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Title | CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Ma Y, Jun GR, Chung J, Zhang X, Kunkle BW, Naj AC, White CC, Bennett DA, De Jager PL, Mayeux R, Haines JL, Pericak-Vance MA, Schellenberg GD, Farrer LA, Lunetta KL |
Corporate Authors | Alzheimer’s Disease Genetics Consortium |
Journal | Aging Cell |
Volume | 18 |
Issue | 4 |
Pagination | e12964 |
Date Published | 08/2019 |
ISSN | 1474-9726 |
Abstract | 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 ) associations were identified with 171 1.0 kb-length windows spanning 932 kb in the APOE region (top p < 2.2 × 10 ), five windows at BIN1 (top p = 1.3 × 10 ), two windows at MS4A6A (top p = 2.7 × 10 ), two windows near MS4A4A (top p = 6.4 × 10 ), and one window at PICALM (p = 6.3 × 10 ). The total number of CGS-derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10 ), brain DNA methylation (p = 2.15 × 10 ), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10 ). 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. |
DOI | 10.1111/acel.12964 |
Alternate Journal | Aging Cell |
PubMed ID | 31144443 |
PubMed Central ID | PMC6612647 |
Grant List | P30 AG010129 / AG / NIA NIH HHS / United States P30 AG049638 / AG / NIA NIH HHS / United States P50 AG016573 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States R01 AG048927 / AG / NIA NIH HHS / United States G0902227 / MRC_ / Medical Research Council / United Kingdom RF1-AG057519 / AG / NIA NIH HHS / United States R01-AG048927 / AG / NIA NIH HHS / United States MR/L023784/1 / MRC_ / Medical Research Council / United Kingdom U01 AG032984 / AG / NIA NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States R01 AG015819 / AG / NIA NIH HHS / United States P30 AG053760 / AG / NIA NIH HHS / United States MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom P50 AG016574 / AG / NIA NIH HHS / United States RF1 AG036042 / AG / NIA NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States R01-AG36042 / AG / NIA NIH HHS / United States P30 AG010124 / AG / NIA NIH HHS / United States RF1 AG057519 / AG / NIA NIH HHS / United States P30 AG010133 / AG / NIA NIH HHS / United States P50 AG005146 / AG / NIA NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States G0300429 / MRC_ / Medical Research Council / United Kingdom P50 AG005136 / AG / NIA NIH HHS / United States U24-AG041689-01 / AG / NIA NIH HHS / United States P50 AG047266 / AG / NIA NIH HHS / United States R01 AG017917 / AG / NIA NIH HHS / United States U01-AG46152 / AG / NIA NIH HHS / United States P30 AG019610 / AG / NIA NIH HHS / United States MR/L501517/1 / MRC_ / Medical Research Council / United Kingdom R01-AG17917 / AG / NIA NIH HHS / United States P30 AG012300 / AG / NIA NIH HHS / United States P30 AG008051 / AG / NIA NIH HHS / United States RC2 AG036528 / AG / NIA NIH HHS / United States P50 AG023501 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States P30 AG028383 / AG / NIA NIH HHS / United States P50 AG008702 / AG / NIA NIH HHS / United States P50 AG047270 / AG / NIA NIH HHS / United States P50 AG005138 / AG / NIA NIH HHS / United States P50 AG005131 / AG / NIA NIH HHS / United States MR/M009076/1 / MRC_ / Medical Research Council / United Kingdom P50 AG005142 / AG / NIA NIH HHS / United States P30 AG008017 / AG / NIA NIH HHS / United States P50 AG047366 / AG / NIA NIH HHS / United States MR/L023784/2 / MRC_ / Medical Research Council / United Kingdom P30 AG013854 / AG / NIA NIH HHS / United States P50 AG025688 / AG / NIA NIH HHS / United States P30 AG013846 / AG / NIA NIH HHS / United States P30 AG035982 / AG / NIA NIH HHS / United States P30-AG10161 / AG / NIA NIH HHS / United States P50 AG005134 / AG / NIA NIH HHS / United States P50 AG033514 / AG / NIA NIH HHS / United States |