Association Between PLXNA4 Polymorphism And Brain Structure In Alzheimer's Disease

Objective: In recent years,a great deal of studies have shown that genetic factors take an important part in the pathogenesis of Alzermer's disease(AD).The hypothesis of gene mutation has become the focus of research on AD.Genome-wide association studies(GWAS)have indicated that there are other 11 new discovered AD susceptibility loci apart from Apolipopotein E,(APOE),Bridging integrator 1(BIN1),Amyloid precursor protein,(APP),Presenilin 1(PS1)and Presenilin 2(PS2).The Plexin A4(PLXNA4)is one of the new discovered AD susceptibility loci.Researches indicated that PLXNA4 goes together with the pathological process of AD,as a novel high affinity cluster protein receptor.The mutation of PLXNA4 participated in the pathlological process of AD by regulating the phosphorylation of Tau.In addition,cysteine repeat modular protein 2(CRMP2),which is present in the neurofilament entanglement of AD patients,is the intracellular signaling molecule of the semaphorins-plexin signal transduction pathway,suggesting that the PLXNA4 gene is associated with the risk of AD.However,whether the PLXNA4 associated with the structure and function of the brain area in AD remains to be confirmed.The aim of this study was to investigate the association between PLXNA4 gene polymorphism and the volume of AD critical brain area.Methods: Through quality control and screening with strict inclusion criteria,finally,a total of 812 subjects were selected from the neuroimaging database of Alzheimer's Disease Neuroimaging Initiative(ADNI)in this study,which including 281 cognitively normal(NC),483 mild cognitive impairment(MCI)individuals and 48 AD patients.To explore the association between PLXNA4 gene polymorphism and the volume of AD critical brain area,we used the Human 610-Quad typing chip(containing 620910 SNPs and CNV specimens)and the human Qmni Express typing chip to type the PLXNA4 gene of the people who were extracted from the GWAS analysis of ADNI database: typing ADNI-1 by Illumina Infinium Human610-Quad typing Chip,typing ADNI-2 and ADNI-Go by Illumina Human Omni Epress typing Chip and separating the specific genotyping of generated SNPs by Bead studio 3.2 software and Genome Studio v2009.1(Illumina)software.The method of selecting SNPs(single nucleotide polymorphisms)from Haploview 4.2 platform is selected in this study,quality control with Plink Software,including SNPs that conforming to the following criteria: Minimum response rate>90%,Minimum allele frequency>0.01,Hardy Weinberg equilibrium test(H-W)P>0.001.After strict quality control,this study extracted the information of 5 targeted PLXNA4 loci(rs5467431,rs1863015,rs156676,rs78036292,rs67468325)from ADNI database GWAS and extracted the neuroimaging information corresponding to the population included synchronously.We set Gender,Age,Education,APOE?4 as covariates,correcting multiple contrast analysis by Bonferroni Correction and use the total number of valid SNPs selected to correct the P value.The differences of continuous variables were compared by single factor analysis of variance(ANOVA)and through the Tukey test,multivariate linear regression to carry out a pair of multiple comparison checkout.In this way,we study the association between the five single nucleotide polymorphisms of PLXNA4 genotype and the neuroimaging phenotypes of AD.The results of GWAS analysis were analyzed and charted with version 3.40 R software.Results: After two years of follow-up,We found that two PLXNA4 loci,rs6467431 and rs1863015,tended to be associated with volume atrophy in the hippocampus,perihippocampal gyrus and middle temporal lobe,carrying rs6467431 mutation genotype AA of PLXNA4 gene site can significantly slow the volume atrophy of left hippocampus,right hippocampus and right hippocampal gyrus,the genotype GG carrying rs1863015 mutation of APOE?4 gene site significantly alleviated bilateral hippocampal atrophy and left middle temporal lobe volume atrophy.Conclusions: The polymorphism of PLXNA4 gene is closely related to the volume change rate of AD critical brain area.The polymorphism of PLXNA4 gene may affect the phenotypes of AD related neuroimaging.