Yiyi Ma1,2,3, Gyungah R Jun1,4, Xiaoling Zhang1, Jaeyoon Chung1, Adam C Naj5, Yuning Chen4, Celine Bellenguez6, Kara Hamilton-Nelson7, Eden R Martin7, Brian W Kunkle7, Joshua C Bis8, Stéphanie Debette9,10, Anita L DeStefano4,11, Myriam Fornage12, Gaël Nicolas13,14,15, Cornelia van Duijn16, David A Bennett17, Philip L De Jager2,3,18,19, Richard Mayeux3, Jonathan L Haines20, Margaret A Pericak-Vance7, Sudha Seshadri11,21,22, Jean-Charles Lambert6, Gerard D Schellenberg5, Kathryn L Lunetta4, Lindsay A Farrer1,4,11,23,24. 1. Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, Massachusetts. 2. Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Clinical Care and Research Center, Division of Neuroimmunology, Columbia University Medical Center, New York, New York. 3. Department of Neurology, Columbia University Medical Center, New York, New York. 4. Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts. 5. Perelman School of Medicine, University of Pennsylvania, Philadelphia. 6. Universite de Lille, INSERM UMR1167, Institute Pasteur de Lille, Lille, France. 7. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida. 8. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle. 9. Bordeaux Population Health Research Center, UMR1219, University Bordeaux, Inserm, Bordeaux, France. 10. Department of Neurology, Bordeaux University Hospital, Bordeaux, France. 11. Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts. 12. School of Public Health, University of Texas Health Science Center at Houston, Houston. 13. UNIROUEN, Inserm U1245, Normandie University, Rouen, France. 14. Department of Genetics, Rouen University Hospital, Rouen, France. 15. Normandy Centre for Genomic and Personalized Medicine, Centre National de Référence pour les Malades Alzheimer Jeunes, Rouen, France. 16. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. 17. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois. 18. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts. 19. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. 20. Institute for Computational Biology, Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio. 21. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts. 22. Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio. 23. Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts. 24. Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts.
Abstract
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.
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.
Authors: Yiyi Ma; Lei Yu; Marta Olah; Rebecca Smith; Stephanie R Oatman; Mariet Allen; Ehsan Pishva; Bin Zhang; Vilas Menon; Nilüfer Ertekin-Taner; Katie Lunnon; David A Bennett; Hans-Ulrich Klein; Philip L De Jager Journal: Alzheimers Dement Date: 2021-09-05 Impact factor: 16.655
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Authors: Xiaoling Zhang; John J Farrell; Tong Tong; Junming Hu; Congcong Zhu; Li-San Wang; Richard Mayeux; Jonathan L Haines; Margaret A Pericak-Vance; Gerard D Schellenberg; Kathryn L Lunetta; Lindsay A Farrer Journal: Alzheimers Dement Date: 2021-06-20 Impact factor: 16.655