{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T01:14:02Z","timestamp":1789607642269,"version":"build-2803163510"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"University of Hawai'i Cancer Center"},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Aim: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer\u2019s disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments. Methods: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et\u00a0al\u2019s study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 participants in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). In our MR analyses, we integrated these mQTLs with single nucleotide polymorphisms (SNP)-ad risk summary statistics derived from 85\u2009934\u00a0ad-related cases and 401\u2009577 normal controls. Results: Among 62\u2009554 cytosine-guanine dinucleotide (CpG) sites, we identified 597 CpG sites (CpGs) significantly associated with ad risk (false discovery rate (FDR)\u2009&amp;lt;\u20090.05). Of these, 289 were confirmed through colocalization and summary-based MR (SMR) analyses, including one CpG site in CRBLM, 285 in DLPFC, one in FCTX, two in PONS, and one in TCTX. By integrating gene expression data, we identified 19 CpG sites with consistent associations across methylation levels, expression of eight target genes, and ad risk, including novel regulatory mechanisms involving RITA1\u2019s modulation of cg11558705 and PCGF3\u2019s regulation of cg10009224. Conclusion: Our findings highlight brain region-specific DNA methylation as a mediator of genetic risk for ad, offering insights into ad pathogenesis and identifying potential therapeutic targets.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf053","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T22:23:39Z","timestamp":1744064619000},"page":"1026-1033","source":"Crossref","is-referenced-by-count":5,"title":["Linking DNA methylation in brain regions to Alzheimer\u2019s disease risk: a Mendelian randomization study"],"prefix":"10.1093","volume":"34","author":[{"given":"Hua","family":"Zhong","sequence":"first","affiliation":[{"name":"Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawai'i Cancer Center, University of Hawai'i at M\u0101noa , 701 Ilalo St, Honolulu, HI 96813 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawai'i at M\u0101noa , 651 Ilalo Street, Honolulu, HI 96813 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Liu","sequence":"additional","affiliation":[{"name":"Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawai'i Cancer Center, University of Hawai'i at M\u0101noa , 701 Ilalo St, Honolulu, HI 96813 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine , 388 Yuhangtang Road, Hangzhou, Zhejiang 310058 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, University of Calgary , 2500 University Drive NW, Calgary Alberta T2N 1N4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center , 7007 Bertner Avenue, Houston, TX 77030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingxin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Statistics and Data Science, University of Pennsylvania , 265 South 37th Street, Philadelphia, PA 19104 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Translational Research, Baylor College of Medicine , One Baylor PlazaBCM 451, Houston, TX 77303 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaohua","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Virginia , 200 Jeanette Lancaster Way, Charlottesville, VA 22903 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, College of Medicine, The Ohio State University , 1800 Cannon Drive 250 Lincoln Tower, Columbus, OH 43210 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science , 1731 E. 120th St, Los Angeles, CA 90059 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changwei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Peter J. O\u2019Donnell School of Public Health, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Population Sciences, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, TN 38105 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyong","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Public Health, The Ohio State University , Cunz Hall 250 1841 Neil Ave, Columbus, OH 43210 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyi","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , 1161 21st Ave S # D3300, Nashville, TN 37232 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Degui","family":"Zhi","sequence":"additional","affiliation":[{"name":"School of Biomedical Informatics, The University of Texas Health Science Center at Houston , 7000 Fannin St Suite 600, Houston, TX 77030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youping","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, John A. 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