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1 the DOPAMINERGIC NETWORK and GENETIC SUSCEPTIBILITY to SCHIZOPHRENIA by Michael E. Talkowski B.S., Biology, the Pennsylvania S

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1 the DOPAMINERGIC NETWORK and GENETIC SUSCEPTIBILITY to SCHIZOPHRENIA by Michael E. Talkowski B.S., Biology, the Pennsylvania S THE DOPAMINERGIC NETWORK AND GENETIC SUSCEPTIBILITY TO SCHIZOPHRENIA by Michael E. Talkowski B.S., Biology, The Pennsylvania State University B.S., Psychology, The Pennsylvania State University 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 2008 1 UNIVERSITY OF PITTSBURGH Graduate School of Public Health This dissertation was presented by Michael E. Talkowski It was defended on July 24th, 2008 and approved by Thesis Advisor: Vishwajit L. Nimgaonkar, M.D., Ph.D., Professor of Psychiatry and Human Genetics School of Medicine and Graduate School of Public Health, University of Pittsburgh Committee Chairperson: Eleanor Feingold, Ph.D. Associate Professor of Human Genetics and Biostatistics Graduate School of Public Health, University of Pittsburgh Bernard Devlin, Ph.D. Associate Professor of Psychiatry and Human Genetics School of Medicine and Graduate School of Public Health, University of Pittsburgh M. Michael Barmada, Ph.D. Associate Professor of Human Genetics Graduate School of Public Health, University of Pittsburgh Gonzalo E. Torres, Ph.D. Assistant Professor of Neurobiology School of Medicine, University of Pittsburgh 2 Copyright © by Michael E. Talkowski 2008 3 THE DOPAMINERGIC NETWORK AND GENETIC SUSCEPTIBLITY TO SCHIZOPHRENIA Michael E. Talkowski, Ph.D. University of Pittsburgh, 2008 Background: Schizophrenia is a disabling illness with unknown pathogenesis. Estimates of heritability suggest a substantial genetic contribution; however genetic studies to date have been equivocal. Uncovering liability loci may therefore require analyses of functionally related genes. Rooted in this assumption, this dissertation describes a series of studies investigating a genetic epidemiological foundation for the commonly cited hypothesis suggesting dopaminergic dysfunction in schizophrenia pathogenesis, i.e. the ‘dopamine hypothesis’. Studies: The initial study investigated DRD3 and identified novel associations across the gene. The second study considered a larger network of dopaminergic genes in two independent Caucasian samples, detecting replicated associations and epistatic interactions. The study proposed a risk model for schizophrenia centered on the dopamine transporter. Study #3 investigated a dopamine precursor, phenylalanine hydroxylase, in four independent samples, identifying a single SNP (rs1522305) that was significantly replicated in two samples. Study #4 was motivated the hypothesis of a shared genetic etiology for schizophrenia and bipolar disorder. This study comprehensively evaluated the dopaminergic network, selecting 431 ‘tag’ SNPs from 40 genes among large schizophrenia and bipolar cohorts contrasted with adult controls. Across all genes 60% of nominally significant schizophrenia risk factors were also associated with 4 bipolar disorder. The results supported DRD3 variations as risk factors for both disorders, confirmed several previously reported associations, and proposed new targets for future research. Conclusion: These results suggest dopaminergic gene variations could play an etiological role in the pathogenesis of schizophrenia and possibly bipolar 1 disorder. Additional replicate studies are warranted . Public Health Significance: Schizophrenia (SZ) is devastating. When the Global Burden of Disease study calculated disability adjusted life years, weighted for the severity of disability, they determined active psychosis seen in schizophrenia produces disability equal to quadriplegia. Schizophrenia has been estimated to be among the top ten causes of disability worldwide. As schizophrenia is common (roughly 1% point prevalence worldwide), the economic burden to society is substantial. Pathogenesis is unknown and treatment is palliative. Therefore understanding the genetic etiology could facilitate development of promising therapeutics. 5 TABLE OF CONTENTS PREFACE .................................................................................................................................... 15 1.0 INTRODUCTION ...................................................................................................... 16 1.1 PUBLIC HEALTH SIGNIFICANCE .............................................................. 16 1.2 SCHIZOPHRENIA ........................................................................................... 17 1.2.1 History ............................................................................................................ 17 1.2.2 Clinical presentation...................................................................................... 18 1.2.3 Epidemiology of schizophrenia .................................................................... 20 1.2.4 Treatment of schizophrenia .......................................................................... 22 1.2.5 Schizophrenia pathogenesis: dopaminergic neurotransmission ............... 23 1.3 SCHIZOPHRENIA: A COMPLEX GENETIC DISORDER ....................... 27 1.3.1 Genetic epidemiology .................................................................................... 27 1.3.2 Linkage to schizophrenia .............................................................................. 29 1.3.3 Genetic association studies of schizohprenia............................................... 31 2.0 DOPAMINE GENES AND SCHIZOPHRENIA: CASE CLOSED OR EVIDENCE PENDING? ............................................................................................................ 34 2.1 ABSTRACT ........................................................................................................ 35 2.2 INTRODUCTION ............................................................................................. 36 2.2.1 The dopamine hypothesis .............................................................................. 37 6 2.2.2 Genetic association studies using dopamine polymorphisms .................... 38 2.2.3 Dopamine D2 receptor (DRD2) .................................................................... 40 2.2.4 Dopamine D3 receptor (DRD3) .................................................................... 41 2.2.5 Catechol-o-methyltransferase (COMT) ....................................................... 42 2.2.6 Dopamine transporter (DAT, DAT1, SLC6A3) ........................................... 43 2.3 PUBLISHED DOPAMINE ASSOCIATION STUDIES ................................ 44 2.4 SUGGESTIONS FOR FUTURE ANALYSES ............................................... 46 2.4.1 Are more genetic association studies needed? ............................................ 46 2.4.2 Which genes should be targeted? ................................................................. 46 2.4.3 Which polymorphisms should be investigated? .......................................... 47 2.4.4 Sample Configurations .................................................................................. 50 2.4.4.1 Sample size ........................................................................................... 50 2.4.4.2 Which ethnic group/s? ........................................................................ 50 2.4.4.3 Functional Analysis ............................................................................. 51 2.4.4.4 Should genomewide associations (GWAS) supplant candidate gene studies? 51 2.5 CONCLUSIONS ................................................................................................ 52 2.6 ACKNOWLEDGEMENTS .............................................................................. 53 3.0 STUDY #1: NOVEL, REPLICATED ASSOCIATIONS BETWEEN DOPAMINE D3 RECEPTOR POLYMORPHISMS AND SCHIZOPHRENIA ......................................... 54 3.1 ABSTRACT ........................................................................................................ 55 3.2 INTRODUCTION ............................................................................................. 56 3.3 METHODS ......................................................................................................... 58 7 3.3.1 Clinical ............................................................................................................ 58 3.3.2 Laboratory ..................................................................................................... 59 3.3.3 SNP Selection ................................................................................................. 60 3.3.4 Genotyping ..................................................................................................... 61 3.3.5 Statistical Analysis ......................................................................................... 62 3.3.5.1 Genomic Control ................................................................................. 63 3.4 RESULTS ........................................................................................................... 64 3.4.1 Quality Control .............................................................................................. 64 3.4.2 Comparison of linkage disequilibrium (LD) between samples ................. 65 3.4.3 Association testing in U.S. sample ................................................................ 66 3.4.3.1 SNP analyses ........................................................................................ 66 3.4.3.2 Haplotype analyses .............................................................................. 67 3.4.4 Replication testing in the Indian family sample ........................................
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