Dataset Information

Identification of region-specific splicing QTLs in human hippocampal tissue and its distinctive role in brain disorders.

ABSTRACT: Alternative splicing (AS) regulation has an essential role in complex diseases. However, the AS profiles in the hippocampal (HIPPO) region of human brain are underexplored. Here, we investigated cis-acting sQTLs of HIPPO region in 264 samples and identified thousands of significant sQTLs. By enrichment analysis and functional characterization of these sQTLs, we found that the HIPPO sQTLs were enriched among histone-marked regions, transcription factors binding sites, RNA binding proteins sites, and brain disorders-associated loci. Comparative analyses with the dorsolateral prefrontal cortex revealed the importance of AS regulation in HIPPO (r_g = 0.87). Furthermore, we performed a transcriptome-wide association study of Alzheimer's disease and identified 16 significant genes whose genetically regulated splicing levels may have a causal role in Alzheimer. Overall, our study improves our knowledge of the transcriptome gene regulation in the HIPPO region and provides novel insights into elucidating the pathogenesis of potential genes associated with brain disorders.

SUBMITTER: Li X

PROVIDER: S-EPMC10558811 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Identification of region-specific splicing QTLs in human hippocampal tissue and its distinctive role in brain disorders.

Li Xiaoyan X Zhao Yiran Y Kong Hui H Song Chengcheng C Liu Jie J Xia Junfeng J

iScience 20230919 10

Alternative splicing (AS) regulation has an essential role in complex diseases. However, the AS profiles in the hippocampal (HIPPO) region of human brain are underexplored. Here, we investigated <i>cis</i>-acting sQTLs of HIPPO region in 264 samples and identified thousands of significant sQTLs. By enrichment analysis and functional characterization of these sQTLs, we found that the HIPPO sQTLs were enriched among histone-marked regions, transcription factors binding sites, RNA binding proteins ...[more]

PMID: 37810239

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Project description:MotivationAnnotating a given genomic locus or a set of genomic loci is an important yet challenging task. This is especially true for the non-coding part of the genome which is enormous yet poorly understood. Since gene set enrichment analyses have demonstrated to be effective approach to annotate a set of genes, the same idea can be extended to explore the enrichment of functional elements or features in a set of genomic intervals to reveal potential functional connections.ResultsIn this study, we describe a novel computational strategy named loci2path that takes advantage of the newly emerged, genome-wide and tissue-specific expression quantitative trait loci (eQTL) information to help annotate a set of genomic intervals in terms of transcription regulation. By checking the presence or the absence of millions of eQTLs in a set of input genomic intervals, combined with grouping eQTLs by the pathways or gene sets that their target genes belong to, loci2path build a bridge connecting genomic intervals to functional pathways and pre-defined biological-meaningful gene sets, revealing potential for regulatory connection. Our method enjoys two key advantages over existing methods: first, we no longer rely on proximity to link a locus to a gene which has shown to be unreliable; second, eQTL allows us to provide the regulatory annotation under the context of specific tissue types. To demonstrate its utilities, we apply loci2path on sets of genomic intervals harboring disease-associated variants as query. Using 1 702 612 eQTLs discovered by the Genotype-Tissue Expression (GTEx) project across 44 tissues and 6320 pathways or gene sets cataloged in MSigDB as annotation resource, our method successfully identifies highly relevant biological pathways and revealed disease mechanisms for psoriasis and other immune-related diseases. Tissue specificity analysis of associated eQTLs provide additional evidence of the distinct roles of different tissues played in the disease mechanisms.Availability and implementationloci2path is published as an open source Bioconductor package, and it is available at http://bioconductor.org/packages/release/bioc/html/loci2path.html.Supplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

Identification of region-specific splicing QTLs in human hippocampal tissue and its distinctive role in brain disorders.

Publications

Identification of region-specific splicing QTLs in human hippocampal tissue and its distinctive role in brain disorders.

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