Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD
Purpose Alzheimer disease (AD) is one of the most complex diseases and is characterized by AD-related neuropathological features, including accumulation of amyloid-β plaques and tau neurofibrillary tangles. Dysregulation of alternative splicing (AS) contributes to these features, and there is hetero...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Korean Continence Society
2022-11-01
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| Series: | International Neurourology Journal |
| Subjects: | |
| Online Access: | http://einj.org/upload/pdf/inj-2244258-129.pdf |
| _version_ | 1828125336734269440 |
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| author | Sara Kim Seonggyun Han Soo-ah Cho Kwangsik Nho Insong Koh Younghee Lee |
| author_facet | Sara Kim Seonggyun Han Soo-ah Cho Kwangsik Nho Insong Koh Younghee Lee |
| author_sort | Sara Kim |
| collection | DOAJ |
| description | Purpose Alzheimer disease (AD) is one of the most complex diseases and is characterized by AD-related neuropathological features, including accumulation of amyloid-β plaques and tau neurofibrillary tangles. Dysregulation of alternative splicing (AS) contributes to these features, and there is heterogeneity in features across brain regions between AD patients, leading to different severity and progression rates; however, brain region-specific AS mechanisms still remain unclear. Therefore, we aimed to systemically investigate AS in multiple brain regions of AD patients and how they affect clinical features. Methods We analyzed RNA sequencing (RNA-Seq) data obtained from brain regions (frontal and temporal) of AD patients. Reads were mapped to the hg19 reference genome using the STAR aligner, and exon skipping (ES) rates were estimated as percent spliced in (PSI) by rMATs. We focused on AD-risk genes discovered by genome-wide association studies, and accordingly evaluated associations between PSI of skipped exons in AD-risk genes and Braak stage and plaque density mean (PM) for each brain region. We also integrated whole-genome sequencing data of the ascertained samples with RNA-Seq data to identify genetic regulators of feature-associated ES. Results We identified 26 and 41 ES associated with Braak stage in frontal and temporal regions, respectively, and 10 and 50 ES associated with PM. Among those, 10 were frontal-specific (CLU and NTRK2), 65 temporal-specific (HIF1A and TRPC4AP), and 26 shared ES (APP) that accompanied functional Gene Ontology terms, including axonogenesis in shared-ES genes. We further identified genetic regulators that account for 44 ES (44% of the total). Finally, we present as a case study the systematic regulation of an ES in APP, which is important in AD pathogenesis. Conclusions This study provides new insights into brain region-dependent AS regulation of the architecture of AD-risk genes that contributes to AD pathologies, ultimately allowing identification of a treatment target and region-specific biomarkers for AD. |
| first_indexed | 2024-04-11T15:19:17Z |
| format | Article |
| id | doaj.art-64e84016d55b45c599868e989c7f635f |
| institution | Directory Open Access Journal |
| issn | 2093-4777 2093-6931 |
| language | English |
| last_indexed | 2024-04-11T15:19:17Z |
| publishDate | 2022-11-01 |
| publisher | Korean Continence Society |
| record_format | Article |
| series | International Neurourology Journal |
| spelling | doaj.art-64e84016d55b45c599868e989c7f635f2022-12-22T04:16:25ZengKorean Continence SocietyInternational Neurourology Journal2093-47772093-69312022-11-0126Suppl 2S12613610.5213/inj.2244258.1291022Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in ADSara Kim0Seonggyun Han1Soo-ah Cho2Kwangsik Nho3Insong Koh4Younghee Lee5 Department of Biomedical Informatics, Hanyang University, Seoul, Korea Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA College of Veterinary Medicine, Seoul National University, Seoul, Korea Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA Department of Biomedical Informatics, Hanyang University, Seoul, Korea College of Veterinary Medicine, Seoul National University, Seoul, KoreaPurpose Alzheimer disease (AD) is one of the most complex diseases and is characterized by AD-related neuropathological features, including accumulation of amyloid-β plaques and tau neurofibrillary tangles. Dysregulation of alternative splicing (AS) contributes to these features, and there is heterogeneity in features across brain regions between AD patients, leading to different severity and progression rates; however, brain region-specific AS mechanisms still remain unclear. Therefore, we aimed to systemically investigate AS in multiple brain regions of AD patients and how they affect clinical features. Methods We analyzed RNA sequencing (RNA-Seq) data obtained from brain regions (frontal and temporal) of AD patients. Reads were mapped to the hg19 reference genome using the STAR aligner, and exon skipping (ES) rates were estimated as percent spliced in (PSI) by rMATs. We focused on AD-risk genes discovered by genome-wide association studies, and accordingly evaluated associations between PSI of skipped exons in AD-risk genes and Braak stage and plaque density mean (PM) for each brain region. We also integrated whole-genome sequencing data of the ascertained samples with RNA-Seq data to identify genetic regulators of feature-associated ES. Results We identified 26 and 41 ES associated with Braak stage in frontal and temporal regions, respectively, and 10 and 50 ES associated with PM. Among those, 10 were frontal-specific (CLU and NTRK2), 65 temporal-specific (HIF1A and TRPC4AP), and 26 shared ES (APP) that accompanied functional Gene Ontology terms, including axonogenesis in shared-ES genes. We further identified genetic regulators that account for 44 ES (44% of the total). Finally, we present as a case study the systematic regulation of an ES in APP, which is important in AD pathogenesis. Conclusions This study provides new insights into brain region-dependent AS regulation of the architecture of AD-risk genes that contributes to AD pathologies, ultimately allowing identification of a treatment target and region-specific biomarkers for AD.http://einj.org/upload/pdf/inj-2244258-129.pdfalzheimer diseaserna-seqalternative splicing |
| spellingShingle | Sara Kim Seonggyun Han Soo-ah Cho Kwangsik Nho Insong Koh Younghee Lee Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD International Neurourology Journal alzheimer disease rna-seq alternative splicing |
| title | Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD |
| title_full | Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD |
| title_fullStr | Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD |
| title_full_unstemmed | Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD |
| title_short | Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD |
| title_sort | brain region dependent alternative splicing of alzheimer disease ad risk genes is associated with neuropathological features in ad |
| topic | alzheimer disease rna-seq alternative splicing |
| url | http://einj.org/upload/pdf/inj-2244258-129.pdf |
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