title: CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA. Electronic address: david.fardo@uky.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Fardo
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Katsumata
authors.affiliation: Department of Biology, BYU, Provo, UT, USA.
authors.forename: John S K
authors.initials: JSK
authors.lastname: Kauwe
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Yuetiva
authors.initials: Y
authors.lastname: Deming
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Harari
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Pathology, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000134:cerebrospinal fluid*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D051152:Clusterin / Q000134:cerebrospinal fluid; D016208:Databases, Factual; D003704:Dementia / Q000134:cerebrospinal fluid / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins / Q000134:cerebrospinal fluid; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D053320:Receptors, Tumor Necrosis Factor, Member 10c / Q000134:cerebrospinal fluid; D012044:Regression Analysis; D012307:Risk Factors; D012598:Sclerosis; D019010:Vascular Cell Adhesion Molecule-1 / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D051152:Clusterin; D058851:GPI-Linked Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C108661:TNFRSF10C protein, human; D019010:Vascular Cell Adhesion Molecule-1; D016875:tau Proteins
keywords: Biomarkers; Clusterin; Granulin; Neuroinflammation; Progranulin; Proteomics