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CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN.

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.

journal_name

Exp Gerontol

journal_title

Experimental gerontology

authors

Fardo DW,Katsumata Y,Kauwe JSK,Deming Y,Harari O,Cruchaga C,Alzheimer's Disease Neuroimaging Initiative.,Nelson PT

doi

10.1016/j.exger.2017.01.025

subject

Has Abstract

pub_date

2017-04-01 00:00:00

pages

83-89

eissn

0531-5565

issn

1873-6815

pii

S0531-5565(16)30180-2

journal_volume

90

pub_type

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