Unknown

Dataset Information

0

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


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.

SUBMITTER: Lee Y 

PROVIDER: S-EPMC5961815 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Lee Younghee Y   Han Seonggyun S   Kim Dongwook D   Kim Dokyoon D   Horgousluoglu Emrin E   Risacher Shannon L SL   Saykin Andrew J AJ   Nho Kwangsik K  

AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science 20180518


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 Ca  ...[more]

Similar Datasets

| S-EPMC3486879 | biostudies-literature
| S-EPMC4719003 | biostudies-literature
| S-EPMC3067828 | biostudies-literature
| S-EPMC6678912 | biostudies-literature
| S-EPMC6357347 | biostudies-literature
| S-EPMC8425305 | biostudies-literature
| S-EPMC6831832 | biostudies-literature
| S-EPMC4486480 | biostudies-literature
| S-EPMC3501452 | biostudies-literature
| S-EPMC8673534 | biostudies-literature