Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype.

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 <= 1x10(-5) were further evaluated in the replication data sets and combined by meta-analysis. ResultsAmong 3145 patients with AD and 4213 controls lacking epsilon 4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P=2.22x10(-7)) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P=7.81x10(-8)). GPAA1 was also associated with expression in the brain of GPAA1 (beta=-0.08; P=.03) and its repressive transcription factor, FOXG1 (beta =0.13; P=.003), and global cognition function (beta=-0.53; P=.009). Significant gene-wide associations (threshold P <= 6.35x10(-7)) were observed for OR8G5 (P=4.67x10(-7)), IGHV3-7 (P=9.75x10(-16)), and SLC24A3 (P=2.67x10(-12)) in 2377 patients with AD and 706 controls with epsilon 4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women). Conclusions and RelevanceThe study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE epsilon 4 alleles that reinforce known and suggest additional pathways leading to AD. This case-control study evaluates APOE associations with variants, using whole-exome sequencing, in participants with and without APOE epsilon 4 alleles.