Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype
Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype
复制标题
Alzheimer病APOE基因全外显子测序结果分析
DOI：
10.1001/jamaneurol.2019.1456
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发表时间：
2019-09-01
期刊：
影响因子：
29
通讯作者：
Stern, Yaakov
中科院分区：
文献类型：
--
作者：
Ma, Yiyi;Jun, Gyungah R.;Stern, Yaakov
在拥有或缺乏APOE β 4等位基因的个体中，是否存在与阿尔茨海默病相关的罕见变异？这一病例对照，全外显子组测序研究10441人确定了一个可能的新的关联与GPAA 1变异体之间缺乏APOE β 4等位基因，这一发现是重复的独立数据集和支持的分析全基因组和RNA测序数据来自人脑组织。在携带APOE β 4等位基因的个体中发现了ISYNA 1、OR 8 G5、IGHV 3 -7和SLC 24 A3变异体的新关联。MeaningThis study supports the apparent involvement of genes in Alzheimer disease which effects are dependent on APOE genotype.ImportancePrevious genome-wide association studies of common variants identified association for Alzheimer disease（AD）loci evidence only among individuals with specific APOE alleles.目的应用全外显子测序技术，研究载脂蛋白E基因型与罕见变异的关系。设计，设置，和missantsThe发现阶段包括10441非西班牙裔白色参与阿尔茨海默病测序项目。在2个独立的全外显子组测序数据集（1766例AD患者，2906例非AD患者[对照]）和基于芯片的基因型插补数据集（8728例AD患者，9808例对照）中寻求重复。使用从包括402名AD患者和647名对照的纵向队列样本获得的临床、认知、神经病理、全外显子组测序和基因表达数据进行生物信息学和功能分析。分析了2017年3月至2018年9月期间的数据。主要结果和测量采用Score、Firth和序列核关联检验来检测AD风险与APOE β 4携带者和非携带者亚组中个体变异和基因的关联。结果P
Key PointsQuestionAre there rare variants associated with Alzheimer disease among individuals who possess or lack the APOE epsilon 4 allele? FindingsThis case-control, whole-exome sequencing study of 10441 individuals identified a possibly novel association with a GPAA1 variant among those who lacked the APOE epsilon 4 allele, a finding that was replicated in independent data sets and supported by analyses of whole-genome and RNA sequencing data derived from human brain tissue. Novel associations were identified among individuals with the APOE epsilon 4 allele for variants in ISYNA1, OR8G5, IGHV3-7, and SLC24A3. MeaningThis study supports the apparent involvement of genes in Alzheimer disease whose effects are dependent on APOE genotype.ImportancePrevious genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. ObjectiveTo identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. Design, Setting, and ParticipantsThe discovery stage included 10441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018. Main Outcomes and MeasuresScore, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE epsilon 4 carriers and noncarriers. Results with P