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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.

Author information

1
Departments of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
2
Biomedical and Translational Informatics Institute, Geisinger Health System, Danville, PA USA.
3
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.

Abstract

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.

PMID:
29888056
PMCID:
PMC5961815

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