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AMIA Jt Summits Transl Sci Proc. 2018 May 18;2017:124-131. eCollection 2018.

Genetic variation affecting exon skipping contributes to brain structural atrophy in Alzheimer's disease.

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Departments of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Biomedical and Translational Informatics Institute, Geisinger Health System, Danville, PA USA.
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.


Genetic 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.


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