GWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion
Abstract Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe encephalopathy preceded by viral infections with high fever. AESD is a multifactorial disease, however, few disease susceptibility genes have previously been identified. Here, we conducted a genome-wid...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-01-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-04576-y |
| _version_ | 1819282293550743552 |
|---|---|
| author | Mariko Kasai Yosuke Omae Yosuke Kawai Akiko Shibata Ai Hoshino Masashi Mizuguchi Katsushi Tokunaga |
| author_facet | Mariko Kasai Yosuke Omae Yosuke Kawai Akiko Shibata Ai Hoshino Masashi Mizuguchi Katsushi Tokunaga |
| author_sort | Mariko Kasai |
| collection | DOAJ |
| description | Abstract Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe encephalopathy preceded by viral infections with high fever. AESD is a multifactorial disease, however, few disease susceptibility genes have previously been identified. Here, we conducted a genome-wide association study (GWAS) and assessed functional variants in non-coding regions to study genetic susceptibility in AESD using 254 Japanese children with AESD and 799 adult healthy controls. We also performed a microRNA enrichment analysis using GWAS statistics to search for candidate biomarkers in AESD. The variant with the lowest p-value, rs1850440, was located in the intron of serine/threonine kinase 39 gene (STK39) on chromosome 2q24.3 (p = 2.44 × 10−7, odds ratio = 1.71). The minor allele T of rs1850440 correlated with the stronger expression of STK39 in peripheral blood. This variant possessed enhancer histone modification marks in STK39, the encoded protein of which activates the p38 mitogen-activated protein kinase (MAPK) pathway. In the replication study, the odds ratios of three SNPs, including rs1850440, showed the same direction of association with that in the discovery stage GWAS. One of the candidate microRNAs identified by the microRNA enrichment analysis was associated with inflammatory responses regulated by the MAPK pathway. This study identified STK39 as a novel susceptibility locus of AESD, found microRNAs as potential biomarkers, and implicated immune responses and the MAPK cascade in its pathogenesis. |
| first_indexed | 2024-12-24T01:13:17Z |
| format | Article |
| id | doaj.art-a46b08ff42fc47f5a85fe22302c90f32 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-24T01:13:17Z |
| publishDate | 2022-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a46b08ff42fc47f5a85fe22302c90f322022-12-21T17:22:50ZengNature PortfolioScientific Reports2045-23222022-01-011211910.1038/s41598-021-04576-yGWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusionMariko Kasai0Yosuke Omae1Yosuke Kawai2Akiko Shibata3Ai Hoshino4Masashi Mizuguchi5Katsushi Tokunaga6Department of Developmental Medical Sciences, Graduate School of Medicine, The University of TokyoGenome Medical Science Project, National Center for Global Health and MedicineGenome Medical Science Project, National Center for Global Health and MedicineDepartment of Developmental Medical Sciences, Graduate School of Medicine, The University of TokyoDepartment of Developmental Medical Sciences, Graduate School of Medicine, The University of TokyoDepartment of Developmental Medical Sciences, Graduate School of Medicine, The University of TokyoGenome Medical Science Project, National Center for Global Health and MedicineAbstract Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe encephalopathy preceded by viral infections with high fever. AESD is a multifactorial disease, however, few disease susceptibility genes have previously been identified. Here, we conducted a genome-wide association study (GWAS) and assessed functional variants in non-coding regions to study genetic susceptibility in AESD using 254 Japanese children with AESD and 799 adult healthy controls. We also performed a microRNA enrichment analysis using GWAS statistics to search for candidate biomarkers in AESD. The variant with the lowest p-value, rs1850440, was located in the intron of serine/threonine kinase 39 gene (STK39) on chromosome 2q24.3 (p = 2.44 × 10−7, odds ratio = 1.71). The minor allele T of rs1850440 correlated with the stronger expression of STK39 in peripheral blood. This variant possessed enhancer histone modification marks in STK39, the encoded protein of which activates the p38 mitogen-activated protein kinase (MAPK) pathway. In the replication study, the odds ratios of three SNPs, including rs1850440, showed the same direction of association with that in the discovery stage GWAS. One of the candidate microRNAs identified by the microRNA enrichment analysis was associated with inflammatory responses regulated by the MAPK pathway. This study identified STK39 as a novel susceptibility locus of AESD, found microRNAs as potential biomarkers, and implicated immune responses and the MAPK cascade in its pathogenesis.https://doi.org/10.1038/s41598-021-04576-y |
| spellingShingle | Mariko Kasai Yosuke Omae Yosuke Kawai Akiko Shibata Ai Hoshino Masashi Mizuguchi Katsushi Tokunaga GWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion Scientific Reports |
| title | GWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion |
| title_full | GWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion |
| title_fullStr | GWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion |
| title_full_unstemmed | GWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion |
| title_short | GWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion |
| title_sort | gwas identifies candidate susceptibility loci and microrna biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion |
| url | https://doi.org/10.1038/s41598-021-04576-y |
| work_keys_str_mv | AT marikokasai gwasidentifiescandidatesusceptibilitylociandmicrornabiomarkersforacuteencephalopathywithbiphasicseizuresandlatereduceddiffusion AT yosukeomae gwasidentifiescandidatesusceptibilitylociandmicrornabiomarkersforacuteencephalopathywithbiphasicseizuresandlatereduceddiffusion AT yosukekawai gwasidentifiescandidatesusceptibilitylociandmicrornabiomarkersforacuteencephalopathywithbiphasicseizuresandlatereduceddiffusion AT akikoshibata gwasidentifiescandidatesusceptibilitylociandmicrornabiomarkersforacuteencephalopathywithbiphasicseizuresandlatereduceddiffusion AT aihoshino gwasidentifiescandidatesusceptibilitylociandmicrornabiomarkersforacuteencephalopathywithbiphasicseizuresandlatereduceddiffusion AT masashimizuguchi gwasidentifiescandidatesusceptibilitylociandmicrornabiomarkersforacuteencephalopathywithbiphasicseizuresandlatereduceddiffusion AT katsushitokunaga gwasidentifiescandidatesusceptibilitylociandmicrornabiomarkersforacuteencephalopathywithbiphasicseizuresandlatereduceddiffusion |