Whole-genome sequencing identifies novel genes for autism in Chinese trios  

作　　者：Suhua Chang Jia Jia Liu Yilu Zhao Tao Pang Xiangyu Zheng Zhirui Song Anyi Zhang Xuping Gao Lingxue Luo Yanqing Guo Jing Liu Li Yang Lin Lu 

机构地区：[1]Peking University Sixth Hospital,Peking University Institute of Mental Health,NHC Key Laboratory of Mental Health(Peking University),National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital),Beijing 100191,China [2]Chinese Academy of Medical Sciences Research Unit(No.2018RU006),Peking University,Beijing 100191,China [3]School of Nursing,Peking University,Beijing 100191,China [4]Wuhan Biobank,Wuhan 430075,China [5]National Institute on Drug Dependence,Peking University,Beijing 100191,China

出　　处：《Science China(Life Sciences)》2024年第11期2368-2381,共14页中国科学（生命科学英文版）

基　　金：supported by the National Program for Brain Science and Brain-like Intelligence Technology of China (2021ZD0200800);Beijing Municipal Science and Technology Commission (Z181100001518005);the National Natural Science Foundation of China (31401139, 32170613, 81671358, 81873803);the Natural Science Foundation of Beijing Municipality (7232225)

摘　　要：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 noncoding 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.

关 键 词：AUTISM whole-genome sequencing de novo variants inherited variants SNV structural variants 

分 类 号：R749.94[医药卫生—神经病学与精神病学]