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Gene\u2013environment interactions may explain AD missing heritability.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n Lifetime smoking data from 22,032 European ancestry and 3126 African ancestry participants from the Alzheimer's Disease Genetic Consortium and the Framingham Heart Study were used to conduct genome\u2010wide single nucleotide polymorphism (SNP)\u2010by\u2010smoking interaction and smoking\u2010stratified association studies. For top\u2010ranked loci, brain\u2010derived bulk and single nuclei RNA\u2010sequencing were used for differential expression and colocalization analyses.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Among smokers only, there was a genome\u2010wide significant association in the\n APAF1\/ANKS1B<\/jats:italic>\n region (rs12368451; odds ratio\u00a0=\u00a01.19, 95% confidence interval: [1.12, 1.27],\n p<\/jats:italic>\n \u00a0=\u00a03.0 \u00d7 10\n \u22128<\/jats:sup>\n ). Rs12368451 had expression quantitative trait locus (eQTL) activity that differed by smoking status and brain cell types but showed the most significant posterior probability (PP\u00a0=\u00a00.15) for being causal via\n ANKS1B<\/jats:italic>\n expression in oligodendrocytes among smokers.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n \n Potentially causal in smokers via eQTL activity, the top SNP may alter expression of\n ANKS1B<\/jats:italic>\n , which encodes amyloid beta precursor protein intracellular domain associated\u20101, known to regulate amyloid beta plaques.\n <\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n \n Among smokers only, a novel chromosome 12 single nucleotide polymorphism (SNP) near\n ANKS1B<\/jats:italic>\n was associated with Alzheimer's disease.\n <\/jats:p>\n <\/jats:list-item>\n \n Evidence came from European and African ancestry cohorts.<\/jats:p>\n <\/jats:list-item>\n \n \n RNA\u2010sequencing analyses implicated the top SNP as causal via\n ANKS1B<\/jats:italic>\n expression in oligodendrocytes.\n <\/jats:p>\n <\/jats:list-item>\n \n \n A genome\u2010wide African ancestry\u2013specific significant SNP\u2013smoking interaction was observed on chromosome 6 in\n SLC22A23<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.70922","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T11:05:28Z","timestamp":1763723128000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Alzheimer's disease multi\u2010ancestry genome\u2010wide interaction and stratified study with smoking"],"prefix":"10.1002","volume":"21","author":[{"given":"Ryan","family":"Dacey","sequence":"first","affiliation":[{"name":"Department of Medicine Boston University Chobanian & Avedisian School of Medicine Boston Massachusetts USA"},{"name":"Framingham Heart Study Boston 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