Lee, YoungheeHan, SeonggyunKim, DongwookKim, DokyoonHorgousluoglu, EmrinRisacher, Shannon L.Saykin, Andrew J.Nho, KwangsikAlzheimer’s Disease Neuroimaging Initiative2019-02-182019-02-182018-05-18Lee, Y., Han, S., Kim, D., Kim, D., Horgousluoglu, E., Risacher, S. L., Saykin, A. J., … Nho, K. (2018). Genetic variation affecting exon skipping contributes to brain structural atrophy in Alzheimer's disease. AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science, 2017, 124-131.https://hdl.handle.net/1805/18422Genetic variation in cis-regulatory elements related to splicing machinery and splicing regulatory elements (SREs) results in exon skipping and undesired protein products. We developed a splicing decision model to identify actionable loci among common SNPs for gene regulation. The splicing decision model identified SNPs affecting exon skipping by analyzing sequence-driven alternative splicing (AS) models and by scanning the genome for the regions with putative SRE motifs. We used non-Hispanic Caucasians with neuroimaging, and fluid biomarkers for Alzheimer's disease (AD) and identified 17,088 common exonic SNPs affecting exon skipping. GWAS identified one SNP (rs1140317) in HLA-DQB1 as significantly associated with entorhinal cortical thickness, AD neuroimaging biomarker, after controlling for multiple testing. Further analysis revealed that rs1140317 was significantly associated with brain amyloid-f deposition (PET and CSF). HLA-DQB1 is an essential immune gene and may regulate AS, thereby contributing to AD pathology. SRE may hold potential as novel therapeutic targets for AD.en-USAttribution 3.0 United StatesGenetic variation in cis-regulatory elementsSplicing machinerySplicing regulatory elementsExon skippingUndesired protein productsSplicing decision modelSNPsGene regulationSequence-driven alternative splicing modelsSRE motifsNon-Hispanic CaucasiansNeuroimagingAlzheimer's diseaseFluid biomarkersGWASHLA-DQB1Entorhinal cortical thicknessrs1140317Brain amyloid-f depositionArticle