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Osu1291037634.Pdf (3.74 Expression Genetics in the Human Brain: Evolution and Disease DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ryan Matthew Smith Neuroscience Graduate Studies Program The Ohio State University 2010 Dissertation Committee: Wolfgang Sadee, Advisor Christine E. Beattie Jack A. Boulant John D. Oberdick Copyright by Ryan Matthew Smith 2010 Abstract Genetic diversity is a major factor driving phenotypic differences between individuals. The wide spectrum of heritable traits ranges from mild personality differences to extreme instances of Mendelian genetic disorders. Consequently, researchers have expended significant resources attempting to find genetic variants that contribute to phenotypic diversity, especially those relating to human disease. Past efforts have been most successful at uncovering highly penetrant mutations that occur in the protein coding regions of genes. Promoter and intronic variants can also have drastic effects on phenotype, with recent estimates suggesting that variants acting at the RNA level contribute to greater than 60% of all genetic disease. Most of these genetic variants affect RNA processing, especially transcript splicing. Here, I present a series of studies exploring relationships between genetic variants that significantly affect RNA expression and three neurological phenotypes. First, I uncovered a transcription enhancer region contributing to nicotinic α5 receptor subunit mRNA expression and subsequently tested its relationship to nicotine addiction. Next, I revealed a significant correlation between splicing of serotonin 2A receptor mRNA transcripts and a genetic variant implicated in clinical responsiveness to atypical antipsychotics and antidepressants. Finally, in a survey of autism-related risk genes, I uncovered ii evidence for genetic variations affecting mRNA expression in multiple genes, including cellular adhesion molecules, alternative splicing molecules, and integral components of glutamatergic and gamma-aminobutyric acid signaling. The broad range of neurological phenotypes affected by non-protein coding variants investigated here suggests a pervasive role for RNA processing in human disease. The accumulation of these RNA processing variants throughout human evolution is discussed in the context of human disease. iii Dedicated to my wife and son, grandmother and grandfather, mother, father, brother, extended family, and great friends, whose love and support has fueled my ambition. My achievements are a reflection of your sacrifices, all of which are more greatly appreciated than can be expressed through written word. iv Acknowledgments I am grateful to acknowledge my many personal and professional mentors at Ohio State. Specifically, Wolfgang Sadee, thank you for the opportunity to study as a member of your laboratory and for challenging me to be a better scientist and professional. David Beversdorf, thank you for providing my first opportunity to understand the human mind from a scientific perspective. Members of my dissertation committee, Christine Beattie, Jack Boulant, and John Oberdick, thank you for your time and support. Finally, to my many colleagues at Ohio State, thank you for contributing to my success by providing me with knowledge, companionship, and advice. v Vita December 5th, 1981 ................................ Born, Fremont, Ohio June 2010 ............................................... Gibsonburg High School 2003 to 2005........................................... Undergraduate Research Associate, Department of Neurology, The Ohio State University June 12th 2005 ........................................ B.A. Psychology, The Ohio State University 2006 ...................................................... Post-Baccalaureate Research Assistant, Department of Neurology, The Ohio State University 2006 to Present ...................................... Graduate Research Associate, Departments of Neurology, Psychology, and Pharmacology, The Ohio State University 2008 ....................................................... International Meeting for Autism Research Student Travel Award 2009 ....................................................... Edward J. Ray Travel Award for Scholarship and Service vi Vita Con’t Publications Sadee W, Wang D, Papp AC, Pinsonneault JK, Smith RM, Moyer RA, and Johnson AD. (in press). Pharmacogenomics of the RNA world: Structural RNA polymorphisms (srSNPs) in drug therapy. Clin Pharmacol Ther Moyer RA, Wang D, Papp AC, Smith RM, Duque L, Mash DC, and Sadee W (in press). Intronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse. Neuropsychopharmacology Smith RM, Alakchar H, Papp AC, Wang D, Mash DC, Wang JC, Bierut LJ, & Sadee W (2010). Nicotinic α5 receptor subunit mRNA expression is associated with distant 5’ upstream polymorphisms. Eur J Hum Genet, advance online publication 11 August 2010; doi: 10.1038/ejhg.2010.120 Jones KL, Smith RM, Edwards KS, Givens B, Tilley MR, & Beversdorf DQ (2010). Combined effect of maternal serotonin transporter genotype and prenatal stress in modulating offspring social interaction. Int J Dev Neurosci, 26, 529-536 Smith RM & Beversdorf DQ (2008). Effects of semantic relatedness on recall of stimuli preceding emotional oddballs. J Int Neuropsycol Soc, 14, 620-628. vii Vita Con’t Alexander JK, Hillier A, Smith RM, Tivarus ME, & Beversdorf DQ (2007). Βeta- adrenergic modulation of cognitive flexibility during stress. J Cog Neurosci, 19, 468-478. Smith RM, Tivarus M, Campbell HL, Hillier A, & Beversdorf DQ (2006). Apparent transient effects of recent “ecstasy” use on cognitive performance and extrapyramidal signs in human subjects. Cogn Behav Neurol, 19, 157-164. Field of Study Major Field: Neuroscience Graduate Studies Program viii Table of Contents Abstract .................................................................................................................ii Acknowledgments ................................................................................................ v Vita .......................................................................................................................vi List of Tables ........................................................................................................xi List of Figures ...................................................................................................... xii Chapter 1: Introduction to Functional Genetics..................................................... 1 Chapter 2: Functional Genetics of CHRNA5: Role in Nicotine Dependence ....... 9 2.1 Introduction and Background ...................................................................... 9 2.2 Materials and Methods .............................................................................. 13 2.3 Results ...................................................................................................... 18 2.4 Discussion ................................................................................................. 29 Chapter 3: Variability in Serotonin 2A Receptor Genetics and Therapeutic Response ........................................................................................................... 34 3.1 Introduction and Background .................................................................... 34 3.2 Materials and Methods .............................................................................. 39 3.3 Results ...................................................................................................... 42 ix 3.4 Discussion ................................................................................................. 48 Chapter 4: Surveying Candidate Risk Genes in Autism Spectrum Disorders ..... 55 4.1 Introduction and Background .................................................................... 55 4.2 Materials and Methods .............................................................................. 59 4.3 Results ...................................................................................................... 62 4.4 Discussion ................................................................................................. 69 Chapter 5: Concluding Remarks ......................................................................... 77 References ......................................................................................................... 82 Appendix A: Abbreviations............................................................................... 114 Appendix B: Tables ......................................................................................... 118 Appendix C: Figures ........................................................................................ 128 x List of Tables Table 1. Correlation and LD between rs3841324 and selected SNPs ................ 12 Table 2. Influence of demographic variables on CHRNA5 mRNA expression in BA46 prefrontal cortex samples .......................................................................... 20 Table 3. Single-SNP and joint-effect association models testing for nicotine dependence in COGEND ................................................................................... 28 Table 4. rs905740/rs16969968 haplotype frequencies in brain samples ............ 28 Table 5. Influence of demographic variables on HTR2A mRNA expression in BA46 prefrontal cortex samples .........................................................................
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