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Genome-Wide Association Study of Dementia in a Community-Based Sample of Oldest-Old

Harper, Jordan Deon (2021) Genome-Wide Association Study of Dementia in a Community-Based Sample of Oldest-Old. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Background and Public Health Significance: Dementia broadly describes conditions that affect a person’s memory, cognition, and behavior with Alzheimer’s disease (AD) being the most common cause. AD is a complex disease influenced by both the environment and genetics, however, much of the genetic component remains unaccounted for. AD affects millions of people in the U.S. and around the world causing a significant financial burden and placing significant stress on caretakers. The purpose of this work was to use genome-wide association analyses to investigate a sample of older adults age 75 and above who developed dementia over the course of that study.

Aims:

Aim 1: Perform a genome-wide association study (GWAS) on the genome-wide genotyped and imputed data (14, 113, 004 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia cases and 2,206 non-demented subjects

Aim 2: Check for replication of novel variants in an independent sample and perform bioinformatics analyses on novel signals

Results: The established association of APOE*4 with AD was confirmed in this community-based sample of oldest-old (OR=2.22; P=9.36E-14). In addition, a genome-wide significant novel locus on chromosome 12 was observed near FAR2 and CCDC91 (rs148377161: OR=3.31; P=1.66E-08). Sex-stratified analyses showed a stronger association of APOE*4 with AD in females (P=1.74E-10) than in males (P=2.43E-05). In males, a novel SNP, rs140076909 on chromosome 1 near LOC729987 and SNX7 reached genome-wide significance (OR=4.51; P=3.72E-08). Of the known AD genes, SNPs near or at TREM2, NME8/EPDR1, MS4A6A/MS4A4E, PICALM, APH1B, and PLCG2 showed nominal significance. Bioinformatics analysis of novel SNPs showed there were no significant eQTLs, but revealed some evidence for regulatory functions.

Conclusions: The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD. Replication of these signals and further study of these regions and genes will help to provide a clearer picture for their role in AD.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Harper, Jordan Deonjoh115@pitt.edujoh115
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKamboh, M. Ilyaskamboh@pitt.edukamboh
Committee MemberFan, Kang-Hsienfrank.fan@pitt.edufrank.fan
Committee MemberSnitz, Bethbes9@pitt.edubes9
Date: 29 June 2021
Date Type: Publication
Defense Date: 17 June 2021
Approval Date: 29 June 2021
Submission Date: 21 June 2021
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 162
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Alzheimer's disease; genetics; sex-stratified analysis; APOE*4 carrier-stratified analysis; bioinformatics analysis
Date Deposited: 29 Jun 2021 13:06
Last Modified: 29 Jun 2021 13:06
URI: http://d-scholarship.pitt.edu/id/eprint/41329

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