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Novel Insights Into the Genetic Basis of Chronic Obstructive NOVEL INSIGHTS INTO THE GENETIC BASIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE by Josiah E. Radder B.S. in Biochemistry, Arizona State University, 2007 B.S. in Biology, Arizona State University, 2007 B.A. in Religious Studies, Arizona State University, 2007 Submitted to the Graduate Faculty of University of Pittsburgh School of Medicine in partial fulfillment of the requirements for the degree of Ph.D. in Cellular and Molecular Pathology University of Pittsburgh 2016 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Josiah E. Radder It was defended on August 9, 2016 and approved by Wendy M. Mars, PhD Committee Chair Associate Professor, Department of Pathology M. Michael Barmada, PhD Associate Professor, Department of Human Genetics Yuri E. Nikiforov, MD, PhD Professor, Department of Pathology Frank C. Sciurba, MD Associate Professor, Department of Medicine Steven D. Shapiro, MD Major Advisor Distinguished Professor, Department of Medicine ii Copyright © by Josiah E. Radder 2016 Portions of this dissertation were adapted from the following publication, with permission of Future Medicine Ltd: Radder JE, Shapiro SD, Berndt AM. Personalized Medicine for Chronic, Complex Diseases: COPD as an Example. Personalized Medicine. October 2014. Vol. 11, No. 7, Pages 669-679. iii NOVEL INSIGHTS INTO THE GENETIC BASIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Josiah E. Radder, Ph.D. University of Pittsburgh, 2016 Chronic obstructive pulmonary disease (COPD), defined as irreversible airflow limitation, is caused by a complex interaction of environmental exposures, most commonly cigarette smoke, and genetic factors. Genetic studies of COPD have used tests of genome-wide linkage and association to identify loci that contribute to disease susceptibility. However, as seen in other chronic diseases, the best-replicated loci associated with COPD only account for a small portion of disease heritability. Identifying additional genetic determinants of chronic diseases offers the opportunity to better understand their biology as well as the promise of better disease prediction and patient stratification, first steps in the development of precision medicine. The genetic architecture underlying chronic disease is complex, and it is likely that there is still common variation contributing to COPD that has been masked from association studies by phenotypic and genotypic heterogeneity. Further, there is evidence that rare variation contributes to chronic disease susceptibility, and rare variants in SERPINA1 leading to alpha-1 antitrypsin deficiency support this in COPD. The trio of studies presented in this work aim to detect both of these types of variation. In the first, we employ an extreme-trait study design to detect rare variants in the first whole genome sequencing study of COPD. Using this approach, we identify a previously unreported non-synonymous variant associated with COPD, and two suggestively associated candidate genes, PTPRO and ZNF816. In the second and third studies, we integrate mouse and human genetic data to identify undetected common variants associated with human iv disease and mouse models of disease. The first study uses a mouse model of cigarette smoke- induced emphysema and identifies the gene ABI3BP as a potential candidate gene. The second looks at early life determinants of chronic disease by measuring airspace size in mice at maturity, leading to identification of IL1R2, which plays a previously undescribed role in lung development. Finally, we demonstrate that by integrating the results of genetic studies, it is possible to gather additional information about the genetic architecture of chronic diseases like COPD. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XVI ACKNOWLEDGEMENTS ............................................................................................ XVI ABBREVIATIONS ............................................................................................................ XX 1.0 INTRODUCTION ........................................................................................................ 1 1.1 CHRONIC OBSTRUCTIVE PULMONARY DISEASE ................................ 2 1.1.1 Pathophysiology ............................................................................................... 2 1.1.2 Pathogenesis ..................................................................................................... 3 1.1.3 Clinical characteristics .................................................................................... 6 1.1.4 Burden .............................................................................................................. 8 1.1.5 Treatments ....................................................................................................... 9 1.2 GENETICS OF COPD ...................................................................................... 11 1.2.1 Mendelian inheritance ................................................................................... 11 1.2.2 Early genetic epidemiology ........................................................................... 12 1.2.3 Linkage analyses ............................................................................................ 13 1.2.4 Candidate gene association studies .............................................................. 15 1.2.5 Common variant association studies............................................................ 16 1.2.6 Identification of causal variants and genes ................................................. 21 1.2.7 Genetic architecture of complex traits ......................................................... 23 1.2.8 Rare variant association studies ................................................................... 27 1.3 PRECISION MEDICINE FOR COMPLEX DISEASE ................................ 28 2.0 EXTREME TRAIT WHOLE GENOME SEQUENCING OF EMPHYSEMA .. 31 vi 2.1 INTRODUCTION ............................................................................................. 31 2.2 METHODS ......................................................................................................... 32 2.2.1 Study Design ................................................................................................... 32 2.2.2 Sequencing and genotyping .......................................................................... 35 2.2.3 Data analysis .................................................................................................. 35 2.2.4 Rare variant filtering ..................................................................................... 38 2.2.5 Definition of regions and genes..................................................................... 39 2.2.6 Association testing and statistics .................................................................. 39 2.3 RESULTS ........................................................................................................... 40 2.3.1 Cohort characteristics ................................................................................... 40 2.3.2 Sequencing Results ........................................................................................ 43 2.3.3 Genome-wide single rare variant association tests ..................................... 44 2.3.4 Genome-wide region-based rare variant association tests ......................... 45 2.3.5 Gene-based and non-synonymous rare variant association tests .............. 48 2.4 DISCUSSION ..................................................................................................... 54 2.5 CONCLUSIONS ................................................................................................ 58 3.0 INTEGRATED MURINE AND HUMAN GENOME-WIDE SCANS OF SUSCEPTIBILITY TO CIGARETTE SMOKE-INDUCED EMPHYSEMA ...................... 60 3.1 INTRODUCTION ............................................................................................. 60 3.2 METHODS ......................................................................................................... 62 3.2.1 Animal experiments ....................................................................................... 62 3.2.2 Genetic association testing ............................................................................ 64 3.2.3 Identification of genomic regions enriched for nominal associations ....... 65 vii 3.2.4 Identification of nominal associations in human GWAS data .................. 65 3.2.5 Searching for nominal SNPs in meta-analysis of human COPD .............. 66 3.2.6 Identification of candidate genes .................................................................. 66 3.2.7 mRNA expression .......................................................................................... 66 3.2.8 Statistics .......................................................................................................... 67 3.3 RESULTS: .......................................................................................................... 67 3.3.1 Susceptibility to cigarette smoke-induced emphysema varies continuously in inbred mouse strains .............................................................................................. 67 3.3.2 Genetic contribution to cigarette smoke-induced emphysema is complex in the mouse .................................................................................................................... 71 3.3.3 Identification
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