CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease.

Autor: Ma Y; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.; Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Clinical Care and Research Center, Division of Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York., Jun GR; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.; Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts., Chung J; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts., Zhang X; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts., Kunkle BW; John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida., Naj AC; Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., White CC; Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's, Boston, Massachusetts.; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Bennett DA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois., De Jager PL; Center for Translational & Computational Neuroimmunology, Multiple Sclerosis Clinical Care and Research Center, Division of Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York.; Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's, Boston, Massachusetts.; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Mayeux R; Department of Neurology and Sergievsky Center, Columbia University, New York, New York., Haines JL; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio., Pericak-Vance MA; John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida., Schellenberg GD; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Farrer LA; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.; Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts.; Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.; Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts., Lunetta KL; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2019 Aug; Vol. 18 (4), pp. e12964. Date of Electronic Publication: 2019 May 29.
DOI: 10.1111/acel.12964
Abstrakt: CpG-related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome-wide association study using a sliding-window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome-wide significant (p < 5 × 10 -8 ) associations were identified with 171 1.0 kb-length windows spanning 932 kb in the APOE region (top p < 2.2 × 10 -308 ), five windows at BIN1 (top p = 1.3 × 10 -13 ), two windows at MS4A6A (top p = 2.7 × 10 -10 ), two windows near MS4A4A (top p = 6.4 × 10 -10 ), and one window at PICALM (p = 6.3 × 10 -9 ). The total number of CGS-derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10 -10 ), brain DNA methylation (p = 2.15 × 10 -10 ), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10 -4 ). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage-derived genetic score to predict AD risk.
(© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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