DataSheet_1_Target Genes of Autism Risk Loci in Brain Frontal Cortex.pdf

Autism spectrum disorder (ASD) is a complex neuropsychiatric disorder. A number of genetic risk loci have been identified for ASD from genome-wide association studies (GWAS); however, their target genes in relevant tissues and cell types remain to be investigated. The frontal cortex is a key region in the human brain for communication and cognitive function. To identify risk genes contributing to potential dysfunction in the frontal cortex of ASD patients, we took an in silico approach integrating multi-omics data. We first found genes with expression in frontal cortex tissue that correlates with ASD risk loci by leveraging expression quantitative trait loci (eQTLs) information. Among these genes, we then identified 76 genes showing significant differential expression in the frontal cortex between ASD cases and controls in microarray datasets and further replicated four genes with RNA-seq data. Among the ASD GWAS single nucleotide polymorphisms (SNPs) correlating with the 76 genes, 20 overlap with histone marks and 40 are associated with gene methylation level. Thus, through multi-omics data analyses, we identified genes that may work as target genes of ASD risk loci in the brain frontal cortex.

自闭症谱系障碍（ASD）是一种复杂的神经精神疾病。通过全基因组关联研究（GWAS），已鉴定出多个与ASD相关的遗传风险位点；然而，这些位点在相关组织与细胞类型中的靶基因尚未得到充分研究。额叶皮层是人类大脑中负责沟通与认知功能的关键区域。为识别导致自闭症谱系障碍患者额叶皮层潜在功能障碍的风险基因，我们采用了一种整合多组学数据的计算机模拟方法。首先，我们利用表达数量性状位点（eQTLs）信息，发现了在额叶皮层组织中表达且与ASD风险位点相关的基因。在这些基因中，我们进一步在微阵列数据集中确定了76个基因，其在自闭症病例与对照组的额叶皮层中表现出显著差异表达，并通过RNA-seq数据进一步验证了其中四个基因。在ASD GWAS的单核苷酸多态性（SNPs）中，与这76个基因相关联的有20个与组蛋白标记重叠，40个与基因甲基化水平相关。因此，通过多组学数据分析，我们鉴定出可能在脑额叶皮层中作为ASD风险位点靶基因的基因。