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Role of Genomic Copy Number Variation in Alzheimer's Disease And ROLE OF GENOMIC COPY NUMBER VARIATION IN ALZHEIMER'S DISEASE AND MILD COGNITIVE IMPAIRMENT Shanker Swaminathan Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Medical and Molecular Genetics, Indiana University August 2012 Accepted by the Faculty of Indiana University, in partial fulfillment of the requirements for the Degree of Doctor of Philosophy. ____________________________________ Andrew J. Saykin, PsyD, Chair ____________________________________ Tatiana Foroud, PhD Doctoral Committee ____________________________________ John I. Nurnberger, Jr, MD, PhD May 23, 2012 ____________________________________ Li Shen, PhD ii To my parents and sister iii ACKNOWLEDGEMENTS This work would not have been possible without the help and support of a lot of people. I would like to thank Dr. Andrew Saykin, my thesis advisor, for providing me the opportunity to be a part of his lab and be able to pursue research in the field of imaging genetics. Dr. Saykin has always encouraged me to be pursue new information and be up to date with the current developments in the field. He has been a constant source of support and guidance and was a person whom I could always turn to when I have had problems. His feedback and suggestions have been very helpful. I would also like to thank the members of my research committee: Drs. Tatiana Foroud, John Nurnberger and Li Shen for their help in this work. They encouraged me to pursue this work and offered feedback and suggestions which were very helpful. They also made sure that I was on track with the program requirements and was making smooth progress towards the PhD degree. I would like to thank other members of the lab including Dr. Li Shen, Dr. Sungeun Kim, Dr. Kwangsik Nho, Dr. Shannon Risacher, Susan Conroy, John West, Jing Wan, Kelley Holohan and Vijay Ramanan for their help with this work. I was fortunate to work with them on a number of projects, which enabled me to learn some of the methods used in imaging analyses and genetic analyses. I am also grateful to Dr. Mark Inlow for his help and guidance on the statistical analyses. I would also like to thank the faculty and staff at the Center for Neuroimaging. I express my gratitude to Dr. Kenneth Cornetta, Dr. Brittney-Shea Herbert, Dr. Terry Reed and Peggy Knople for their guidance on the program requirements and for making sure I was completing the requirements in a timely manner. I also thank the faculty and iv staff at the Department of Medical and Molecular Genetics as well as the staff of the IUPUI Graduate Office and the Graduate Division of the Indiana University School of Medicine for their help during the course of my study. Finally, I would like to offer my heartfelt thanks to my family. They encouraged me to pursue my interests in performing research and were there with me at every step. They follow my progress keenly and are very interested in learning about the various projects I am involved in as well the Genetics field in general. Their motivation and support has helped me progress along smoothly and I would like to express my sincere gratitude to them. v ABSTRACT Shanker Swaminathan ROLE OF GENOMIC COPY NUMBER VARIATION IN ALZHEIMER'S DISEASE AND MILD COGNITIVE IMPAIRMENT Alzheimer's disease (AD) is the most common form of dementia defined by loss in memory and cognitive abilities severe enough to interfere significantly with daily life activities. Amnestic mild cognitive impairment (MCI) is a clinical condition in which an individual has memory deficits not normal for the individual's age, but not severe enough to interfere significantly with daily functioning. Every year, approximately 10-15% of individuals with MCI will progress to dementia. Currently, there is no treatment to slow or halt AD progression, but research studies are being conducted to identify causes that can lead to its earlier diagnosis and treatment. Genetic variation plays a key role in the development of AD, but not all genetic factors associated with the disease have been identified. Copy number variants (CNVs), a form of genetic variation, are DNA regions that have added genetic material (duplications) or loss of genetic material (deletions). The regions may overlap one or more genes possibly affecting their function. CNVs have been shown to play a role in certain diseases. At the start of this work, only one published study had examined CNVs in late-onset AD and none had examined MCI. In order to determine the possible involvement of CNVs in AD and MCI susceptibility, genome-wide CNV analyses were performed in participants from three cohorts: the ADNI cohort, the NIA-LOAD/NCRAD Family Study cohort, and a vi unique cohort of clinically characterized and neuropathologically verified individuals. Only participants with DNA samples extracted from blood/brain tissue were included in the analyses. CNV calls were generated using genome-wide array data available on these samples. After detailed quality review, case (AD and/or MCI)/control association analyses including candidate gene and genome-wide approaches were performed. Although no excess CNV burden was observed in cases compared to controls in the three cohorts, gene-based association analyses identified a number of genes including the AD candidate genes CHRFAM7A, RELN and DOPEY2. Thus, the present work highlights the possible role of CNVs in AD and MCI susceptibility warranting further investigation. Future work will include replication of the findings in independent samples and confirmation by molecular validation experiments. Andrew J. Saykin, PsyD, Chair vii TABLE OF CONTENTS List of Tables ................................................................................................................... x List of Figures ................................................................................................................ xii List of Abbreviations ..................................................................................................... xiv I. Introduction A. Alzheimer's disease ......................................................................................... 1 B. Role of genetic variation in Alzheimer's disease .............................................. 4 C. Copy number variation .................................................................................. 11 D. Mechanisms for formation of copy number variations .................................... 12 E. Methods for copy number variation detection ................................................ 16 F. Copy number variation detection algorithms .................................................. 20 G. Copy number variation in selected neuropsychiatric disorders ...................... 23 H. Copy number variation in Alzheimer's disease .............................................. 33 I. Statement of purpose ...................................................................................... 35 II. Genomic Copy Number Analysis in Alzheimer's Disease and Mild Cognitive Impairment: An ADNI Study A. Introduction .................................................................................................... 37 B. Methods......................................................................................................... 40 C. Results .......................................................................................................... 47 D. Discussion ..................................................................................................... 59 III. Analysis of Copy Number Variation in Alzheimer's Disease: the NIA-LOAD/NCRAD Family Study A. Introduction .................................................................................................... 65 B. Methods......................................................................................................... 68 C. Results .......................................................................................................... 75 viii D. Discussion ..................................................................................................... 88 IV. Analysis of Copy Number Variation in Alzheimer's Disease in a Cohort of Clinically Characterized and Neuropathologically Verified Individuals A. Introduction .................................................................................................... 97 B. Methods......................................................................................................... 99 C. Results ........................................................................................................ 104 D. Discussion ................................................................................................... 116 V. Summary and Future Directions .............................................................................. 120 References .................................................................................................................. 127 Curriculum Vitae ix LIST OF TABLES 1. Genes associated with early-onset familial Alzheimer's disease .................................. 6 2. Summary of published genome-wide association studies in Alzheimer's disease ............................................................................................................................7 3. Examples of copy number variations and selected neuropsychiatric disorders ......................................................................................................................
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