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Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU

Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk...

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Autores principales: Han, Seonggyun, Nho, Kwangsik, Lee, Younghee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582367/
https://www.ncbi.nlm.nih.gov/pubmed/32992916
http://dx.doi.org/10.3390/ijms21197079
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author Han, Seonggyun
Nho, Kwangsik
Lee, Younghee
author_facet Han, Seonggyun
Nho, Kwangsik
Lee, Younghee
author_sort Han, Seonggyun
collection PubMed
description Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of CLU on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership—Alzheimer’s Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain—the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of CLU; as the number of alternative alleles (G) increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation.
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spelling pubmed-75823672020-10-28 Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU Han, Seonggyun Nho, Kwangsik Lee, Younghee Int J Mol Sci Communication Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of CLU on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership—Alzheimer’s Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain—the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of CLU; as the number of alternative alleles (G) increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation. MDPI 2020-09-25 /pmc/articles/PMC7582367/ /pubmed/32992916 http://dx.doi.org/10.3390/ijms21197079 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Han, Seonggyun
Nho, Kwangsik
Lee, Younghee
Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU
title Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU
title_full Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU
title_fullStr Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU
title_full_unstemmed Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU
title_short Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU
title_sort alternative splicing regulation of an alzheimer’s risk variant in clu
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582367/
https://www.ncbi.nlm.nih.gov/pubmed/32992916
http://dx.doi.org/10.3390/ijms21197079
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