Whole-Exome Sequencing Analysis of Alzheimer's Disease in Non-APOE*4 Carriers.
In: Journal of Alzheimer's Disease, Jg. 76 (2020-08-15), Heft 4, S. 1553-1565
academicJournal
Zugriff:
The genetics of late-onset Alzheimer's disease (AD) is complex due to the heterogeneous nature of the disorder. APOE*4 is the strongest genetic risk factor for AD. Genome-wide association studies have identified more than 30 additional loci, each having relatively small effect size. Known AD loci explain only about 30% of the genetic variance, and thus much of the genetic variance remains unexplained. To identify some of the missing heritability of AD, we analyzed whole-exome sequencing (WES) data focusing on non-APOE*4 carriers from two WES datasets: 720 cases and controls from the University of Pittsburgh and 7,252 cases and controls from the Alzheimer's Disease Sequencing Project. Following separate WES analyses in each dataset, we performed meta-analysis for overlapping markers present in both datasets. Among the four variants reaching the exome-wide significance threshold, three were from known AD loci: APOE/rs7412 (odds ratio (OR) = 0.40; p = 5.46E-24), TOMM40/rs157581 (OR = 1.49; p = 4.04E-07), and TREM2/rs75932628 (OR = 4.00; p = 1.15E-07). The fourth significant variant, rs199533, was from a novel locus on chromosome 17 in the NSF gene (OR = 0.78; p = 2.88E-07). NSF was also significant in the gene-based analysis (p = 1.20E-05). In the GTEx data, NSF/rs199533 is a cis-eQTL for multiple genes in the brain and blood, including NSF that is highly expressed across all brain tissues, including regions that typically show amyloid-β accumulation. Further characterization of genes that are affected by NSF/rs199533 may help to shed light on the roles of these genes in AD etiology. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Alzheimer's Disease is the property of IOS Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Titel: |
Whole-Exome Sequencing Analysis of Alzheimer's Disease in Non-APOE*4 Carriers.
|
---|---|
Autor/in / Beteiligte Person: | Fan, Kang-Hsien ; Feingold, Eleanor ; Rosenthal, Samantha L. ; Demirci, F. Yesim ; Ganguli, Mary ; Lopez, Oscar L. ; Kamboh, M. Ilyas |
Zeitschrift: | Journal of Alzheimer's Disease, Jg. 76 (2020-08-15), Heft 4, S. 1553-1565 |
Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
ISSN: | 1387-2877 (print) |
DOI: | 10.3233/JAD-200037 |
Schlagwort: |
|
Sonstiges: |
|