Genome-Wide Association Study Of Hippocampal Atrophy Rate In Non-Demented Elders

Background:The hippocampus is a structure that is highly vulnerable to brain damage,buried deep in the medial temporal lobe of the human body.Hippocampal atrophy has been reported to be closely associated with cognitive disorders,such as the most common Alzheimer’s disease（AD）and some non-AD disorders.The previous genome-wide association study（GWAS）used baseline hippocampal volume as a quantitative trait and found new susceptibility genes for AD.However,the genetic modifiers of hippocampal atrophy rates are still unclear.Herein we firstly performed a GWAS to identify genetic loci that regulate hippocampal atrophy rates.Method:A total of 602 non-Hispanic Caucasian elders without dementia were included from the Alzheimer’s Disease Neuroimaging Initiative（ADNI）database.In PLINK v1.9software,we utilized multiple linear regression to explore the associations of hippocampal atrophy rates with genetic polymorphisms under the additive genetic model.The Quality control procedures were implemented following the stringent criteria:detection rates for single nucleotide polymorphisms（SNPs）>98%,individual call rates>95%,minimum allele frequencies>0.10,and Hardy-Weinberg balance examination P>0.001.The thresholds of P<5×10^-8 and P<1×10^-5 were used for genome-wide significant and suggestive associations,respectively.Thereby,genetic factors related to hippocampal atrophy rates were obtained.Then we explored the correlations of these genome-wide significant SNPs with both baseline and longitudinal cognitive scores and specific brain structures.These cross-sectional and longitudinal analyses were determined using multiple linear regression models and linear mixed-effects models,respectively.Moreover,we conducted survival analyses and assessed the risk of cognitive decline in multivariate Cox proportional hazard models.Results:Following strict criteria,all 602 subjects remained in the analysis and 695,203SNPs passed quality control protocols.After adjusting for the first three multidimensional scaling components,age of entry,gender,years of education,intracranial volume,and magnetic resonance imaging,we found that 3 SNPs（rs4420638,rs56131196,and rs157582）in the TOMM40-APOC1 region were linked to hippocampal atrophy rates at genome-wide significance.Besides,3 additional SNPs（rs2075650 within the TOMM40gene,rs4271662 near the MIR302F gene,and rs2900721 near the MIR302F gene）reached suggestive levels of significance.Strong linkage disequilibrium between rs4420638 and rs56131196 was observed.The minor allele of rs4420638（G）and the minor allele of rs157582（T）showed associations with lower Mini-mental State Examination score,higher Alzheimer Disease Assessment Scale-cognitive subscale 11score and smaller entorhinal volume using both baseline and longitudinal measurements,as well as with accelerated cognitive decline in survival analyses.Furthermore, rs56131196(P=1.96×10^-454)and rs157582(P=9.70×10^-434)were risk loci for AD.Conclusions:Collectively,rs4420638,rs56131196 and rs157582 were found to be associated with hippocampal atrophy rate.Besides,they were also identified as genetic loci for cognitive decline.Our findings provide evidence that TOMM40 and APOC1 as candidate genes may promote the application of hippocampal atrophy rate as an early biomarker for predicting cognitive progression and detecting disease trajectories.