Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk

Wang, Alex W.; Avramopoulos, Dimitrios; Lori, Adriana; Mullé, Jennifer G.; Conneely, Karen N.; Powers, Abigail; Duncan, Erica; Almli, Lynn M.; Massa, Nicholas; McGrath, John A.; Schwartz, Ann C.; Goes, Fernando S.; Weng, Lei; Wang, Ruihua; Yolken, Robert H.; Ruczinski, Ingo; Gillespie, Charles F.; Jovanović, Tanja; Ressler, Kerry J.; Pulver, Ann E.; Pearce, Brad D.

doi:10.1016/j.pnpbp.2018.12.019

Cited by 30 publications

(27 citation statements)

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“…As our GWAS controlled for psychiatric diagnosis, this could be an interesting illustration of a complex genetic factor, perhaps exhibiting pleiotropic effects and/or interactions with other factors. More recently, this gene has been highlighted in studies of schizophrenia and specific infections: Cytomegalovirus and Toxoplasma gondii, although the associations with SNPs in this gene were not genome-wide significant 14,44 . Thus, while no single SNP reached genome-wide significance in our study, possibly due to small effect sizes and a not-large-enough sample size, our results might still be informative regarding potential candidate genes for infection, and for studying the genetic overlaps between infection and mental disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have often provided conflicting results and been hampered by low power, differences in study designs, and/or high risk of publication bias 7 . Recently, acknowledging the potential links between psychiatric disorders and infection, studies looking into the genetic of specific infections have been performed, including a study of infection (Toxoplasma gondii, Herpes simplex virus 1, Cytomegalovirus and Human herpesvirus 6) and inflammation in individuals with schizophrenia and bipolar disorder 13 , and a study of Toxoplasma gondii in individuals with schizophrenia 14 highlighted several genes and/or pathways.…”

Section: Introductionmentioning

confidence: 99%

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A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population

et al. 2019

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Infections and mental disorders are two of the major global disease burdens. While correlations between mental disorders and infections have been reported, the possible genetic links between them have not been assessed in large-scale studies. Moreover, the genetic basis of susceptibility to infection is largely unknown, as large-scale genome-wide association studies of susceptibility to infection have been lacking. We utilized a large Danish population-based sample (N = 65,534) linked to nationwide population-based registers to investigate the genetic architecture of susceptibility to infection (heritability estimation, polygenic risk analysis, and a genome-wide association study (GWAS)) and examined its association with mental disorders (comorbidity analysis and genetic correlation). We found strong links between having at least one psychiatric diagnosis and the occurrence of infection (P = 2.16 × 10−208, OR = 1.72). The SNP heritability of susceptibility to infection ranged from ~2 to ~7% in samples of differing psychiatric diagnosis statuses (suggesting the environment as a major contributor to susceptibility), and polygenic risk scores moderately but significantly explained infection status in an independent sample. We observed a genetic correlation of 0.496 (P = 2.17 × 10−17) between a diagnosis of infection and a psychiatric diagnosis. While our GWAS did not identify genome-wide significant associations, we found 90 suggestive (P ≤ 10−5) associations for susceptibility to infection. Our findings suggest a genetic component in susceptibility to infection and indicate that the occurrence of infections in individuals with mental illness may be in part genetically driven.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population

et al. 2019

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“…These include differences in reelin and chondroitin sulfate proteoglycans, which may lead to impairments in neuronal migration and the synaptic function of GABAgeric, glutamatergic, and dopaminergic connectivity [103]. HA is another major component of the ECM that binds to the cell adhesion molecule CD44 [102, 105]. In a postmortem study, CD44 was found to be upregulated in the dorsolateral prefrontal cortex of patients with schizophrenia [66].…”

Section: Brain Microvascular Abnormalities In Schizophreniamentioning

confidence: 99%

The Role of Brain Microvascular Endothelial Cell and Blood-Brain Barrier Dysfunction in Schizophrenia

et al. 2020

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Background: Despite decades of research, little clarity exists regarding pathogenic mechanisms related to schizophrenia. Investigations on the disease biology of schizophrenia have primarily focused on neuronal alterations. However, there is substantial evidence pointing to a significant role for the brain’s microvasculature in mediating neuroinflammation in schizophrenia. Summary: Brain microvascular endothelial cells (BMEC) are a central element of the microvasculature that forms the blood-brain barrier (BBB) and shields the brain against toxins and immune cells via paracellular, transcellular, transporter, and extracellular matrix proteins. While evidence for BBB dysfunction exists in brain disorders, including schizophrenia, it is not known if BMEC themselves are functionally compromised and lead to BBB dysfunction. Key Messages: Genome-wide association studies, postmortem investigations, and gene expression analyses have provided some insights into the role of the BBB in schizophrenia pathophysiology. However, there is a significant gap in our understanding of the role that BMEC play in BBB dysfunction. Recent advances differentiating human BMEC from induced pluripotent stem cells (iPSC) provide new avenues to examine the role of BMEC in BBB dysfunction in schizophrenia.

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“…A genome wide association study found a number of genes associated with T. gondii infection were related to neurodevelopment and psychiatric disorders, especially schizophrenia (A.W. Wang et al, 2019). Niebuhr and colleagues (2008) found a significant positive association between T. gondii antibodies and diagnosis of schizophrenia among military personnel.…”

Section: Infectious Disease As a Cause Of Schizophreniamentioning

confidence: 99%

Schizophrenia: Epidemiology, Causes, Neurobiology, Pathophysiology, and Treatment

Volkan¹

2020

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Schizophrenia is a severe mental illness that has devastating consequences for those who suffer from the disorder. The epidemiology of schizophrenia indicates that it occurs relatively often, in many different contexts, and in conjunction with other disorders, decreasing quality of life and causing premature death. There has been an enormous amount of research into the causes of schizophrenia and there is now have a much better understanding of the genetic, environmental, and psychological factors that contribute to the disease. While there are numerous ways to understand and conceptualize schizophrenia, a unified picture of the neurobiology, changes in brain structure, cognitive and social-cognitive impairments related to the disorder has yet to emerge. Convulsive therapies and psychosurgery were used unsuccessfully, indiscriminately and without scientific validation in the past to treat schizophrenia. Medical advances including advanced imaging technology have now provided the ability to perform specifically focused neuromodulation and psychosurgery in severe and treatment resistant cases of schizophrenia. While still at a preliminary stage, these approaches have the potential to yield effective treatments in the future. For the last 70 years antipsychotic medication has become the prevailing treatment for schizophrenia. However, many people suffering from the disorder have trouble with side-effects and adhering to a regimen of antipsychotic medication. Newer pharmacological agents are being developed and include not only novel antipsychotic drugs, but anti-inflammatory and immunomodulating agents as well. These new agents, used either alone or in combination, have the potential to improve outcomes for people suffering from schizophrenia. Nevertheless, conclusively better pharmacotherapies will likely not arise until there is better understanding of the pathophysiology underlying schizophrenia. After the development of antipsychotic medication, psychotherapeutic methods for treating schizophrenia fell out of favor, but there is currently some reversal of this trend. The use of newer psychotherapies and modified forms of older therapeutic treatments are not only targeting the symptoms of schizophrenia but are also now focusing on recovery from the disorder. These newer approaches as well as efforts at preventing schizophrenia show promise in reducing the suffering caused by this disease.

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Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk

Cited by 30 publications

References 83 publications

A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population

A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population

The Role of Brain Microvascular Endothelial Cell and Blood-Brain Barrier Dysfunction in Schizophrenia

Schizophrenia: Epidemiology, Causes, Neurobiology, Pathophysiology, and Treatment

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