Association of the Alzheimer's Gene SORL1 With Hippocampal Volume in Young, Healthy Adults
Association of the Alzheimer's Gene SORL1 With Hippocampal Volume in Young, Healthy Adults
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DOI：
10.1176/appi.ajp.2011.10101509
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发表时间：
2011-10-01
影响因子：
17.7
通讯作者：
Franke, Barbara
中科院分区：
文献类型：
--
作者：
Bralten, Janita;Arias-Vasquez, Alejandro;Franke, Barbara
目的：阿尔茨海默病是最常见的神经退行性疾病之一。SORL 1（分拣蛋白受体1）基因与该疾病相关，但不同的变体似乎有所贡献。作者使用了一种全基因的方法来测试SORL 1是否与海马体的体积相关，海马体是年轻健康个体中最早受到阿尔茨海默病影响的结构之一，试图绘制从基因到疾病的潜在途径。方法：使用基于阵列的方法对个体进行基因分型，SORL 1及其周围的117个单核苷酸多态性（SNP）被纳入分析。通过使用的大脑分割协议，SNP的SNP和全基因协会与双边海马体积进行了评估，在两个大的，独立的样本组成的446（发现队列）和490（复制队列）健康的年轻individuals.Results：SORL 1基因与海马体积的显着关联观察发现和复制样本，以及在合并后的样本。全基因的关联是独立的载脂蛋白E基因型和耐删除四个显着相关的单SNPs.Conclusions：这项研究提供了第一个证据表明，SORL 1基因与海马体积的差异在年轻，健康的成年人。研究表明，全基因分析技术可以克服关联研究中等位基因异质性引起的功效问题。研究结果支持了SORL 1基因通过影响海马体积而增加阿尔茨海默病风险的假设。
Objective: Alzheimer's disease is among the most common neurodegenerative disorders. The SORL1 (sortilin receptor 1) gene is associated with the disease, but different variants seem to contribute. The authors used a gene-wide approach to test whether SORL1 is associated with volume of the hippocampus, one of the first structures to be affected by Alzheimer's disease in young, healthy individuals, in an attempt to map potential pathways from gene to disease.Method: Individuals were genotyped using an array-based method, and a total of 117 single nucleotide polymorphisms (SNPs) in and surrounding SORL1 were included in the analysis. Through the use of a brain segmentation protocol, SNP-by-SNP and gene-wide associations with bilateral hippocampal volume were assessed in two large, independent samples consisting of 446 (discovery cohort) and 490 (replication cohort) healthy young individuals.Results: Significant association of the SORL1 gene with hippocampal volume was observed in both the discovery and replication samples as well as in the combined sample. The gene-wide association was independent of the apolipoprotein E genotype and resistant to removal of four significantly associated single SNPs.Conclusions: This study provides the first evidence that the SORL1 gene is associated with differences in hippocampal volume in young, healthy adults. It is demonstrated that gene-wide analysis techniques may overcome power problems caused by allelic heterogeneity in association studies. The results support the hypothesis that the SORL1 gene contributes to an increased risk for Alzheimer's disease through effects on hippocampal volume.