{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:06:27Z","timestamp":1789563987347,"version":"build-2803163510"},"reference-count":27,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T00:00:00Z","timestamp":1600992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R03 AG063250"],"award-info":[{"award-number":["R03 AG063250"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R03 AG054936"],"award-info":[{"award-number":["R03 AG054936"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000092","name":"U.S. National Library of Medicine","doi-asserted-by":"publisher","award":["R01 LM012535"],"award-info":[{"award-number":["R01 LM012535"]}],"id":[{"id":"10.13039\/100000092","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["NRF-2017M3C9A6047623"],"award-info":[{"award-number":["NRF-2017M3C9A6047623"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Information Technology Research Center Korea","award":["IITP-2018-2018-0-01833"],"award-info":[{"award-number":["IITP-2018-2018-0-01833"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer\u2019s 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\u2014Alzheimer\u2019s Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain\u2014the 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.<\/jats:p>","DOI":"10.3390\/ijms21197079","type":"journal-article","created":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T09:15:23Z","timestamp":1601025323000},"page":"7079","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Alternative Splicing Regulation of an Alzheimer\u2019s Risk Variant in CLU"],"prefix":"10.3390","volume":"21","author":[{"given":"Seonggyun","family":"Han","sequence":"first","affiliation":[{"name":"Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangsik","family":"Nho","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Sciences and Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6850-0082","authenticated-orcid":false,"given":"Younghee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0165-0173(00)00019-9","article-title":"Tau protein isoforms, phosphorylation and role in neurodegenerative disorders","volume":"33","author":"Buee","year":"2000","journal-title":"Brain Res. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"28257","DOI":"10.1074\/jbc.270.47.28257","article-title":"Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer\u2019s disease","volume":"270","author":"Rockenstein","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/s41576-018-0064-4","article-title":"Altered splicing in Alzheimer transcriptomes","volume":"19","author":"Koch","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nrg2164","article-title":"Splicing in disease: Disruption of the splicing code and the decoding machinery","volume":"8","author":"Wang","year":"2007","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/s41588-018-0238-1","article-title":"Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer\u2019s disease susceptibility","volume":"50","author":"Raj","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/ng.440","article-title":"Genome-Wide association study identifies variants at CLU and PICALM associated with Alzheimer\u2019s disease","volume":"41","author":"Harold","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/s12035-012-8237-1","article-title":"The role of clusterin in Alzheimer\u2019s disease: Pathways, pathogenesis, and therapy","volume":"45","author":"Yu","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1038\/tp.2011.17","article-title":"Alzheimer\u2019s risk variants in the clusterin gene are associated with alternative splicing","volume":"1","author":"Szymanski","year":"2011","journal-title":"Transl. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.neurobiolaging.2016.02.011","article-title":"Sex differences in metabolic aging of the brain: Insights into female susceptibility to Alzheimer\u2019s disease","volume":"42","author":"Zhao","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1159\/000366365","article-title":"The chaperone activity of clusterin is dependent on glycosylation and redox environment","volume":"34","author":"Rohne","year":"2014","journal-title":"Cell Physiol. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13024-015-0024-9","article-title":"Reduced secreted clusterin as a mechanism for Alzheimer-associated CLU mutations","volume":"10","author":"Bettens","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0167-4781(96)00017-6","article-title":"Modification of the alternative splicing process of testosterone-repressed prostate message-2 (TRPM-2) gene by protein synthesis inhibitors and heat shock treatment","volume":"1307","author":"Kimura","year":"1996","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Hayashi, I., Wong, J., Tugusheva, K., Renger, J.J., and Zerbinatti, C. (2014). Intracellular clusterin interacts with brain isoforms of the bridging integrator 1 and with the microtubule-associated protein Tau in Alzheimer\u2019s disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0103187"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1038\/s41467-018-04559-0","article-title":"Precise temporal regulation of alternative splicing during neural development","volume":"9","author":"Feng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3389\/fmolb.2018.00012","article-title":"Alternative Splicing in Neurogenesis and Brain Development","volume":"5","author":"Su","year":"2018","journal-title":"Front. Mol. Biosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1007\/s12311-019-01026-4","article-title":"Human Brain Region-Specific Alternative Splicing of TRPC3, the Type 3 Canonical Transient Receptor Potential Non-Selective Cation Channel","volume":"18","author":"Cederholm","year":"2019","journal-title":"Cerebellum"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.neuron.2015.05.004","article-title":"Alternative Splicing in the Mammalian Nervous System: Recent Insights into Mechanisms and Functional Roles","volume":"87","author":"Raj","year":"2015","journal-title":"Neuron"},{"key":"ref_18","unstructured":"Jansen, I., Savage, J., Watanabe, K., Bryois, J., Williams, D., Steinberg, S., Sealock, J., Karlsson, I., Hagg, S., and Athanasiu, L. (2018). Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer\u2019s disease risk. bioRxiv, 258533."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"26027","DOI":"10.1038\/srep26027","article-title":"Effect of CLU genetic variants on cerebrospinal fluid and neuroimaging markers in healthy, mild cognitive impairment and Alzheimer\u2019s disease cohorts","volume":"6","author":"Tan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1093\/hmg\/ddh334","article-title":"Branch site haplotypes that control alternative splicing","volume":"13","author":"Kralovicova","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/nmeth.1528","article-title":"Analysis and design of RNA sequencing experiments for identifying isoform regulation","volume":"7","author":"Katz","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"160089","DOI":"10.1038\/sdata.2016.89","article-title":"Human whole genome genotype and transcriptome data for Alzheimer\u2019s and other neurodegenerative diseases","volume":"3","author":"Allen","year":"2016","journal-title":"Sci. Data"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"180185","DOI":"10.1038\/sdata.2018.185","article-title":"The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer\u2019s disease","volume":"5","author":"Wang","year":"2018","journal-title":"Sci. Data"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E5593","DOI":"10.1073\/pnas.1419161111","article-title":"rMATS: Robust and flexible detection of differential alternative splicing from replicate RNA-Seq data","volume":"111","author":"Shen","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lee, Y., Gamazon, E.R., Rebman, E., Lee, Y., Lee, S., Dolan, M.E., Cox, N.J., and Lussier, Y.A. (2012). Variants affecting exon skipping contribute to complex traits. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002998"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2490","DOI":"10.1093\/hmg\/ddl171","article-title":"An increased specificity score matrix for the prediction of SF2\/ASF-specific exonic splicing enhancers","volume":"15","author":"Smith","year":"2006","journal-title":"Hum. Mol Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/19\/7079\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:13:43Z","timestamp":1760177623000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/19\/7079"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,25]]},"references-count":27,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ijms21197079"],"URL":"https:\/\/doi.org\/10.3390\/ijms21197079","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,25]]}}}