TY - JOUR
T1 - Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk
AU - Wang, Alex W.
AU - Avramopoulos, Dimitrios
AU - Lori, Adriana
AU - Mulle, Jennifer
AU - Conneely, Karen
AU - Powers, Abigail
AU - Duncan, Erica
AU - Almli, Lynn
AU - Massa, Nicholas
AU - McGrath, John
AU - Schwartz, Ann C.
AU - Goes, Fernando S.
AU - Weng, Lei
AU - Wang, Ruihua
AU - Yolken, Robert
AU - Ruczinski, Ingo
AU - Gillespie, Charles F.
AU - Jovanovic, Tanja
AU - Ressler, Kerry
AU - Pulver, Ann E.
AU - Pearce, Brad D.
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/6/8
Y1 - 2019/6/8
N2 - T. gondii (TOXO) infects over one billion people worldwide, yet the literature lacks a Genome Wide Association Study (GWAS) focused on genetic variants controlling the persistence of TOXO infection. To identify putative T. gondii susceptibility genes, we performed a GWAS using IgG seropositivity as the outcome variable in a discovery sample (n = 790) from an Ashkenazi dataset, and a second sample of predominately African Americans (The Grady Trauma Project, n = 285). We also performed a meta-analyses of the 2 cohorts. None of the SNPs in these analyses was statistically significant after Bonferroni correction for multiple comparisons. In the Ashkenazi population, the gene region of CHIA (chitinase) showed the most nominally significant association with TOXO. Prior studies have shown that the production of chitinase by macrophages in the brain responding to TOXO infection is crucial for controlling the burden of T. gondii cysts. We found a surprising number of genes involved in neurodevelopment and psychiatric disorders among our top hits even though our outcome variable was TOXO infection. In the meta-analysis combining the Ashkenazi and Grady Trauma Project samples, there was enrichment for genes implicated in schizophrenia spectrum disorders (p <.05). Upon limiting our sample to those without mental illness, two schizophrenia related genes (CNTNAP2, GABAR2) still had significant TOXO–associated variants at the p <.05 level, but did not pass the genome wide significance threshold after correction for multiple comparisons. Using Ingenuity Systems molecular network analysis, we identified molecular nodes suggesting that while different genetic variants associated with TOXO in the two population samples, the molecular pathways for TOXO susceptibility nevertheless converged on common pathways. Molecular nodes in these common pathways included NOTCH1, CD44, and RXRA. Prior studies show that CD44 participates in TOXO-induced immunopathology and that RXRA is instrumental in regulating T-helper immune responses. These data provide new insights into the pathophysiology of this common neurotropic parasite.
AB - T. gondii (TOXO) infects over one billion people worldwide, yet the literature lacks a Genome Wide Association Study (GWAS) focused on genetic variants controlling the persistence of TOXO infection. To identify putative T. gondii susceptibility genes, we performed a GWAS using IgG seropositivity as the outcome variable in a discovery sample (n = 790) from an Ashkenazi dataset, and a second sample of predominately African Americans (The Grady Trauma Project, n = 285). We also performed a meta-analyses of the 2 cohorts. None of the SNPs in these analyses was statistically significant after Bonferroni correction for multiple comparisons. In the Ashkenazi population, the gene region of CHIA (chitinase) showed the most nominally significant association with TOXO. Prior studies have shown that the production of chitinase by macrophages in the brain responding to TOXO infection is crucial for controlling the burden of T. gondii cysts. We found a surprising number of genes involved in neurodevelopment and psychiatric disorders among our top hits even though our outcome variable was TOXO infection. In the meta-analysis combining the Ashkenazi and Grady Trauma Project samples, there was enrichment for genes implicated in schizophrenia spectrum disorders (p <.05). Upon limiting our sample to those without mental illness, two schizophrenia related genes (CNTNAP2, GABAR2) still had significant TOXO–associated variants at the p <.05 level, but did not pass the genome wide significance threshold after correction for multiple comparisons. Using Ingenuity Systems molecular network analysis, we identified molecular nodes suggesting that while different genetic variants associated with TOXO in the two population samples, the molecular pathways for TOXO susceptibility nevertheless converged on common pathways. Molecular nodes in these common pathways included NOTCH1, CD44, and RXRA. Prior studies show that CD44 participates in TOXO-induced immunopathology and that RXRA is instrumental in regulating T-helper immune responses. These data provide new insights into the pathophysiology of this common neurotropic parasite.
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U2 - 10.1016/j.pnpbp.2018.12.019
DO - 10.1016/j.pnpbp.2018.12.019
M3 - Article
C2 - 30610941
AN - SCOPUS:85059960602
SN - 0278-5846
VL - 92
SP - 133
EP - 147
JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry
ER -