| Background:Alzheimer’s disease（AD）is a degenerative disease of the central nervous system characterized by progressive cognitive impairment and behavior impairment,which is the most common type of dementia among elders.The typical pathological changes of AD are neuritic plaques（NP）,neurofibrillary tangle（NFT）,neuronal deficiency and glial hyperplasia.We have found no effective treatment for AD up to now,so it is crucial to diagnose and intervene in the preclinical phase of AD,which is the target of many drugs and vaccines.The signs of neuroimaging play important parts in the early diagnosis of AD,including brain atrophy,ventricular enlargement,18F-FDG PET imaging,amyloid PET imaging and so on.Some researchers found that the rate of ventricular enlargement was considered to be a sensitive marker of AD progression.And it increases during the progression from normal cognition to dementia.Therefore,exploring the rates of ventricular enlargement over time is of great significance for screening high-risk groups of AD and monitoring development trajectory of it.We hypothesized that some genetic loci can affect the rate of ventricular enlargement,and we performed a genome-wide association study（GWAS）to explore more genetic risk loci in non-demented elders,and we used the rate of ventricular enlargement as an endophenotype.Methods:In this study,initial data were downloaded from the Alzheimer’s Disease Neuroimaging Initiative（ADNI）database.A total of 507 non-Hispanic nondemented white participants（cognitively normal=196,mild cognitive impairment=311）were included after strict quality control procedures.Based on the additive genetic model,we analyzed the relationship between the rate of ventricular enlargement and single nucleotide polymorphisms（SNP）.Quality control procedures were conducted according to the following standards:call rate of SNPs>98%,call rate of individuals>95%,minor allele frequencies（MAF）>5%,and Hardy-Weinberg equilibrium test P>0.001.After cleaning,we retained 1,231,747 SNPs.Conservative threshold of P value<5×10-8 was used to represent genome-wide significant association and P value<1×10-5 was used to represent genome-wide suggestive association.We further explored the association between genome-wide significant SNPs and four other phenotypes at baseline and their longitudinal changes.Results:We found two SNPs within SIAH3 gene which was associated with increased rate of ventricular enlargement reached genome-wide significance(rs11620312,β=0.023,P=4.04×10-8;rs79174114,β=0.023,P=4.28×10-8).After using the Bonferroni procedure to correct for multiple comparisons,rs11620312-C carriers were longitudinally associated with poor cognitive ability（P=0.037）and brain hypometabolism（P=0.029）.We also identified some intergenic SNPs and SNPs within NKAIN2,TBC1D2,GALNT18,ABCC1 and SRCIN1 genes as potential candidates.Conclusions:We identified two novel genome-wide significant SNPs within SIAH3gene（rs11620312 and rs79174114）were significantly associated with the rate of ventricular enlargement,suggesting that they were genetic factors of the rate of ventricular enlargement and might play a regulatory role on it.The results we found in this study provide clues on the genetic mechanism of the rate of ventricular enlargement during the preclinical stage of AD,and hence contribute to the early diagnosis and intervention of AD. |
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