Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk. Open Access
Wang, Alex (2016)
Abstract
According to a World Health Organization's Global Burden of Disease report, schizophrenia is one of the leading causes of years lost due to disability and is characterized by periods of psychosis, social withdrawal, and disorganized thought patterns and behavior. Like many neurological disorders, it is difficult to pinpoint the reason behind the manifestation of the affliction. However, there is a growing body of evidence that suggests a genetic linkage, with studies showing increased risk from 1% in the general population to over 40% in monozygotic twins. Despite these findings, genetic predisposition is not enough to illicit the onset of the disease phenotype. Instead, it is believed to interact with a second level environmental or generalized stressor to precipitate the development of the disease. One such stressor has been suggested to be infection with a protozoan parasite known as Toxoplasma gondii (T. gondii). Two genetically distinct populations were used in genome-wide association analyses to determine genes that may increase susceptibility to infection with the protozoan parasite and possibly increase risk of developing disorders such as schizophrenia. To conduct the analyses we chose two different outcome variables, one continuous and the other dichotomous classifications of toxoplasmosis infection. From the analyses, a list of single nucleotide polymorphisms was obtained and corresponding genes were identified. Among the top SNPs found in our dichotomous analyses, a variant associated with the gene CHIAP2 and CHIA (rs10857870, p= 5.36E-06) was found. This encodes for a protein called chitinase that plays a role in defense against T. gondii cyst formation. Once the threshold value of p<0.001 was used to identify corresponding genes, a small number of genes were found to overlap in prediction of T. gondii infection between the two populations, among them were the genes found initially in AJ population: FHIT, ALK and RBFOX1. Though no direct linkage to increased susceptibility to infection was identified, pathways of interest that relate to cytokine regulation, transcript level alterations and chitinase activity may hold potential for future research.
Table of Contents
Introduction.........................................................................................................................1
Schizophrenia.......................................................................................................................1
Endophenotypes ..................................................................................................................2
Toxoplasmosis......................................................................................................................3
Latent toxoplasmosis and congenital outcomes ..................................................................4
Latent toxoplasmosis and mental health disorders..............................................................5
Toxoplasmosis and cognitive function.................................................................................7
Genetics and toxoplasmosis .................................................................................................8
Methods ...............................................................................................................................12
Participants..........................................................................................................................12
Immunoassay measurement.................................................................................................13
Genotyping ..........................................................................................................................14
Genotype data cleaning........................................................................................................15
Genome-wide association study...........................................................................................15
Results..................................................................................................................................18
Demographic Information....................................................................................................18
Discovery dataset..................................................................................................................20
Replication dataset...............................................................................................................41
Population comparison ........................................................................................................57
Discussion and Integration of Data ......................................................................................63
Public Health implications ...................................................................................................70
Bibliography..........................................................................................................................71
Appendix ..............................................................................................................................84
Annotated code.....................................................................................................................86
Data Cleaning........................................................................................................................86
Discovery dataset GWAS........................................................................................................88
Calculating principal components.........................................................................................88
HapMap..................................................................................................................................91
Associations’ analyses............................................................................................................92
Replication dataset GWAS ...................................................................................................102
Calculating principal components........................................................................................102
HapMap.................................................................................................................................104
Associations’ analyses...........................................................................................................105
About this Master's Thesis
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Primary PDF
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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. () | 2018-08-28 14:42:10 -0400 |
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Supplemental Files
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Supplemental Tables.pdf () | 2018-08-28 14:45:36 -0400 |
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