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Whole exome and targeted sequencing of Alzheimer’s disease: an integrative approach

Rosenthal, Samantha (2017) Whole exome and targeted sequencing of Alzheimer’s disease: an integrative approach. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Background and Public Health Significance: Late-onset Alzheimer’s disease (LOAD) is a progressive neurodegenerative disease with over twenty risk loci identified. Apolipoprotein E (APOE) confers the strongest genetic risk, but nearly seventy percent of the genetic variance for LOAD has yet to be determined. This work demonstrates approaches to replicating established and identifying novel genetic associations with LOAD risk and interrogating both to better understand the underlying genetic disease mechanisms. LOAD affects over 5 million Americans with cost of care estimated to exceed $200 billion this year. Presently, LOAD has no effective treatments, preventions, or cures, making it an extreme matter of public health significance.
Aim 1. Replicate the association of a rare mutation R74H in TREM2 with LOAD risk.
Aim 2. In-silico examination of the potential regulatory effects of published genome-wide association studies (GWAS) variants and those in strong linkage disequilibrium (r2>0.80, n=614) using RegulomeDB.
Aim 3. Whole-exome and targeted sequencing of 14 candidate gene regions in a LOAD case/control population biased against E*4 carriers (n=773) with internal replication using GWAS data for meta-analysis and Combined Annotation Dependent Depletion (CADD) annotation.
Results: We were able to replicate the association of TREM2 R47H with increased LOAD risk in a Caucasian population of 4,567 cases and controls. (p=3.66E-06, OR=7.40, 95% confidence interval (CI): 3.171-17.26, MAF=0.008) and found strong evidence for regulatory function (RegulomeDB score < 3) for 34 single nucleotide polymorphisms. Analysis of whole-exome sequencing data revealed a novel association between a deletion of T at chr11:26574783 in ANO3 (p=7.598E-08, OR=2.812, MAF=0.3268). ABCA7/rs77620244 (p=3.18E-04, OR=0.1872, MAF= 0.02902) was the most significant SNP in the targeted regions. Of the significant variants (p<0.05) in the sequencing data, 25.4% (whole-exome) and 28.9% (targeted regions) replicated in meta-analysis at the same alpha level. The number of borderline significant variants (0.05<psequencing<0.08) with PHRED > 10 was 26 and 1,653 in the targeted regions and whole-exome, respectively, suggesting that they may be interesting candidates for follow-up.
Conclusions: Taken together, these results suggest the necessity a combinatorial approach of both statistical and biological evidence for determining the importance of genetic associations with disease risk.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Rosenthal, Samanthaslr61@pitt.eduslr610000-0002-5593-7656
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKamboh, M. Ilyaskamboh@pitt.edukamboh0000-0002-3453-1438
Committee MemberDemirci, F. Yesimfyd1@pitt.edufyd10000-0001-6907-9843
Committee MemberBarmada, M. Michaelbarmada@pitt.edubarmada0000-0002-3604-6460
Committee MemberFeingold, Eleanorfeingold@pitt.edufeingold0000-0003-2898-6484
Committee MemberSnitz, Bethsnitbe@upmc.edubes9
Date: 24 February 2017
Date Type: Publication
Defense Date: 14 November 2016
Approval Date: 24 February 2017
Submission Date: 28 November 2016
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 296
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Late onset Alzheimer's disease; genetics; bioinformatics, whole exome sequencing
Date Deposited: 24 Feb 2017 19:21
Last Modified: 01 Jan 2022 06:15


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