1. CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN.
- Author
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Fardo DW, Katsumata Y, Kauwe JSK, Deming Y, Harari O, Cruchaga C, and Nelson PT
- Subjects
- Aged, Aged, 80 and over, Amyloid beta-Peptides cerebrospinal fluid, Clusterin cerebrospinal fluid, Databases, Factual, Dementia cerebrospinal fluid, Female, GPI-Linked Proteins cerebrospinal fluid, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Progranulins, Receptors, Tumor Necrosis Factor, Member 10c cerebrospinal fluid, Regression Analysis, Risk Factors, Sclerosis, Vascular Cell Adhesion Molecule-1 cerebrospinal fluid, tau Proteins cerebrospinal fluid, Aging cerebrospinal fluid, Biomarkers cerebrospinal fluid, Dementia genetics, Hippocampus pathology, Intercellular Signaling Peptides and Proteins genetics
- 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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