusion phenotype in schizophrenia. Mol Neuropsychiatry 1:36-46
Goes, Fernando S; McGrath, John; Avramopoulos, Dimitrios et al. (2015) Genome-wide association study of schizophrenia in Ashkenazi Jews. Am J Med Genet B Neuropsychiatr Genet 168:649-59
Hatzimanolis, Alex; Bhatnagar, Pallav; Moes, Anna et al. (2015) Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood. Am J Med Genet B Neuropsychiatr Genet 168B:392-401
Avramopoulos, Dimitrios; Pearce, Brad D; McGrath, John et al. (2015) Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation. PLoS One 10:e0116696

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