Genome-wide Association Study Identified ATP6V1H Locus Influencing Cerebrospinal Fluid BACE Activity

Background: Amyloid plaque which is composed primarily of amyloid-beta?A??has been reported as an important pathological change of some neurodegenerative diseases including Alzheimer's disease?AD?.A? is generated from the transmembrane polypeptide called amyloid precursor protein?APP?by ?-and ?-secretase enzymes.?-secretase or ?-site APP cleaving enzyme?BACE?is the important rate-limiting enzyme and its increased activity may lead to the elevation of A? in the brain.Previous studies discovered that AD subjects have increased cerebrospinal fluid?CSF?BACE enzymatic activity compared with the controls.So researchers hypothesized that BACE enzymatic activities in CSF may become potential biomarkers for AD.The recent development of a sensitive assay for BACE in CSF makes it feasible to study the association between CSF BACE enzymatic activity and AD.Moreover,the use of quantitative traits in genome-wide association study?GWAS?has been shown to increase statistical power over case-control designs.In this study we regard CSF BACE enzymatic activity as a 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.Objective: To explore the role of genetic factors in CSF BACE among AD patients,mild cognitive impairment?MCI?patients and healthy controls?HC?.Methods: A total of 357 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 using the Bonferroni method.Results: After adjusting for age,gender and APOE?4 status,one SNP?rs1481950,NM₀15941.3:c.871-5558G>T?was identified associated with CSF BACE enzymatic activity at genome-wide significance levels of P <10-8.One SNP?rs1481950?in the region of ATP6V1 H gene reached genome-wide significance after Bonferroni adjustment?corrected P < 0.01?.Moreover,we also got ten suggestive SNPs.Although these SNPs did not reach the genome-wide significance level in this limited sample,they may still have the potential significance in other larger samples.So we regarded these SNPs whose P values reached the level of P < 10-5 as suggestive SNPs.Ten potential candidates?uncorrected P < 10-5?were included?rs2507780,rs4548151,rs1866007,rs3905275,rs7903757,rs877783,rs6473895,rs4075903,rs9693226,rs1900511?.The linkage disequilibrium?LD?pattern between rs1481950 and nearby SNPs were also tested.These nearby SNPs showed association with CSF BACE levels with the P <0.01.When the top SNP?rs1481950?was controlled,these nearby SNPs also disappeared,which indicated that these nearby SNPs were driven by the top SNP.All these eleven SNPs were analyzed further to examine possible interactions among baseline diagnosis and genotypes on associated CSF BACE enzymatic activity by a multiple linear regression test considering age,gender and APOE?4 status as covariates.For the top SNP?rs1481950?,CSF BACE activity in the whole samples showed positive linear association with the G allele in a multiple linear regression model after adjusting for age,gender,and APOE?4 status?GG+GT: 63.86±22.64 p M,TT: 45.49±17.99 p M,P<0.001?.Further analysis found this linear association between genotype and CSF BACE activity in both AD?GG+GT: 60.14±19.13 p M,TT: 43±16.85 p M,P=0.026?and MCI groups?GG+GT: 69.36±23.99 p M,TT: 46.99±18.72 p M,P<0.001?.However,in HC group,results did not show significant differences in CSF BACE activity among three genotype subgroups in both ANOVA?P=0.0637?and multiple linear regression analysis?P=0.167?.Conclusion: In summary,after a separate GWAS of CSF BACE,we found a top SNP?rs1481950?in ATP6V1 H gene with the P value reaching genome-wide significance and ten suggestive SNPs with the P value lower than 10-5.Rs1481950 risk variant?G?in ATP6V1 H may increase the CSF BACE activity.Seven genes?SNX31,RORA,CDH23,RGS20,LRRC4 C,MAPK6PS1,LOC105378355?were regarded as candidate genes.These results provide clues to some novel pathogenic genes associated with some BACE related diseases,such as AD.The in-depth discussion and study of these associations can help us to find the exact mechanisms of AD,which may indicate some new diagnostic methods and therapeutic directions.