CSF Protein Changes Associated with Hippocampal Sclerosis Risk Gene Variants Highlight Impact of GRN/PGRN

Authors

David W. Fardo, University of KentuckyFollow
Yuriko Katsumata, University of KentuckyFollow
John S. K. Kauwe, Brigham Young University
Yuetiva Deming, Washington University School of Medicine
Oscar Harari, Washington University School of Medicine
Carlos Cruchaga, Washington University School of Medicine
Alzheimer’s Disease Neuroimaging Initiative
Peter T. Nelson, University of KentuckyFollow

Abstract

Objective—Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs).

Methods—Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes.

Results—The GRN risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of AXL Receptor Tyrosine Kinase (AXL), TNF-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p < 0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p=5.05×10⁻⁵). Further, the rs5848 SNP status was associated with increased CSF tau protein – a marker of neurodegeneration (p=0.015). These data are remarkable since this GRN SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies.

Document Type

Article

Publication Date

4-2017

Notes/Citation Information

Published in Experimental Gerontology, v. 90, p. 83-89.

© 2017 Elsevier Inc. All rights reserved.

This manuscript version is made available under the CC‐BY‐NC‐ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/.

The document available for download is the author's post-peer-review final draft of the article.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.exger.2017.01.025

Funding Information

This work was supported by the following National Institute of Health [grant numbers K25 AG043546, P30 AG028383, R01-AG044546, P01-AG003991, RF1AG053303, R01-AG035083, and R21 AG050146]. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012).

Due to the large number of funding sources, only the first few are listed in this section. For the complete list of funding sources, please download this article.

Related Content

Refer to Web version on PubMed Central for supplementary material.

Repository Citation

Fardo, David W.; Katsumata, Yuriko; Kauwe, John S. K.; Deming, Yuetiva; Harari, Oscar; Cruchaga, Carlos; Alzheimer’s Disease Neuroimaging Initiative; and Nelson, Peter T., "CSF Protein Changes Associated with Hippocampal Sclerosis Risk Gene Variants Highlight Impact of GRN/PGRN" (2017). Sanders-Brown Center on Aging Faculty Publications. 118.
https://uknowledge.uky.edu/sbcoa_facpub/118