Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease

If you need an accessible version of this item, please submit a remediation request.
Date
2018-09-14
Language
American English
Embargo Lift Date
Committee Members
Degree
Degree Year
Department
Grantor
Journal Title
Journal ISSN
Volume Title
Found At
Biomed Central
Abstract

BACKGROUND:

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that causes problems related to brain function. To some extent it is understood on a molecular level how AD arises, however there are a lack of biomarkers that can be used for early diagnosis. Two popular methods to identify AD-related biomarkers use genetics and neuroimaging. Genes and neuroimaging phenotypes have provided some insights as to the potential for AD biomarkers. While the field of imaging-genomics has identified genetic features associated with structural and functional neuroimaging phenotypes, it remains unclear how variants that affect splicing could be important for understanding the genetic etiology of AD. METHODS:

In this study, rare variants (minor allele frequency < 0.01) in splicing regulatory element (SRE) loci from whole genome sequencing (WGS) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, were used to identify genes that are associated with global brain cortical glucose metabolism in AD measured by FDG PET-scans. Gene-based associated analyses of rare variants were performed using the program BioBin and the optimal Sequence Kernel Association Test (SKAT-O). RESULTS:

The gene, EXOC3L4, was identified as significantly associated with global cortical glucose metabolism (FDR (false discovery rate) corrected p < 0.05) using SRE coding variants only. Three loci that may affect splicing within EXOC3L4 contribute to the association. CONCLUSION:

Based on sequence homology, EXOC3L4 is likely a part of the exocyst complex. Our results suggest the possibility that variants which affect proper splicing of EXOC3L4 via SREs may impact vesicle transport, giving rise to AD related phenotypes. Overall, by utilizing WGS and functional neuroimaging we have identified a gene significantly associated with an AD related endophenotype, potentially through a mechanism that involves splicing.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Miller, J. E., Shivakumar, M. K., Lee, Y., Han, S., Horgousluoglu, E., Risacher, S. L., … Alzheimer’s Disease Neuroimaging Initiative (2018). Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease. BMC medical genomics, 11(Suppl 3), 76. doi:10.1186/s12920-018-0390-6
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
BMC Medical Genetics
Source
PMC
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Full Text Available at
This item is under embargo {{howLong}}