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Examining Alcohol Dependence and Its Correlates from a Genetically Informative Perspective

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Examining Alcohol Dependence and Its Correlates from a Genetically Informative Perspective Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2012 Examining Alcohol Dependence and Its Correlates From A Genetically Informative Perspective Laura Hack Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medical Genetics Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/547 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Laura M. Hack, 2012 All Rights Reserved EXAMINING ALCOHOL DEPENDENCE AND ITS CORRELATES FROM A GENETICALLY INFORMATIVE PERSPECTIVE A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University by Laura Michele Hack Bachelor of Science, The College of William & Mary, 2006 Advisors: Brien P. Riley, Ph.D. Associate Professor, Departments of Psychiatry and Human and Molecular Genetics Kenneth S. Kendler, M.D. Distinguished Professor, Departments of Psychiatry and Human and Molecular Genetics Virginia Commonwealth University Richmond, Virginia September, 2012 Acknowledgement First, I’d like to express my sincere appreciation to my advisors, Drs. Brien Riley and Kenneth Kendler, for the enormous amount of time that they dedicated to mentoring me, guiding me through analytic challenges, and fostering my passion for research. I’d also like to acknowledge the other members of my committee, Drs. Danielle Dick, Jill Bettinger, and Tim York, as well as Drs. Todd Webb and Hermine Maes, for their time, guidance, and support. I want to recognize the research associates and post-docs at VIPBG, including Steve Aggen, Fazil Aliev, Jocilyn Dellava Bergin, Tim Bigdeli, Alexis Edwards, Chuck Gardner, John Myers, Elizabeth Prom- Wormley, and Brad Verhulst, for their countless hours aiding me with statistical analyses. Thank you to past and present members of the Riley lab, including Amy Adkins, Dave Brohawn, Rachel Elves, Gursharan Kalsi, Erik Loken, Cathy Siu, Dawn Thiselton, and Brandon Wormley for their personal and professional support and the good times! Additionally, I couldn’t have made it through my doctoral training without a great deal of assistance from the administrative and IT support staff. Thank you to all of my VIPBG and non-VIPBG friends for your wonderful friendship. I’d like to recognize Dr. Gordon Archer for the opportunity to do my MD-PhD training at VCU and for his guidance over the years. Thank you to Dr. John Griffin, my undergraduate research mentor, for providing me with my first research experience and inspiring me to continue to pursue research. Finally, I’d like to express my profound gratitude to my wonderful family and boyfriend whose endless support, encouragement, and love have been integral to my success. ii Table of Contents Acknowledgement .......................................................................................................................... ii List of Tables ...................................................................................................................................v List of Figures ............................................................................................................................... vii Abbreviations ............................................................................................................................... viii Clarification of Contributions ........................................................................................................ xi General Abstract ........................................................................................................................... xii CHAPTER 1: General Introduction Significance ............................................................................................................................. 1 Etiology ................................................................................................................................... 2 Phenotypes ............................................................................................................................... 3 Study Design............................................................................................................................ 5 Prior Evidence From Association Studies of AD ...................................................................10 Overview of Current Research ...............................................................................................15 CHAPTER 2: Exploring the Association between Education Level & Alcohol Related Phenotypes Using a Genetically Informative Design Abstract .................................................................................................................................. 16 Introduction ........................................................................................................................... 17 Methods ................................................................................................................................. 20 Results ................................................................................................................................... 27 Discussion .............................................................................................................................. 33 CHAPTER 3: Alcoholic Beverage Preference: An Epidemiological & Twin Study Abstract .................................................................................................................................. 37 Introduction ........................................................................................................................... 38 Methods ................................................................................................................................. 40 Results ................................................................................................................................... 47 Discussion .............................................................................................................................. 59 CHAPTER 4: Limited Associations of Dopamine System Genes with Alcohol Dependence and Related Traits in the Irish Affected Sib Pair Study of Alcohol Dependence Abstract .................................................................................................................................. 70 Introduction ....................................................................................................................................... 71 iii Methods ................................................................................................................................. 77 Results ................................................................................................................................... 83 Discussion .............................................................................................................................. 87 CHAPTER 5: Preliminary Genome-wide Association Studies of Alcohol Dependence, Symptom Count, and Externalizing Phenotype in an Irish Family Sample Abstract .................................................................................................................................. 93 Introduction ........................................................................................................................... 94 Methods ................................................................................................................................. 95 Results ......................................................................................................................................105 Discussion ................................................................................................................................112 CHAPTER 6: General Discussion Part I Summary, Future Directions, and Limitations ........................................................... 120 Part II Summary, Future Directions, and Limitations ......................................................... 122 Lessons on Study Design ..................................................................................................... 126 Literature Cited ............................................................................................................................131 Appendix: Supplemental Tables A.1 Marker information and nominal p-values for AD and ARPs for DA SNPs .................157 A.2 Maker information and nominal p-values for disinhibitory symptom counts and factor score for DA SNPs ................................................................................................................159 A.3 Association results for IASPSAD AD with q-values < 0.5 and COGA replication .......161 A.4 Association results for the joint meta-analysis of AD in the IASPSAD and COGA......178 A.5 Association results for the externalizing factor score in the IASPSAD .........................183 Vita .........................................................................................................................................186 iv List of Tables 2.1 Descriptive statistics for education and alcohol measures ......................................................27 2.2 Pearson correlations
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