Identification of Genetic Determinants of Aging Traits PDF
Preview Identification of Genetic Determinants of Aging Traits
University of Miami Scholarly Repository Open Access Dissertations Electronic Theses and Dissertations 2014-08-05 Identification of Genetic Determinants of Aging Traits James E. Hicks Jr University of Miami, [email protected] Follow this and additional works at:https://scholarlyrepository.miami.edu/oa_dissertations Recommended Citation Hicks, James E. Jr, "Identification of Genetic Determinants of Aging Traits" (2014).Open Access Dissertations. 1277. https://scholarlyrepository.miami.edu/oa_dissertations/1277 This Open access is brought to you for free and open access by the Electronic Theses and Dissertations at Scholarly Repository. It has been accepted for inclusion in Open Access Dissertations by an authorized administrator of Scholarly Repository. For more information, please contact [email protected]. UNIVERSITY OF MIAMI IDENTIFICATION OF GENETIC DETERMINANTS OF AGING TRAITS By James Edwin Hicks, Jr. A DISSERTATION Submitted to the Faculty of the University of Miami in partial fulfillment of the requirements for the degree of Doctor of Philosophy Coral Gables, Florida August 2014 ©2014 James Edwin Hicks, Jr. All Rights Reserved UNIVERSITY OF MIAMI A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy IDENTIFICATION OF GENETIC DETERMINANTS OF AGING TRAITS James Edwin Hicks, Jr. Approved: ________________ _________________ William K. Scott, Ph.D. Susan H. Blanton, Ph.D. Professor of Human Genetics Associate Professor of Human Genetics ________________ _________________ John R. Gilbert, Ph.D. M. Brian Blake, Ph.D. Professor of Human Genetics Dean of the Graduate School ________________ Hermes J. Florez, M.D., Ph.D. Associate Professor of Medicine HICKS,JAMESEDWIN,JR. (Ph.D.,HumanGeneticsandGenomics) Identification ofGeneticDeterminants of (August2014) AgingTraits AbstractofadissertationattheUniversityofMiami. DissertationsupervisedbyProfessor WilliamK.Scott. No. ofpagesintext. (150) As the population in developed countries ages, the health problems associated with agingwillbecomeanincreasinglyimportantpublichealthconcern. Whileagingisacom- plex process that takes place over multiple physiological systems, many aspects of aging are under some amount of genetic control. Identification of the loci underpinning these traits could allow for targeting interventions for the most at-risk individuals in old age, improving both lifespan and quality of life. The Amish represent a uniquely appropriate population for the genetic analysis of aging traits. They live a homogenous lifestyle, with high levels of physical activity throughout their lives. The Amish are descended from a small group of religious separatists from Switzerland, and, by examination of documents andfamilyrecords,canbeplacedintoasinglelargepedigree. Gait speed and hand grip strength represent useful measures of physical function in old age. Both are heritable and poor performance on either scale predict incipient mortal- ity. Examination of these traits as continuous measures in the Amish population showed evidence of heritability, but no genome regions showed significant evidence of influence on either trait. The use of gait speed as a continuous trait has the unfortunate side effect of excluding participants too impaired to walk at all. To incorporate these individuals, a dichotomousphenotypeofimpairedmobilitywasdeveloped. Linkageanalysisofthisphe- notype resulted in significant evidence of linkage (LOD > 3) to chromosomes 3, 15, and 22. Not all domains of aging are as easily or objectively measured as gait speed and hand gripstrength. Questionsofstaminaorfinedexterityarebetterinvestigatedbyself-reported responses to questionnaires. I used individual answers to 19 questions from four scales of physical ability to group individuals using latent class analysis. The optimal fit of the model suggested that there are two latent groups within the Amish dataset, and that the major feature separating the two groups was physical endurance. I was unable to identify evidence of heritability for latent class membership and genome-wide screens for linkage andassociationdidnotidentifyanycandidateloci. Performing genetic analysis in the Amish requires making assumptions that may not reflect the reality of the dataset. I developed an alternative approach to linkage analysis that incorporates the large number of genotypes now available. I use the GERMLINE algorithm to identify regions shared identical-by-descent (IBD) between individuals, and present a score statistic to quantify the configuration of IBD states within a dataset. This method performs analysis in a fraction of the time, and identifies regions shared IBD with high sensitivity. The specificity of this method depends on the pedigree configuration. I presentempiricalmethodsofdeterminingstatisticalsignificanceforarbitrarypedigreesby gene-droppingandresamplingbasedapproaches. I demonstrate the performance of this method in two scenarios. As a proof-of-concept, the model is applied to outbred pedigrees of familial essential tremor, a movement disor- der that displays an autosomal dominant pattern of inheritance. My method successfully identified a region shared IBD by all affected pedigree members, and excluded as a false positive another region identified by linkage analysis. Application to a successful aging phenotypesuccessfullyreplicatedalocusonchromosome6thatwasidentifiedbyconven- tionallinkageanalysisandidentifiedanotherregionmissedbylinkage. TheresultsIpresentunderscoretheimportanceofusingobserveddatatorefinethean- alytic approaches to genetic analysis of aging traits. Beginning with predefined constructs of aging would miss the importance of endurance in aged individuals in this dataset. Ex- clusionofindividualsfromcontinuoustraitswouldhaveresultedinmissinglocisharedby individualsunabletowalk. Theuseofconventionallinkageanalysisrequirestheexclusion ofthemajorityofthegenotypeinformation,andcouldresultinmanyfalsenegativesacross thegenome. Agingisa multifactorialprocessandanyinvestigationintoitmustbe careful toincludealltheinformationpresentin the data. Formyparents,JimandDonnaHicks,whoraisedmesowellthatIneverstoppedgoing toschool. iii Acknowledgements IamverygratefultohavehadDr. WilliamScottasmyadvisor. Theguidanceheprovided, bothwhenananalysissucceededandwhenitfailed1,resultedinafullunderstandingofthe myriad nuances that go into a research project. I could not have asked for a better advisor. I would also like to thank the final and former members of my committee: Drs. Susan Blanton,JohnGilbert,HermesFlorez,andBruceTroen. Theyprovidedexcellentguidance and their insistence that I consider the big-picture aspects of my research tempered my habit of becoming too engaged with the small details. For help in traversing the labyrinth ofgraduateschoolrulesandregulations,IamindebtedtoDoriMcLean. I am lucky to have gone through this experience with such a great cohort of students. Dr. Monique Courtenay and I, between work, enjoyed hours of competitive iPhone word games. My vocabulary is larger and my life is better for having known her. In this spirit, I would also like to thank the creators of Ruzzle, Spelltower, and Words with Friends. Drs. SaraLinkerandCrystalHumphriesandIspentmanymid-afternooncoffeebreakstogether, whichI alreadymissdearly. I would like to acknowledge two sources of funding that I have had over these years in graduate school. Travel to the 2011, 2012, and 2013 meetings of the American Society of Human Genetics was funded by FASEB. In July 2013 I attended the Summer Institute in 1Theconversationsthatoccurwhenaprojectdoesnotgoasplannedoftenprovidemoreenlightenmentthanwhenitdoes.Ifthatis thecase,Ireceievedanextremelylargeamountoftraininginhumangenetics. iv StatisticalGeneticsattheUniversityofWashington. Theuniversitywaivedmytuitionand providedmewithan awardfortravel. v
Description:The list of books you might like
