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We conducted a genome\u2010wide association study using a sliding\u2010window 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\u2010wide significant (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a05\u00a0\u00d7\u00a010<jats:sup>\u22128<\/jats:sup>) associations were identified with 171 1.0\u00a0kb\u2010length windows spanning 932\u00a0kb in the <jats:italic>APOE<\/jats:italic> region (top <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a02.2\u00a0\u00d7\u00a010<jats:sup>\u2212308<\/jats:sup>), five windows at <jats:italic>BIN1<\/jats:italic> (top <jats:italic>p<\/jats:italic>\u00a0=\u00a01.3\u00a0\u00d7\u00a010<jats:sup>\u221213<\/jats:sup>), two windows at <jats:italic>MS4A6A<\/jats:italic> (top <jats:italic>p<\/jats:italic>\u00a0=\u00a02.7\u00a0\u00d7\u00a010<jats:sup>\u221210<\/jats:sup>), two windows near <jats:italic>MS4A4A<\/jats:italic> (top <jats:italic>p<\/jats:italic>\u00a0=\u00a06.4\u00a0\u00d7\u00a010<jats:sup>\u221210<\/jats:sup>), and one window at <jats:italic>PICALM<\/jats:italic> (<jats:italic>p<\/jats:italic>\u00a0=\u00a06.3\u00a0\u00d7\u00a010<jats:sup>\u20109<\/jats:sup>). The total number of CGS\u2010derived CpG dinucleotides in the window near <jats:italic>MS4A4A<\/jats:italic> was associated with AD risk (<jats:italic>p<\/jats:italic>\u00a0=\u00a02.67\u00a0\u00d7\u00a010<jats:sup>\u221210<\/jats:sup>), brain DNA methylation (<jats:italic>p<\/jats:italic>\u00a0=\u00a02.15\u00a0\u00d7\u00a010<jats:sup>\u221210<\/jats:sup>), and gene expression in brain (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.03) and blood (<jats:italic>p<\/jats:italic>\u00a0=\u00a02.53\u00a0\u00d7\u00a010<jats:sup>\u22124<\/jats:sup>). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at <jats:italic>MS4A4A<\/jats:italic> (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage\u2010derived genetic score to predict AD risk.<\/jats:p>","DOI":"10.1111\/acel.12964","type":"journal-article","created":{"date-parts":[[2019,5,30]],"date-time":"2019-05-30T04:11:11Z","timestamp":1559189471000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["CpG\u2010related SNPs in the MS4A region have a dose\u2010dependent effect on risk of late\u2013onset Alzheimer disease"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3609-8877","authenticated-orcid":false,"given":"Yiyi","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Medicine (Biomedical Genetics) Boston University School of Medicine Boston Massachusetts"},{"name":"Center for Translational &amp; Computational Neuroimmunology, Multiple Sclerosis Clinical Care and Research Center, Division of Neuroimmunology, Department of Neurology Columbia University Medical Center New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyungah R.","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Medicine (Biomedical Genetics) Boston University School of Medicine Boston Massachusetts"},{"name":"Department of Biostatistics Boston University School of Public Health Boston Massachusetts"},{"name":"Department of Ophthalmology Boston University School of Medicine Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaeyoon","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Medicine (Biomedical Genetics) Boston University School of Medicine Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine (Biomedical Genetics) Boston University School of Medicine Boston Massachusetts"},{"name":"Department of Biostatistics Boston University School of Public Health Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian W.","family":"Kunkle","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics, Miller School of Medicine University of Miami Miami Florida"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam C.","family":"Naj","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology, and Informatics University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania"},{"name":"Department of Pathology and Laboratory Medicine University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles C.","family":"White","sequence":"additional","affiliation":[{"name":"Program in Translational NeuroPsychiatric Genomics Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Boston Massachusetts"},{"name":"Program in Medical and Population Genetics Broad Institute Cambridge Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center Rush University Medical Center Chicago Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[{"name":"Center for Translational &amp; Computational Neuroimmunology, Multiple Sclerosis Clinical Care and Research Center, Division of Neuroimmunology, Department of Neurology Columbia University Medical Center New York New York"},{"name":"Program in Translational NeuroPsychiatric Genomics Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Boston Massachusetts"},{"name":"Program in Medical and Population Genetics Broad Institute Cambridge Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Alzheimer\u2019s Disease Genetics Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Mayeux","sequence":"additional","affiliation":[{"name":"Department of Neurology and Sergievsky Center Columbia University New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan L.","family":"Haines","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics Case Western Reserve University Cleveland Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret A.","family":"Pericak\u2010Vance","sequence":"additional","affiliation":[{"name":"John P. 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