Acharya, Vibha
(2024)
Genetics of cognitive decline in older individuals in population-based cohorts.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
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Abstract
Cognitive decline, deterioration of previously acquired cognitive abilities, is a characteristic of normal and pathologic aging. Due to world population demographic shifting towards aging, cognitive decline is a huge public health concern. Although cognitive decline has substantial genetic influence, there is limited understanding of the genetic contributors of cognitive aging. We leveraged three longitudinal cohorts to derive cognitive slopes across five neurocognitive domains (attention, executive function, memory, language, visuospatial function) and global cognitive function by fitting linear mixed-effect models adjusting for age, education, and sex. Genome-wide analyses for each domain were conducted in each cohort, adjusting for the first four genetic principal components, followed by meta-analyses using the inverse-variance-based fixed-effect meta-analysis. Gene-based analyses and gene-set enrichment analyses were implemented to understand the underlying biology of cognition-implicated genes. We further extended our analyses to understand the genetic architecture of cognitive decline in males and females, as well as in three APOE subgroups: APOE2 carriers, APOE4 carriers and APOE 3/3 homozygous group. Additionally, the role of rare variants in cognitive decline was explored using SKAT-O.
In the single-variant analysis, we replicated the expected association of APOE4 with the decline of memory and global cognitive function and detected a novel association near RASEF in chromosome 9 with the decline of attention. In the gene-based analysis, we detected a novel association of TMRSS11D with the decline of global cognitive function. TMPRSS11D activates viral spike proteins and facilitates the entry of several viruses, including SARS-CoV-2. Sex-stratified analysis identified NDUFA12 as a novel locus for the decline of executive function in females. APOE-stratified analysis identified the association of hearing-loss-associated genes (DTWD2, DMXL1, and HSD17B4) with decline of language in the APOE4 group. Rare variant association analysis detected the association of EVC with the decline of global cognitive function. Gene-set enrichment analysis showed that there are both shared and unique pathways within domain abilities, and several of these pathways are sex and the APOE subgroup, highlighting the importance of stratified analysis.
In conclusion, this study has identified multiple gene loci associated with cognitive decline in older adults and provided further insights into understanding cognitive decline's complex biology.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
14 May 2024 |
| Date Type: |
Publication |
| Defense Date: |
10 April 2024 |
| Approval Date: |
14 May 2024 |
| Submission Date: |
25 April 2024 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
168 |
| 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: |
Genome-wide association, cognitive decline, Sex-stratified, APOE-stratified,TMPRSS11D |
| Date Deposited: |
14 May 2024 18:49 |
| Last Modified: |
14 May 2024 18:49 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46211 |
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