TY - JOUR
T1 - Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype
AU - Ma, Yiyi
AU - Jun, Gyungah R.
AU - Zhang, Xiaoling
AU - Chung, Jaeyoon
AU - Naj, Adam C.
AU - Chen, Yuning
AU - Bellenguez, Celine
AU - Hamilton-Nelson, Kara
AU - Martin, Eden R.
AU - Kunkle, Brian W.
AU - Bis, Joshua C.
AU - Debette, Stéphanie
AU - Destefano, Anita L.
AU - Fornage, Myriam
AU - Nicolas, Gaël
AU - Van Duijn, Cornelia
AU - Bennett, David A.
AU - De Jager, Philip L.
AU - Mayeux, Richard
AU - Haines, Jonathan L.
AU - Pericak-Vance, Margaret A.
AU - Seshadri, Sudha
AU - Lambert, Jean Charles
AU - Schellenberg, Gerard D.
AU - Lunetta, Kathryn L.
AU - Farrer, Lindsay A.
N1 - Funding Information:
Funding/Support: This work was supported in part by NIA grants R01-AG048927, P30-AG13846, and RF1-AG057519. The Alzheimer’s Disease Sequencing Project comprises 2 Alzheimer disease genetics consortia and 3 National Human Genome Research Institute funded Large-Scale Sequencing and Analysis Centers (LSAC). The 3 LSACs are the Human Genome Sequencing Center at the Baylor College of Medicine (grant U54 HG003273), the Broad Institute Genome Center (grant U54HG003067), and the Washington University Genome Institute (grant U54HG003079). The 2 Alzheimer disease genetics consortia are the Alzheimer’s Disease Genetics Consortium funded by NIA grant U01-AG032984, and the Cohorts for Heart and Aging Research in Genomic Epidemiology funded by NIA grant R01-AG033193. This study was also supported by the National Heart, Lung, and Blood Institute, other NIH institutes, and several foreign governmental and nongovernmental organizations. The Discovery Phase analysis of sequence data is supported by NIA grants UF1-AG047133, U01-AG049505, U01-AG049506, U01-AG049507, and U01-AG049508. The Discovery Extension Phase analysis is supported by NIA grants U01-AG052411, U01-AG052410, and U01-AG052409. Data generation and harmonization in the follow-up phases is supported by NIA grant U54-AG052427. ROSMAP data were generated with support from NIA grants R01-AG036836, P30-AG10161, R01-AG15819, R01-AG17917, R01-AG36042, and U01-AG46512. Biological samples and associated phenotypic data used in primary data analyses were stored at study investigator institutions and at the National Cell Repository for Alzheimer’s Disease grant U24AG021886) at Indiana University funded by the NIA. Associated phenotypic data used in primary and secondary data analyses were provided by study investigators, the NIA-funded Alzheimer’s Disease Centers, and the National Alzheimer’s Coordinating Center (grant U01AG016976) and the NIA Genetics of Alzheimer’s Disease Data Storage Site (grants NIAGADS and U24AG041689) at the University of Pennsylvania, funded by NIA, and at the Database for Genotypes and Phenotypes funded by the NIH. This research was supported in part by the Intramural Research Program of the NIH National Library of Medicine. Contributors to the genetic analysis data included study investigators on projects that were individually funded by the NIA and other NIH institutes, and by private US organizations or foreign governmental or nongovernmental organizations. The portion of the study conducted in France was funded by grants from the Clinical Research Hospital Program from the French Ministry of Health (PHRC 2008/067), the Centre National de Référence pour les Malades Alzheimer Jeunes, the Joint Programme-Neurodegenerative Disease Research PERADES (defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease, Using Multiple Powerful Cohorts, Focused Epigenetics and Stem Cell Metabolomics), and the FP7 AgedBrainSysBio, France Génomique, Labex GENMED grant ANR-10-LABX-0013, the National Foundation for Alzheimer’s Disease and Related Disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, Fondation pour la Recherche sur le Cerveau, the Lille Métropole Communauté Urbaine council, and the French government’s LABEX (Laboratory of Excellence Program Investment for the Future) program DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer’s Disease). We are indebted to the Banque d'ADN et de cellules-Institut du Cerveau et de la Moelle épinière (ICM-Inserm) for grants U1127-UPMC P6, UMR S 1127-CNRS, and UMR 7225. The 3C Study received support from the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of SVD of the Brain), the EU Joint Programme-Neurodegenerative Disease Research project, the European Research Council, and the European Union's Horizon 2020 research and innovation programme (grant agreements 640643, 643417, and 667375).
Funding Information:
reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study that are not related to this study. Dr Haines reported receiving grants from the NIH during the conduct of the study. Dr Schellenberg reported receiving grants from National Institute on Aging (NIA) during the conduct of the study. Dr Farrer reported receiving grants from the NIH during the conduct of the study. No other disclosures were reported.
Publisher Copyright:
© 2019 American Medical Association. All rights reserved.
PY - 2019/9
Y1 - 2019/9
N2 - 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 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 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..
AB - 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 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 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..
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U2 - 10.1001/jamaneurol.2019.1456
DO - 10.1001/jamaneurol.2019.1456
M3 - Article
C2 - 31180460
AN - SCOPUS:85067027715
SN - 2168-6149
VL - 76
SP - 1099
EP - 1108
JO - JAMA Neurology
JF - JAMA Neurology
IS - 9
ER -