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Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts
Schizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects o...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463022/ https://www.ncbi.nlm.nih.gov/pubmed/32873781 http://dx.doi.org/10.1038/s41398-020-00987-z |
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author | Jiang, Shan Zhou, Daizhan Wang, Yin-Ying Jia, Peilin Wan, Chunling Li, Xingwang He, Guang Cao, Dongmei Jiang, Xiaoqian Kendler, Kenneth S. Tsuang, Ming Mize, Travis Wu, Jain-Shing Lu, Yimei He, Lin Chen, Jingchun Zhao, Zhongming Chen, Xiangning |
author_facet | Jiang, Shan Zhou, Daizhan Wang, Yin-Ying Jia, Peilin Wan, Chunling Li, Xingwang He, Guang Cao, Dongmei Jiang, Xiaoqian Kendler, Kenneth S. Tsuang, Ming Mize, Travis Wu, Jain-Shing Lu, Yimei He, Lin Chen, Jingchun Zhao, Zhongming Chen, Xiangning |
author_sort | Jiang, Shan |
collection | PubMed |
description | Schizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo. In this study, we conducted whole-genome sequencing for 23 families from two cohorts with unaffected siblings and parents. Two nonsense de novo mutations (DNMs) in GJC1 and HIST1H2AD were identified in SCZ patients. Ten genes (DPYSL2, NBPF1, SDK1, ZNF595, ZNF718, GCNT2, SNX9, AACS, KCNQ1, and MSI2) were found to carry more DNMs in SCZ patients than their unaffected siblings by burden test. Expression analyses indicated that these DNM implicated genes showed significantly higher expression in prefrontal cortex in prenatal stage. The DNM in the GJC1 gene is highly likely a loss function mutation (pLI = 0.94), leading to the dysregulation of ion channel in the glutamatergic excitatory neurons. Analysis of rare variants in independent exome sequencing dataset indicates that GJC1 has significantly more rare variants in SCZ patients than in unaffected controls. Data from genome-wide association studies suggested that common variants in the GJC1 gene may be associated with SCZ and SCZ-related traits. Genes co-expressed with GJC1 are involved in SCZ, SCZ-associated pathways, and drug targets. These evidences suggest that GJC1 may be a risk gene for SCZ and its function may be involved in prenatal and early neurodevelopment, a vulnerable period for developmental disorders such as SCZ. |
format | Online Article Text |
id | pubmed-7463022 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74630222020-09-11 Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts Jiang, Shan Zhou, Daizhan Wang, Yin-Ying Jia, Peilin Wan, Chunling Li, Xingwang He, Guang Cao, Dongmei Jiang, Xiaoqian Kendler, Kenneth S. Tsuang, Ming Mize, Travis Wu, Jain-Shing Lu, Yimei He, Lin Chen, Jingchun Zhao, Zhongming Chen, Xiangning Transl Psychiatry Article Schizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo. In this study, we conducted whole-genome sequencing for 23 families from two cohorts with unaffected siblings and parents. Two nonsense de novo mutations (DNMs) in GJC1 and HIST1H2AD were identified in SCZ patients. Ten genes (DPYSL2, NBPF1, SDK1, ZNF595, ZNF718, GCNT2, SNX9, AACS, KCNQ1, and MSI2) were found to carry more DNMs in SCZ patients than their unaffected siblings by burden test. Expression analyses indicated that these DNM implicated genes showed significantly higher expression in prefrontal cortex in prenatal stage. The DNM in the GJC1 gene is highly likely a loss function mutation (pLI = 0.94), leading to the dysregulation of ion channel in the glutamatergic excitatory neurons. Analysis of rare variants in independent exome sequencing dataset indicates that GJC1 has significantly more rare variants in SCZ patients than in unaffected controls. Data from genome-wide association studies suggested that common variants in the GJC1 gene may be associated with SCZ and SCZ-related traits. Genes co-expressed with GJC1 are involved in SCZ, SCZ-associated pathways, and drug targets. These evidences suggest that GJC1 may be a risk gene for SCZ and its function may be involved in prenatal and early neurodevelopment, a vulnerable period for developmental disorders such as SCZ. Nature Publishing Group UK 2020-09-01 /pmc/articles/PMC7463022/ /pubmed/32873781 http://dx.doi.org/10.1038/s41398-020-00987-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Jiang, Shan Zhou, Daizhan Wang, Yin-Ying Jia, Peilin Wan, Chunling Li, Xingwang He, Guang Cao, Dongmei Jiang, Xiaoqian Kendler, Kenneth S. Tsuang, Ming Mize, Travis Wu, Jain-Shing Lu, Yimei He, Lin Chen, Jingchun Zhao, Zhongming Chen, Xiangning Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts |
title | Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts |
title_full | Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts |
title_fullStr | Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts |
title_full_unstemmed | Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts |
title_short | Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts |
title_sort | identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two han chinese patient-sibling family-based cohorts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463022/ https://www.ncbi.nlm.nih.gov/pubmed/32873781 http://dx.doi.org/10.1038/s41398-020-00987-z |
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