Abstract
BackgroundThe activity of cerebrospinal fluid (CSF) β-site APP cleaving enzyme (BACE) is a potential diagnostic biomarker for Alzheimer disease (AD).MethodsA total of 340 non-Hispanic Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI) database were included in this study with quality-controlled CSF BACE and genotype data. Association of CSF BACE with the genetic variants of single nucleotide polymorphisms (SNPs) was assessed using PLINK under the additive genetic model. The P values of all SNPs for CSF BACE were adjusted for multiple comparisons.ResultsOne SNP (rs1481950) in the ATP6V1H gene reached genome-wide significance for associations with CSF BACE (P = 4.88 × 10− 9). The minor allele (G) of rs1481950 was associated with higher CSF BACE activity. Although seven SNPs in SNX31, RORA, CDH23, RGS20, LRRC4C, MAPK6PS1 and LOC105378355 did not reach genome-wide significance (P < 10− 8), they were identified as suggestive loci (P < 10− 5).ConclusionThis study identified rs1481950 within ATP6V1H influencing human CSF BACE activity, which indicated that ATP6V1H gene may play some roles in the pathogenesis of neurodegenerative diseases such as AD.
Highlights
The activity of cerebrospinal fluid (CSF) β-site amyloid precursor protein (APP) cleaving enzyme (BACE) is a potential diagnostic biomarker for Alzheimer disease (AD)
Aβ is generated from the transmembrane polypeptide called amyloid precursor protein (APP) by β- and γ-secretase enzymes [1, 2]. β-secretase or β-site APP cleaving enzyme (BACE) is the important rate-limiting enzyme and its increased activity may lead to the elevation of Aβ in the brain [1, 2]
Previous studies discovered that AD subjects have increased cerebrospinal fluid (CSF) BACE enzymatic activity compared with the controls [3,4,5,6,7,8,9,10,11,12]
Summary
The activity of cerebrospinal fluid (CSF) β-site APP cleaving enzyme (BACE) is a potential diagnostic biomarker for Alzheimer disease (AD). Β-secretase or β-site APP cleaving enzyme (BACE) is the important rate-limiting enzyme and its increased activity may lead to the elevation of Aβ in the brain [1, 2]. Previous studies discovered that AD subjects have increased cerebrospinal fluid (CSF) BACE enzymatic activity compared with the controls [3,4,5,6,7,8,9,10,11,12]. In this study we regard CSF BACE enzymatic activity as an endophenotype for a separate GWAS in the ADNI (Alzheimer’s Disease Neuroimaging Initiative database, adni.loni.usc.edu) cohort in order to discover genetic factors involved in BACE protein
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