genome-wide association studies at the interface of alzheimer's disease and epidemiologically ...

148 Pages·2016·1.79 MB·English

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University of Kentucky Doctoral Dissertations Graduate School
2011
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Christopher Ryan Simmons
University of Kentucky, [email protected]
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Simmons, Christopher Ryan, "GENOME-WIDE ASSOCIATION STUDIES AT THE INTERFACE OF
ALZHEIMER’S DISEASE AND EPIDEMIOLOGICALLY RELATED DISORDERS" (2011). University of Kentucky
Doctoral Dissertations. 824.
https://uknowledge.uky.edu/gradschool_diss/824
This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been
accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of
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ABSTRACT OF DISSERTATION

Christopher Ryan Simmons

The Graduate School

University of Kentucky

2011
GENOME-WIDE ASSOCIATION STUDIES AT THE INTERFACE OF
ALZHEIMER’S DISEASE AND EPIDEMIOLOGICALLY RELATED DISORDERS

__________________________________

ABSTRACT OF DISSERTATION
_________________________________

A dissertation submitted in partial fulfillment of the
requirements for the degree of Doctor of Philosophy in the
College of Medicine
at the University of Kentucky

By
Christopher Ryan Simmons

Lexington, Kentucky

Director: Dr. Steven Estus, Professor of Physiology

Lexington, Kentucky

2011

Copyright © Christopher Ryan Simmons 2011
ABSTRACT OF DISSERTATION

GENOME-WIDE ASSOCIATION STUDIES AT THE INTERFACE OF
ALZHEIMER’S DISEASE AND EPIDEMIOLOGICALLY RELATED DISORDERS

Genome-wide association studies (GWAS)s provide an unbiased means of
exploring the landscape of complex genetic disease. As such, these studies have
identified genetic variants that are robustly associated with a multitude of conditions.
I hypothesize that these genetic variants serve as excellent tools for evaluation of
the genetic interface between epidemiologically related conditions. Herein, I test the
association between SNPs associated with either (i) plasma lipids, (ii) rheumatoid
arthritis (RA) or (iii) diabetes mellitus (DM) and late-onset Alzheimer’s disease (AD)
to identify shared genetic variants. Regarding the most significantly AD-associated
variants, I have also attempted to elucidate their molecular function.
Only cholesterol-associated SNPs, as a group, are significantly associated
with AD. This association remains after excluding APOE SNPs and suggests that
peripheral and or central cholesterol metabolism contribute to AD risk. The general
lack of association between RA-associated SNPs and AD is also significant in that
these data challenge the hypothesis that genetic variants that increase risk of RA
confer protection against AD. Functional studies of variants exhibiting novel
associations with AD reveal that the lipid-associated SNP rs3846662 modulates
HMGCR exon 13 splicing differentially in different cell types. Although less clear,
trends were also observed between the RA-associated rs2837960 and the
expression of several BACE2 isoforms, and between the DM-associated rs7804356
and expression of a rare SKAP2 isoform, respectively.
In conclusion, the overlap of lipid-, RA- or DM-associated SNPs with AD is
modest but in several instances significant. Continued analysis of the interface
between GWAS of separate conditions will likely facilitate novel associations missed
by conventional GWAS. Furthermore, the identification of functional variants
associated with multiple conditions should provide insight into novel mechanisms of
disease and may lead to the identification of new therapeutic targets in an era of
personalized genomic medicine.
KEYWORDS: Genome-Wide Association Studies, Single Nucleotide Polymorphisms,
Functional Genetics, Neurodegenerative Disease, Complex Genetic
Diseases

Christopher Ryan Simmons

June 13, 2011
GENOME-WIDE ASSOCIATION STUDIES AT THE INTERFACE OF
ALZHEIMER’S DISEASE AND EPIDEMIOLOGICALLY RELATED DISORDERS

By

Christopher Ryan Simmons

G. Steven Estus, Ph.D.
Director of Dissertation

Bret N. Smith, Ph.D.
Director of Graduate Studies

June 13, 2011
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DISSERTATION

Christopher Ryan Simmons

The Graduate School

University of Kentucky

2011
GENOME-WIDE ASSOCIATION STUDIES AT THE INTERFACE OF
ALZHEIMER’S DISEASE AND EPIDEMIOLOGICALLY RELATED DISORDERS

__________________________________

DISSERTATION
_________________________________

A dissertation submitted in partial fulfillment of the
requirements for the degree of Doctor of Philosophy in the
College of Medicine
at the University of Kentucky

By
Christopher Ryan Simmons

Lexington, Kentucky

Director: Dr. Steven Estus, Professor of Physiology

Lexington, Kentucky

2011

Copyright © Christopher Ryan Simmons 2011
DEDICATION

This dissertation is dedicated to all of those who have believed in me and to those
who love me. None of this would have been possible without my mom and dad, who
taught me to cherish creativity and perseverance; my sister Amy, who taught me to
learn from struggle; and my wife Katie, whose love and sense of humor help me to
keep life in perspective. I also want to thank my dog Bailey, for not eating my
homework… this time