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Whole-genome sequencing identifies novel genes for autism in Chinese trios
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heritability but heterogeneity. Fully understanding its genetics requires whole-genome sequencing (WGS), but the ASD studies utilizing WGS data in Chinese population are limited. In this study, we present a WGS study f...
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| Published in: | Science China. Life sciences 2024-11, Vol.67 (11), p.2368-2381 |
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| container_title | Science China. Life sciences |
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| creator | Chang, Suhua Liu, Jia Jia Zhao, Yilu Pang, Tao Zheng, Xiangyu Song, Zhirui Zhang, Anyi Gao, Xuping Luo, Lingxue Guo, Yanqing Liu, Jing Yang, Li Lu, Lin |
| description | Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heritability but heterogeneity. Fully understanding its genetics requires whole-genome sequencing (WGS), but the ASD studies utilizing WGS data in Chinese population are limited. In this study, we present a WGS study for 334 individuals, including 112 ASD patients and their non-ASD parents. We identified 146
de novo
variants in coding regions in 85 cases and 60 inherited variants in coding regions. By integrating these variants with an association model, we identified 33 potential risk genes (
P |
| doi_str_mv | 10.1007/s11427-023-2564-8 |
| format | article |
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de novo
variants in coding regions in 85 cases and 60 inherited variants in coding regions. By integrating these variants with an association model, we identified 33 potential risk genes (
P
<0.001) enriched in neuron and regulation related biological process. Besides the well-known ASD genes (
SCN2A, NF1, SHANK3, CHD8
etc.), several high confidence genes were highlighted by a series of functional analyses, including
CTNND1, DGKZ, LRP1, DDN, ZNF483, NR4A2, SMAD6, INTS1
, and
MRPL12
, with more supported evidence from GO enrichment, expression and network analysis. We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression. We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype. Regarding variants in non-coding regions, a total of 74
de novo
variants and 30 inherited variants were predicted as pathogenic with high confidence, which were mapped to specific genes or regulatory features. The number of
de novo
variants found in patient was significantly associated with the parents’ ages at the birth of the child, and gender with trend. We also identified small
de novo
structural variants in ASD trios. The results in this study provided important evidence for understanding the genetic mechanism of ASD.</description><identifier>ISSN: 1674-7305</identifier><identifier>ISSN: 1869-1889</identifier><identifier>EISSN: 1869-1889</identifier><identifier>DOI: 10.1007/s11427-023-2564-8</identifier><identifier>PMID: 39126614</identifier><language>eng</language><publisher>Beijing: Science China Press</publisher><subject>Biomedical and Life Sciences ; Life Sciences ; Research Paper</subject><ispartof>Science China. Life sciences, 2024-11, Vol.67 (11), p.2368-2381</ispartof><rights>Science China Press 2024</rights><rights>2024. Science China Press.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c226t-3563f4f7f04f09af321e4ed2c419a44234004ce91384f9ad8c1ba3e9ad5340fe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39126614$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chang, Suhua</creatorcontrib><creatorcontrib>Liu, Jia Jia</creatorcontrib><creatorcontrib>Zhao, Yilu</creatorcontrib><creatorcontrib>Pang, Tao</creatorcontrib><creatorcontrib>Zheng, Xiangyu</creatorcontrib><creatorcontrib>Song, Zhirui</creatorcontrib><creatorcontrib>Zhang, Anyi</creatorcontrib><creatorcontrib>Gao, Xuping</creatorcontrib><creatorcontrib>Luo, Lingxue</creatorcontrib><creatorcontrib>Guo, Yanqing</creatorcontrib><creatorcontrib>Liu, Jing</creatorcontrib><creatorcontrib>Yang, Li</creatorcontrib><creatorcontrib>Lu, Lin</creatorcontrib><title>Whole-genome sequencing identifies novel genes for autism in Chinese trios</title><title>Science China. Life sciences</title><addtitle>Sci. China Life Sci</addtitle><addtitle>Sci China Life Sci</addtitle><description>Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heritability but heterogeneity. Fully understanding its genetics requires whole-genome sequencing (WGS), but the ASD studies utilizing WGS data in Chinese population are limited. In this study, we present a WGS study for 334 individuals, including 112 ASD patients and their non-ASD parents. We identified 146
de novo
variants in coding regions in 85 cases and 60 inherited variants in coding regions. By integrating these variants with an association model, we identified 33 potential risk genes (
P
<0.001) enriched in neuron and regulation related biological process. Besides the well-known ASD genes (
SCN2A, NF1, SHANK3, CHD8
etc.), several high confidence genes were highlighted by a series of functional analyses, including
CTNND1, DGKZ, LRP1, DDN, ZNF483, NR4A2, SMAD6, INTS1
, and
MRPL12
, with more supported evidence from GO enrichment, expression and network analysis. We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression. We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype. Regarding variants in non-coding regions, a total of 74
de novo
