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dc.contributor.authorReiman, Eric
dc.date.accessioned2019-08-26T20:05:12Z
dc.date.available2019-08-26T20:05:12Z
dc.date.issued2019-08
dc.identifier.citationMa, Y, Jun, GR, Chung, J, et al. CpG‐related SNPs in the MS4A region have a dose‐dependent effect on risk of late–onset Alzheimer disease. Aging Cell. 2019; 18:e12964. https://doi.org/10.1111/acel.12964en_US
dc.identifier.issn1474-9718
dc.identifier.pmid31144443
dc.identifier.doi10.1111/acel.12964
dc.identifier.urihttp://hdl.handle.net/10150/633988
dc.description.abstractCpG-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.en_US
dc.description.sponsorshipNIA [U24-AG041689-01, P30 AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P50 AG005131, P50 AG023501]; National Institute on Aging (NIA) [U24 AG21886, U01-AG032984, RC2AG036528]; NIA/NIH [U01 AG016976]; [P30 AG035982]; [P30 AG028383]; [P30 AG053760]; [P30 AG010124]; [P50 AG005133]; [P50 AG005142]; [P30 AG012300]; [P30 AG049638]; [P50 AG005136]; [P50 AG033514]; [P50 AG005681]; [P50 AG047270]; [P30-AG10161]; [R01-AG17917]; [R01-AG36042]; [U01-AG46152]; [R01-AG048927]; [RF1-AG057519]en_US
dc.language.isoenen_US
dc.publisherWILEYen_US
dc.rights© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.en_US
dc.subjectAlzheimer diseaseen_US
dc.subjectDNA methylationen_US
dc.subjecteQTLen_US
dc.subjectepigeneticsen_US
dc.subjectgeneticsen_US
dc.subjectmQTLen_US
dc.titleCpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer diseaseen_US
dc.typeArticleen_US
dc.identifier.eissn1474-9726
dc.contributor.departmentUniv Arizona, Dept Psychiaten_US
dc.identifier.journalAGING CELLen_US
dc.description.noteOpen access journalen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleAging cell
refterms.dateFOA2019-08-26T20:05:12Z


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