Identification of Genetic Determinants of Aging Traits

169 Pages·2017·4.15 MB·English

University of Miami
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2014-08-05
Identification of Genetic Determinants of Aging
Traits
James E. Hicks Jr
University of Miami, [email protected]
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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