variants and 30 inherited variants were predicted as pathogenic with high confidence, which were mapped to specific genes or regulatory features. The number of
de novo
variants found in patient was significantly associated with the parents’ ages at the birth of the child, and gender with trend. We also identified small
de novo
structural variants in ASD trios. The results in this study provided important evidence for understanding the genetic mechanism of ASD.</description><subject>Biomedical and Life Sciences</subject><subject>Life Sciences</subject><subject>Research Paper</subject><issn>1674-7305</issn><issn>1869-1889</issn><issn>1869-1889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9kE1LAzEQhoMottT-AC-yRy_RfO3XUYqfFLwoHkO6O2lTdpOa7Ar-e6e0enQu85J55yXzEHLJ2Q1nrLxNnCtRUiYkFXmhaHVCprwqasqrqj5FXZSKlpLlEzJPacuwpGSiLM_JRNZcFAVXU_LysQkd0DX40EOW4HME3zi_zlwLfnDWQcp8-IIuQwtqG2JmxsGlPnM-W2wcPkI2RBfSBTmzpkswP_YZeX-4f1s80eXr4_PibkkbIYqByryQVtnSMmVZbawUHBS0olG8NkoJqRhTDdRcVsrWpq0avjISUOU4siBn5PqQu4sBv5sG3bvUQNcZD2FMWjK8DkEIiVZ-sDYxpBTB6l10vYnfmjO9p6gPFDVS1HuKusKdq2P8uOqh_dv4ZYYGcTAkHPk1RL0NY_R48j-pP4npfHM</recordid><startdate>20241101</startdate><enddate>20241101</enddate><creator>Chang, Suhua</creator><creator>Liu, Jia Jia</creator><creator>Zhao, Yilu</creator><creator>Pang, Tao</creator><creator>Zheng, Xiangyu</creator><creator>Song, Zhirui</creator><creator>Zhang, Anyi</creator><creator>Gao, Xuping</creator><creator>Luo, Lingxue</creator><creator>Guo, Yanqing</creator><creator>Liu, Jing</creator><creator>Yang, Li</creator><creator>Lu, Lin</creator><general>Science China Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20241101</creationdate><title>Whole-genome sequencing identifies novel genes for autism in Chinese trios</title><author>Chang, Suhua ; Liu, Jia Jia ; Zhao, Yilu ; Pang, Tao ; Zheng, Xiangyu ; Song, Zhirui ; Zhang, Anyi ; Gao, Xuping ; Luo, Lingxue ; Guo, Yanqing ; Liu, Jing ; Yang, Li ; Lu, Lin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c226t-3563f4f7f04f09af321e4ed2c419a44234004ce91384f9ad8c1ba3e9ad5340fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Biomedical and Life Sciences</topic><topic>Life Sciences</topic><topic>Research Paper</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chang, Suhua</creatorcontrib><creatorcontrib>Liu, Jia Jia</creatorcontrib><creatorcontrib>Zhao, Yilu</creatorcontrib><creatorcontrib>Pang, Tao</creatorcontrib><creatorcontrib>Zheng, Xiangyu</creatorcontrib><creatorcontrib>Song, Zhirui</creatorcontrib><creatorcontrib>Zhang, Anyi</creatorcontrib><creatorcontrib>Gao, Xuping</creatorcontrib><creatorcontrib>Luo, Lingxue</creatorcontrib><creatorcontrib>Guo, Yanqing</creatorcontrib><creatorcontrib>Liu, Jing</creatorcontrib><creatorcontrib>Yang, Li</creatorcontrib><creatorcontrib>Lu, Lin</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Science China. Life sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chang, Suhua</au><au>Liu, Jia Jia</au><au>Zhao, Yilu</au><au>Pang, Tao</au><au>Zheng, Xiangyu</au><au>Song, Zhirui</au><au>Zhang, Anyi</au><au>Gao, Xuping</au><au>Luo, Lingxue</au><au>Guo, Yanqing</au><au>Liu, Jing</au><au>Yang, Li</au><au>Lu, Lin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Whole-genome sequencing identifies novel genes for autism in Chinese trios</atitle><jtitle>Science China. Life sciences</jtitle><stitle>Sci. China Life Sci</stitle><addtitle>Sci China Life Sci</addtitle><date>2024-11-01</date><risdate>2024</risdate><volume>67</volume><issue>11</issue><spage>2368</spage><epage>2381</epage><pages>2368-2381</pages><issn>1674-7305</issn><issn>1869-1889</issn><eissn>1869-1889</eissn><abstract>Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heritability but heterogeneity. Fully understanding its genetics requires whole-genome sequencing (WGS), but the ASD studies utilizing WGS data in Chinese population are limited. In this study, we present a WGS study for 334 individuals, including 112 ASD patients and their non-ASD parents. We identified 146
de novo
variants in coding regions in 85 cases and 60 inherited variants in coding regions. By integrating these variants with an association model, we identified 33 potential risk genes (
P
<0.001) enriched in neuron and regulation related biological process. Besides the well-known ASD genes (
SCN2A, NF1, SHANK3, CHD8
etc.), several high confidence genes were highlighted by a series of functional analyses, including
CTNND1, DGKZ, LRP1, DDN, ZNF483, NR4A2, SMAD6, INTS1
, and
MRPL12
, with more supported evidence from GO enrichment, expression and network analysis. We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression. We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype. Regarding variants in non-coding regions, a total of 74
de novo
variants and 30 inherited variants were predicted as pathogenic with high confidence, which were mapped to specific genes or regulatory features. The number of
de novo
variants found in patient was significantly associated with the parents’ ages at the birth of the child, and gender with trend. We also identified small
de novo
structural variants in ASD trios. The results in this study provided important evidence for understanding the genetic mechanism of ASD.</abstract><cop>Beijing</cop><pub>Science China Press</pub><pmid>39126614</pmid><doi>10.1007/s11427-023-2564-8</doi><tpages>14</tpages></addata></record> |
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| title | Whole-genome sequencing identifies novel genes for autism in Chinese trios |
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