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Genetic Architecture of Hematologic Traits and Healthy Aging- Related Endophenotypes in the Long Life Family Study

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Genetic Architecture of Hematologic Traits and Healthy Aging- Related Endophenotypes in the Long Life Family Study GENETIC ARCHITECTURE OF HEMATOLOGIC TRAITS AND HEALTHY AGING- RELATED ENDOPHENOTYPES IN THE LONG LIFE FAMILY STUDY by Jatinder Singh B.Sc., Punjabi University, India, 2002 M.Sc., Thapar University, India, 2005 Submitted to the Graduate Faculty of Graduate School of Public Health in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2014 UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH This dissertation was presented by Jatinder Singh It was defended on December 17th, 2013 and approved by M. Michael Barmada, Ph.D. Associate Professor, Department of Human Genetics Graduate School of Pittsburgh, University of Pittsburgh Daniel E. Weeks, Ph.D. Professor, Department of Human Genetics Graduate School of Pittsburgh, University of Pittsburgh Anne B. Newman, M.D., M.P.H. Professor and Chair, Department of Epidemiology Graduate School of Pittsburgh, University of Pittsburgh Dissertation Advisor: Candace M. Kammerer, Ph.D. Associate Professor, Department of Human Genetics Graduate School of Pittsburgh, University of Pittsburgh ii Copyright © by Jatinder Singh 2014 iii GENETIC ARCHITECTURE OF HEMATOLOGIC TRAITS AND HEALTHY AGING-RELATED ENDOPHENOTYPES IN THE LONG LIFE FAMILY STUDY Jatinder Singh, PhD University of Pittsburgh, 2014 ABSTRACT One of the goals of medicine and public health is to increase functional longevity. Anemia and other age-related blood cell trait abnormalities have been shown to be associated with adverse outcomes such as disability, hospitalization, morbidity and mortality in older adults. Results from the third National Health and Nutrition Survey (1988-1994) indicated that 11.0% of men and 10.2% of women ≥ 65 years of age were anemic. As the US and global populations age, the prevalence of hematologic disorders and all age-related disorders will increase. The One of the goals of medicine and public health is to increase functional longevity. identification of genes or novel biological pathways that regulate hematologic traits and healthy- Anemia and other age-related blood cell trait abnormalities have been shown to be associated aging phenotypes could lead to insights and possible future interventions to delay the onset of with adverse outcomes such as disability, hospitalization, morbidity and mortality in older hematologic diseases, increase functional longevity, and concomitantly, decrease the burden of adults. Results from the third National Health and Nutrition Survey (1988-1994) indicated age-related diseases on public health. In the current study, data on from a unique population that 11.0% of men and 10.2% of women ≥65 years of age were anemic. As the U.S. and comprising long-lived siblings and their families (the Long Life Family Study) were used to global populations age, the prevalence of hematologic disorders and all age-related disorders identify genes that may influence age-related traits, such hematologic traits and healthy aging will increase. The identification of genes or novel biological pathways that regulate endophenotypes. Using family-based whole genome linkage and association analyses, I hematologic traits and healthy-aging phenotypes could lead to insights and possible future identified multiple loci that may affect hematologic traits and endophenotypes. The most interventions to delay the onset of hematologic diseases, increase functional longevity, and promising results are as follows. I identified (and subsequently replicated) a locus on concomitantly, decrease the burden of age-related diseases on public health. In the current chromosome 11p15.2 near SOX6 (a transcription factor gene) that influenced RBC count. I also study, data on from a unique population comprising long-lived siblings and their families (the used factor analyses to extend results of previously developed endophenotypes derived from five Long Life Family Study) were used to identify genes that may influence age-related traits, health domains (cognition, physical function, cardiovascular, metabolic and pulmonary). The such hematologic traits and healthy aging endophenotypes. Using family-based whole iv genome linkage and association analyses, I identified multiple loci that may affect hematologic traits and endophenotypes. The most promising results are as follows. I identified primary endophenotype (predominantly reflecting pulmonary and physical function traits) was significantly related to reduced mortality. In addition, this endophenotype and the relationship to mortality was replicated in an independent, population-based cohort. I also identified (and replicated) association of this endophenotype to a locus on chromosome 18q11.2 near ZNF521, a transcription factor gene. Intriguingly, both SOX6 and ZNF521 have been reported to play a role in erythropoiesis, consistent with the hypothesis that aging may result, in part, from fundamental biological processes that influence multiple disorders. These results also indicate that genetic studies in a unique set of families may reveal novel findings that will increase our understanding of the genetic regulation of aging. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XXI 1.0 INTRODUCTION ........................................................................................................ 1 1.1 PUBLIC HEALTH SIGNIFICANCE................................................................ 1 1.1.1 Hematologic traits ............................................................................................ 1 1.1.2 Healthy Aging-Related Endophenotypes and the Healthy Aging Index .... 4 1.1.3 Summary of Public Health Impact ................................................................ 5 1.2 GENETIC EPIDEMIOLOGY OF HEMATOLOGIC TRAITS AND ENDOPHENOTYPES ......................................................................................................... 5 1.2.1 Hematologic Traits .......................................................................................... 5 1.2.2 Endophenotypes Derived from Five Health-Related Domains (Five- Domain Endophenotypes) ......................................................................................... 10 1.2.3 Summary ........................................................................................................ 11 1.3 STUDY APPROACH AND SPECIFIC AIMS ............................................... 12 1.4 STUDY POPULATIONS .................................................................................. 14 1.4.1 Long Life Family Study (LLFS) ................................................................... 14 1.4.2 Replication Population – Health Aging and Body Composition Study (HABC) ....................................................................................................................... 15 1.5 STUDY DATA ................................................................................................... 15 vi 1.5.1 Phenotypes ...................................................................................................... 15 1.5.2 Genotypes, Imputation, and Admixture Principle Components ............... 16 1.5.2.1 Long Life Family Study ...................................................................... 16 1.5.2.2 HABC Study ........................................................................................ 18 1.5.3 Genotypes/Haplotypes for Linkage Analyses in LLFS .............................. 19 1.6 STATISTICAL METHODS ............................................................................. 21 1.6.1 Development of Endophenotypes for Hematologic Traits and Healthy Aging-Related Endophenotypes ................................................................................ 21 1.6.2 Relationship with Mortality (Cox Proportional Hazards Regression) ..... 23 1.6.3 Effects of Known Covariates and Heritability ............................................ 24 1.6.4 Association Analysis Studies ......................................................................... 25 1.6.5 Linkage Analysis ............................................................................................ 26 1.6.6 Replication in HABC Cohort ........................................................................ 27 2.0 PHENOTYPIC AND GENETIC CHARACTERIZATION OF HEMATOLOGIC TRAITS ...................................................................................................................................... 29 2.1 INTRODUCTION ............................................................................................. 29 2.2 METHODS ......................................................................................................... 31 2.2.1 Quality Control and Population Characteristics ........................................ 31 2.2.2 Development of Hematologic Endophenotypes .......................................... 31 2.2.3 Univariate and Bivariate Genetic Analyses................................................. 32 2.2.4 Genomewide Linkage Analyses .................................................................... 32 2.2.5 Genomewide Association Analyses .............................................................. 33 2.3 RESULTS ........................................................................................................... 34 vii 2.3.1 Quality Control and Population Characteristics ........................................ 34 2.3.2 Development of Endophenotypes ................................................................
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