Genome-wide Association Study Of White Matter Hyperintensities In Alzheimer's Disease

Objective:Alzheimer's disease?AD?is the most common cause of dementia in the elderly.It is a degenerative disease of the central nervous system characterized by progressive cognitive decline and behavioral impairment,which seriously threatens the life and quality of the elderly.The present study suggests that environmental and genetic factors are involved in the occurrence and development of AD,of which genetic factors account for about 80%.In recent years,Genome-wide association study?GWAS?has found many genes associated with the risk of AD,but because of the technical limitations,the risk genes in the GWAS study are generally limited to more than 5%of the common mutations in the population.The risk genes of AD can affect the changes in the AD's internal phenotype,such as the biological markers of cerebrospinal fluid or neuroimaging,and then affect the progression of the pathogenesis of AD and the course of the disease.Therefore,we use AD's internal phenotype to explore the genetic factors associated with AD risk,to a certain extent,to make up for the deficiency of the traditional GWAS method.Structural imaging plays an important role in the early diagnosis of AD,such as the changes in cortical thickness and volume can appear in the key brain regions?hippocampus,the middle temporal lobe,the entorhinal cortex?of the early mild cognitive impairment?MCI?.It was found that white matter damage was found in early AD and MCI patients without changes in cortical structure,and the degree of white matter damage was closely related to the decline of cognitive function in early AD patients,suggesting the possibility of white matter hyperintensities?WMH?as an potential image marker of AD diagnosis.We performed a genome-wide association study?GWAS?of WMH in Alzheimer's Disease Neuroimaging Initiative?ADNI?cohort to identify novel variants associated with AD.Methods:This study included 167 patients with AD,347 patients with MCI and 206cognitive healthy controls?HC?.All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control?QC?criteria.Association of WMH with the genetic variants was assessed using PLINK with an additive genetic model,i.e.dose-dependent effect of the minor allele,with the following stringent criteria:minimum call rate for single nucleotide polymorphisms?SNPs?and individuals>95%,minimum minor allele frequencies?MAF?>0.20,Hardy-Weinberg equilibrium test P>0.001.Differences in continuous variables were examined using one-way analysis of variance?ANOVA?,and Tukey's multiple comparisons test was used to perform pairwise analysis after ANOVA.Results:AD patients had higher volume of WMH than those in MCI and healthy controls?P<0.001?.One SNP?rs923851?near the denticleless E3 ubiquitin protein ligase homolog?DTL?gene reached genome-wide association for associations with WMH(P=2.04×10^-10).Moreover,this locus survived Bonferroni corrections for multiple testing.The minor allele?C?of rs923851 was associated with higher volume of WMH in AD patients,MCI patients and normal control group.Although other 27 SNPs did not reach genome-wide association(P<10^-8),they were identified as suggestive loci(P<10^-5).Conclusion:GWAS found that one SNP?rs923851?near the DTL gene was associated with the volume of WMH.We believe that rs923851 may be a new risk locus for AD,because WMH is an important pathological change in AD.