| Objective:Alzheimer's disease?AD?is a progressive neurodegenerative disorder.It is featured with pathological changes:abnormal deposition of amyloid?-protein?A??and neurofibrillary tangles?NFT?of tau proteins.Nowadays,fluorodeoxyglucose positron emission tomography?18F-FDG PET?is regarded as sole biomarker of degenerative diseases functional neuroimaging.It can increase the certainty of pathophysiological processes in research,which can also be used as clinical diagnostic tool.The links between AD and glucose metabolism has been obtained wide attention,for brain activities have close relationship with glucose function.Patients with glucose metabolic disorder are inclined to have higher risk to present AD.Previous studies indicated that glucose metabolic disorder is the significant driving force of AD.Glucose metabolism level in cerebral cortex not only can reflect the brain function disorder of AD patients in the each phase,but also observe the progresses of AD.Fluorodeoxyglucose?18F-FDG?metabolism can accurately reflect the glucose metabolism.In AD-related field,glucose metabolism has been testified to slow down.However,we have little information about generic association of glucose metabolism.Endophenotypes genome-wide association study?GWAS?is an effective complement to traditional case-control GWAS,which can make up for the deficiency of case-control GWAS and improve the statistical efficiency.Therefore,in this research,18F-FDG metabolism was used as the endophenotype for the first GWAS of brain18F-FDG metabolism.We aim to identify new specific variatants of 18F-FDG metabolism.Method:The study subjects and data were from database of Alzheimer's Disease Neuroimaging Initiative?ADNI?.The National Institution of Neurologic Communicative Disorders and Stroke-AD and Related Disorders Association?NINCDS-ADRDA?criteria were used for the diagnosis of AD.The score of Mini-mental State Examination?MMSE?ranged from 20to 26.The score of Clinical Dementia Rating?CDR?is 0.5 or 1.MMSE score of mild cognitive impairment?MCI?ranged from 24 to 30.Memory rating score is 0.5 at least.The disease history was collected thoroughly and systemly for all subject patients.We also conduct laboratory,imaging examination.We excluded patients with serious non-AD somatic disorders?stroke,myocardial infarction,congestive heart failure,brain trauma or brain damage,diabetes and autoimmunity?.We also exclude patients taking anti-psychotic drugs,antidepressants and anti-anxiety drugs,sedative hypnotics as well as emotional stabilizers.Our study population consisted of 757 subjects with AD,MCI and cognitively normal?male 449,female 308?from the ANDI.After quality control,71 Hispanic white were excluded.We excluded 151 subjects due to missing genotype data and deleted 313subjects without 18F-FDG data.Finally,our study retained 222 subjects?AD=37,MCI=126,HC=59?.All subjects were non-Hispanic white and met all quality control?QC?standards.The 18F-FDG analysis data came from the data set of the cortical sugar metabolic rate obtained after the analysis and processing of the original 18F-FDG PET image at the University of California,Berkeley and Lawrence Berkeley National Laboratory.Gene typing used Illumina Infinium Human 610-Quad chips.Combining the data from the Hapmap database,the optimized label SNP was genotyped so that it could best represent the universal variation of all genes.The specific classification of SNP was generated by IlluminaBeadStudio software.Stringent QC assessment was performed using the PLINK1.07 software with the following criteria:minimum call rate for SNPs and individuals>98%,minimum minor allele frequencies?MAF?>0.04,and Hardy-Weinberg equilibrium test P>0.001.The restriction to SNPs with a MAF greater than 0.04 served to reduce the probability of false positive results and enhance statistical power.Rs7412and rs429358 that define apolipoprotein E?APOE?alleles,were genotyped separately with an APOE genotyping kit.For the comparison of continuity variables between different diagnostic populations,One-way variance of variance?ANOVA?was used,and the comparison of classification variables was applied to Chi square tests.PLINK 1.07 and R3.2.3 was used to evaluate the relationship between 18F-FDG and genetic variation.The thresholds of P<10-5and P<10-77 were used for suggestive and genome-wide significant associations respectively.QC measures were taken to reduce the possible bias in genotyping using PLINK 1.07software for 620901 SNPs.Based on all these SNPs,we excluded 36957 SNPs due to missing genotype data and 1154 SNPs for Hardy-Weinberg equilibrium test and 52935SNPs because of the MAF threshold.Finally,529855 SNPs were included after strict QC.In addition,we also analyzed the link disequilibrium?LD?relationship between the upper and lower 500 KB loci of rs12444565 by haploview software.Finally,in order to explore the relationship between rs12444565 polymorphism in RNA-binding protein homologous 1?RNA-binding Fox1,RBFOX1?gene and AD-related phenotype,another population independently associated with this GWAS analysis was selected in the ADNI database to validate the association between rs12444565polymorphism and AD-related phenotypes.Statistical analyses were performed with R3.2.3 software.Results:There was no statistical difference in age and gender composition between the three groups of subjects?P=0.677,0.910?.The difference in education level,the carrying ratio of APOE?4 alleles,MMSE score,CDRSB score,ADAS11 score and glucose metabolism was statistically significant?P=0.008,0.021,0.000,0.000,0.000,0.007?.Rs 12444565 in RBFOX1 gene had a strong correlation with 18F-FDG metabolism(P=5.89×10-8).Rs255141,rs79037,rs12526331 and rs12529764 had a certain correlation with 18F-FDG metabolism(P=3.80×10-7,4.95×10-7,1.57×10-7,1.57×10-7).The linkage disequilibrium analysis of 500 KB on rs12444565 locus showed that there was no linkage disequilibrium between these loci.The correlation analysis between rs12444565 polymorphism and AD-related phenotypes showed that there was no significant difference in MMSE,CDRSB,ADAS11scores,hippocampal volume,endoolfactory cortex volume,and cerebrospinal fluid A?,tau,phosphorylated tau levels among the three genotypes?C/C,C/A and A/A?of rs12444565?P=0.340,0.20345,0.538,0.1050,0.454874,0.800,0.8981,0.9063?.Concusion:1.Rs 12444565 in RBFOX1 gene and rs235141,rs79037,rs12526331,rs12529764are related to glucose metabolism.2.The anomaly of the RBFOX1 regulating circuit is a risk factor for autism spectrum disorder?ASD?and Epilepsy.Both ASD and epilepsy have abnormal glucose metabolism.18F-FDG PET can be used as a possible biomarker of ASD and epilepsy.3.There was no significant correlation between rs12444565 polymorphism in RBFOX1 gene and AD-related phenotypes?hippocampal volume,volume of the endoolfactory cortex,cerebrospinal fluid A?,tau and phosphorylated tau?,indicating that rs12444565 in RBFOX1 may not be involved in the pathological process of AD by affecting the volume of hippocampus and entorhinal cortex,or by affecting the levels of cerebrospinal fluid A?,tau and phosphorylated tau. |
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