[Skip to Content]
[Skip to Content Landing]
Views 2,756
Citations 0
Original Investigation
June 10, 2019

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

Author Affiliations
  • 1Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • 2Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Clinical Care and Research Center, Division of Neuroimmunology, Columbia University Medical Center, New York, New York
  • 3Department of Neurology, Columbia University Medical Center, New York, New York
  • 4Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • 5Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 6Universite de Lille, INSERM UMR1167, Institute Pasteur de Lille, Lille, France
  • 7John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
  • 8Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle
  • 9Bordeaux Population Health Research Center, UMR1219, University Bordeaux, Inserm, Bordeaux, France
  • 10Department of Neurology, Bordeaux University Hospital, Bordeaux, France
  • 11Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • 12School of Public Health, University of Texas Health Science Center at Houston, Houston
  • 13UNIROUEN, Inserm U1245, Normandie University, Rouen, France
  • 14Department of Genetics, Rouen University Hospital, Rouen, France
  • 15Normandy Centre for Genomic and Personalized Medicine, Centre National de Référence pour les Malades Alzheimer Jeunes, Rouen, France
  • 16Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 17Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
  • 18Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts
  • 19Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
  • 20Institute for Computational Biology, Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio
  • 21National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts
  • 22Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio
  • 23Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • 24Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
JAMA Neurol. 2019;76(9):1099-1108. doi:10.1001/jamaneurol.2019.1456
Key Points

Question  Are there rare variants associated with Alzheimer disease among individuals who possess or lack the APOE ε4 allele?

Findings  This case-control, whole-exome sequencing study of 10 441 individuals identified a possibly novel association with a GPAA1 variant among those who lacked the APOE ε4 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 ε4 allele for variants in ISYNA1, OR8G5, IGHV3-7, and SLC24A3.

Meaning  This study supports the apparent involvement of genes in Alzheimer disease whose effects are dependent on APOE genotype.


Importance  Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles.

Objective  To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing.

Design, Setting, and Participants  The discovery stage included 10 441 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 Measures  Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ε4 carriers and noncarriers. Results with P ≤ 1 × 10−5 were further evaluated in the replication data sets and combined by meta-analysis.

Results  Among 3145 patients with AD and 4213 controls lacking ε4 (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 = 2.22 × 10−7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10−8). GPAA1 was also associated with expression in the brain of GPAA1 (β = −0.08; P = .03) and its repressive transcription factor, FOXG1 (β = 0.13; P = .003), and global cognition function (β = −0.53; P = .009). Significant gene-wide associations (threshold P ≤ 6.35 × 10−7) were observed for OR8G5 (P = 4.67 × 10−7), IGHV3-7 (P = 9.75 × 10−16), and SLC24A3 (P = 2.67 × 10−12) in 2377 patients with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women).

Conclusions and Relevance  The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ε4 alleles that reinforce known and suggest additional pathways leading to AD.