{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T18:53:56Z","timestamp":1793904836940,"version":"4.8.0"},"reference-count":53,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T00:00:00Z","timestamp":1561680000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG057522"],"award-info":[{"award-number":["R01 AG057522"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["O.C.-F"],"award-info":[{"award-number":["O.C.-F"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Genome\u2010wide association studies (GWAS) discovered multiple late\u2010onset Alzheimer's disease (LOAD)\u2010associated SNPs and inferred the genes based on proximity; however, the actual causal genes are yet to be identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We defined LOAD\u2010GWAS regions by the most significantly associated SNP \u00b10.5\u00a0Mb and developed a bioinformatics pipeline that uses and integrates chromatin state segmentation track to map active enhancers and virtual 4C software to visualize interactions between active enhancers and gene promoters. We augmented our pipeline with biomedical and functional information.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We applied the bioinformatics pipeline using three \u223c1\u00a0Mb LOAD\u2010GWAS loci: <jats:italic>BIN1<\/jats:italic>, <jats:italic>PICALM, CELF1<\/jats:italic>. These loci contain 10\u201324 genes, an average of 106 active enhancers and 80 CTCF sites. Our strategy identified all genes corresponding to the promoters that interact with the active enhancer that is closest to the LOAD\u2010GWAS\u2010SNP and generated a shorter list of prioritized candidate LOAD genes (5\u201014\/loci), feasible for post\u2010GWAS investigations of causality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Interpretation of LOAD\u2010GWAS discoveries requires the integration of brain\u2010specific functional genomic data sets and information related to regulatory activity.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.jalz.2019.04.014","type":"journal-article","created":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T11:19:38Z","timestamp":1561720778000},"page":"1048-1058","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Bioinformatics strategy to advance the interpretation of Alzheimer's disease GWAS discoveries: The roads from association to causation"],"prefix":"10.1002","volume":"15","author":[{"given":"Michael W.","family":"Lutz","sequence":"first","affiliation":[{"name":"Department of Neurology Duke University Medical Center Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Sprague","sequence":"additional","affiliation":[{"name":"Department of Neurology Duke University Medical Center Durham NC USA"},{"name":"Center for Genomic and Computational Biology Duke University Medical Center Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornit","family":"Chiba\u2010Falek","sequence":"additional","affiliation":[{"name":"Department of Neurology Duke University Medical Center Durham NC USA"},{"name":"Center for Genomic and Computational Biology Duke University Medical Center Durham NC 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