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Interaction Between Herpesviruses and Genetic Variation in Schizophrenia Pathogenesis: a Candidate Gene Approach

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Interaction Between Herpesviruses and Genetic Variation in Schizophrenia Pathogenesis: a Candidate Gene Approach INTERACTION BETWEEN HERPESVIRUSES AND GENETIC VARIATION IN SCHIZOPHRENIA PATHOGENESIS: A CANDIDATE GENE APPROACH by Brian H. Shirts BA, University of Utah, 2001 Submitted to the Graduate Faculty of the Graduate School of Public Health in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2006 UNIVERISTY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH This dissertation was presented by Brian H. Shirts It was defended on July 26th, 2006 and approved by Bernie Devlin, Ph.D., Associate Professor Departments of Psychiatry and Human Genetics Schools of Medicine and Graduate School of Public Health, University of Pittsburgh Eleanor Feingold, Ph.D., Associate Professor Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh Michael Pogue-Geile, Ph.D., Associate Professor, Clinical Program Chair Department of Psychology, School of Arts and Sciences, University of Pittsburgh Massimo Trucco, M. D., Hillman Professor Division of Immunogenetics, Departments of Pediatrics and Human Genetics Schools of Medicine and Graduate School of Public Health, University of Pittsburgh Robert Yolken, M.D., Professor Stanley Division of Neurovirology, Department of Pediatrics School of Medicine, Johns Hopkins University Dissertation Advisor: Vishwajit L. Nimgaonkar, M.D., Ph.D., Professor Departments of Psychiatry and Human Genetics Schools of Medicine and Graduate School of Public Health, University of Pittsburgh ii INTERACTION BETWEEN HERPESVIRUSES AND GENETIC VARIATION IN SCHIZOPHRENIA PATHOGENESIS: A CANDIDATE GENE APPROACH Brian H. Shirts, Ph.D. University of Pittsburgh, 2006 Schizophrenia is a debilitating disorder characterized by disturbances in thought with lifetime prevalence of one percent. The public health burden of schizophrenia due to medical care, social disability, and co-morbid conditions is substantial. Genetic variation, viral infection, or interaction of the two could influence schizophrenia risk. An understanding of these disease pathways could lead to strategies for prevention and treatment of schizophrenia. We used a positional approach to identify schizophrenia candidate genes that could interact with cytomegalovirus and herpes simplex viruses (HSV). We focused on three groups of genes: TNF and MICB near D6S2672, which was associated with schizophrenia and CMV in our previous studies; IL1β, IL1RN, and IL10, immune related genes associated with schizophrenia in published articles; and IL-18, IL18BP, IL18RAP, IL12A, and IL12B, positional candidate genes in the IL-18 pathway. We used multiple case-control and family-based samples to test these hypotheses. We comprehensively sequenced TNF, and genotyped eight SNPs in a case-control sample. We detected no significant associations. We used a dual-luciferase expression assay to quantify TNF expression driven by common promoter haplotypes. Differences in TNF expression did not correlate with schizophrenia. iii To localize the D6S2672 association, we genotyped 26 SNPs spanning 100kb in a case- control sample. Based on suggestive associations, we selected five SNPs to assay among additional samples. A SNP in MICB was associated with schizophrenia in these samples. The opposite allele was associated with HSV1 in two non-schizophrenia groups. We used comprehensive sequencing data to select tag SNPs at IL1β, IL1RN, IL10, and IL-18 pathway genes. Tag SNPs were evaluated in a case-control sample. In IL1β, IL1RN, and IL10 significant associations were not detected. However, meta-analysis of rs16944 (IL1β –511) studies suggests modest, but significant, risk for schizophrenia in Caucasian samples. In IL-18 pathway genes, a IL18RAP SNP was associated with schizophrenia, the opposite allele was associated with HSV1. Identified associations with schizophrenia may be due to host gene-virus interaction. These genetic variants could clarify which patients are vulnerable to viral infection. Treatment or prevention may be feasible, if our results are confirmed. Further replicate studies are warranted, as are functional studies of associated polymorphisms. iv TABLE OF CONTENTS 1. INTRODUCTION ...................................................................................................................... 1 1.1. SCHIZOPHRENIA......................................................................................................... 1 1. 2. GENETIC EPIDEMIOLOGY OF SCHIZOPHRENIA ..................................................... 3 1.3. IMMUNE SYSTEM DYSFUNCTION IN SCHIZOPHRENIA......................................... 5 1.4. EPIDEMIOLOGIC EVIDENCE OF INFECTIOUS DISEASE RISK ............................... 7 1.5. HERPES VIRUSES AND SCHIZOPHRENIA.................................................................. 7 1.6. GENE-VIRUS INTERACTION AND SCHIZOPHRENIA ............................................... 9 1.7. SIGNIFICANCE................................................................................................................ 11 2. SPECIFIC AIMS ..................................................................................................................... 13 2.1. COMPLETION OF SPECIFIC AIMS FOR INDIVIDUAL CANDIDATE GENES...... 14 2.2. SELECTION OF INFECTIOUS AGENTS TO BE EVALUATED................................ 15 2.3. MANUSCRIPTS............................................................................................................... 16 3. POSITIONAL AND FUNCTIONAL CANDIDATES FOR VIRUS-ENVIRONMENT INTERACTION............................................................................................................................ 18 3.1. DESIGN OF CANDIDATE GENE ASSOCIATION STUDIES...................................... 18 3.2. CONSIDERATIONS FOR SELECTION OF POSITIONAL CANDIDATE GENES FOR GENE-ENVIRONMENT INTERACTION ............................................................................. 22 3.3. CANDIDATE GENES INVESTIGATED ....................................................................... 24 3.3.1. Regions Associated with Schizophrenia and CMV Infection in Our Previous Studies ............................................................................................................................................... 27 v 3.3.2. Immune-Related Genes Previously Associated with Schizophrenia......................... 29 3.3.3. IL-18 Pathway Positional Candidates Involved in Herpes Virus Infection............... 33 4. GENERAL EXPERIMENTAL METHODS........................................................................... 36 4.1. SAMPLES USED ............................................................................................................. 36 4.1.1. Pittsburgh Trios and Singleton Cases ......................................................................... 36 4.1.2. Pittsburgh Neonatal Controls...................................................................................... 37 4.1.3. Baltimore Schizophrenia Cases, Bipolar Cases, and Controls .................................. 37 4.1.4. Mental Health Interventional Research Center Samples ........................................... 38 4.2. GENOTYPING AND SEQUENCING............................................................................. 39 4.2.1. SNAPshot Assay......................................................................................................... 39 4.2.2. Illumina Golden Gate assay........................................................................................ 39 4.2.3. Pooled DNA Sequencing ............................................................................................ 40 4.3. IMMUNOASSAYS ........................................................................................................... 41 4.4. STATISTICAL ANALYSES AND QUALITY CONTROL............................................ 42 4.4.1. Quality Control and Data Management ...................................................................... 42 4.4.2. Power calculations, Tag SNPs, and Linkage Disequilibrium..................................... 43 4.4.3. Association Analysis for Individual SNPs.................................................................. 44 4.4.4. Genomic Control......................................................................................................... 45 4.4.5. Haplotype Analysis..................................................................................................... 47 4.4.6. Analysis of Gene-Environment Interaction ................................................................ 48 4.4.6.1. Standard Methods of Gene-Environment Interaction.......................................... 48 4.4.6.2. Case-Only Analysis of Gene-Environment Interaction ....................................... 49 4.4.6.3. Family-Based Analysis of Gene-Environment Interaction.................................. 49 vi 5. GENETIC ASSOCIATION AND FUNCTIONAL STUDY OF TNF..................................... 51 5.1. INTRODUCTION ............................................................................................................. 51 5.2. SPECIFIC METHODS ...................................................................................................... 51 5.2.1. Clinical sample............................................................................................................ 51 5.2.2. Pooled sequencing ...................................................................................................... 52 5.2.3. Immunoassays for antibody titers of sera of subjects ................................................
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