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Objective: Rising evidence has indicated that long non-coding RNA (lncRNA) may play an essential role in the development of autism spectrum disorder (ASD). However, identifying the lncRNAs associated with ASD and the risk loci on them remains a major challenge. This study aims to identify potential causative variants and explore the related mechanisms., Methods: By leveraging differential expression analysis, WGCNA analysis and cis-expression quantitative analysis, our study mined functional SNPs with the regulated long non-coding RNA genes in brain tissues. We recruited 611 ASD children and 645 healthy children in the case-control study., Results: Total 68 different expressed lncRNAs were validated by calculating the brain tissue-specific expression using RNA-seq data. By the WGCNA method, 9 functional lncRNAs classified as e-lncRNA were found to interact with 976 ASD risk genes. Furthermore, we mined functional SNPs regulated long non-coding RNAs in brain tissues. We analyzed the association between candidate SNPs and ASD risks in Chinese children, which showed BDNF-AS rs1565228 allele G to C reduced the risk of ASD (OR = 0.81, 95%CI: 0.66-0.98). Further bioinformatics analysis showed that the variant rs1565228 C>G with the low binding affinity of transcription factor SRF caused the decreased expression of lncRNA BDNF-AS. Our study revealed that rs2295412 in the non-coding sequence of the lncRNA gene region was significantly associated with the risk of ASD., Discussion: These findings suggested that the SNPs in the non-coding region of lncRNA may play important roles in the genetic susceptibility of ASD, which may facilitate the early screening of ASD., Competing Interests: Competing Interests The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) is associated with altered gut microbiota. However, there has been little consensus on the altered bacterial species and studies have had small sample sizes. We aimed to identify the taxonomic composition and evaluate the changes in the fecal microbiota in Chinese children with ASD by using a relatively large sample size. We conducted a case-control study of 101 children with ASD and 103 healthy controls in China. Demographic information and fecal samples were collected, and the V3-V4 hypervariable regions of the bacterial 16S ribosomal RNA (rRNA) gene were sequenced. The alpha and beta diversities between the two groups were significantly different. After correcting for multiple comparisons, at the phylum level the relative abundances of Actinobacteria and Proteobacteria in the case group were significantly higher than those in the control group. The relative abundance of the Escherichia-Shigella genus in the case group was significantly higher than that of the control group, and the relative abundance of Blautia and unclassified_f__Lachnospiraceae in the control group were higher than that of the case group. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis showed that children with ASD may have disturbed functional pathways, such as amino acid metabolism, cofactor and vitamin metabolism, and the AMP-activated protein kinase signaling pathway. This study revealed the characteristics of the intestinal flora of Chinese children with ASD and provided further evidence of gut microbial dysbiosis in ASD. LAY SUMMARY: This study characterized the gut microbiota composition of 101 children with ASD and 103 healthy controls in China. The altered gut microbiota may contribute significantly to the risk of ASD, including significant increases in the relative abundances of Actinobacteria, Proteobacteria and Escherichia-Shigella and significant decrease of Blautia and unclassified_f__Lachnospiraceae. This study provided further evidence of gut microbial dysbiosis in ASD., (© 2022 International Society for Autism Research and Wiley Periodicals LLC.)

Although recent genome-wide association studies have identified risk loci that strongly associates with autism spectrum disorder (ASD), how to pinpoint the causal genes remains a challenge. We aimed to pinpoint the potential causal genes and explore the possible susceptibility and mechanism. A convergent functional genomics (CFG) method was used to prioritize the candidate genes by combining lines of evidence, including Sherlock analysis, spatio-temporal expression patterns, expression analysis, protein-protein interactions, co-expression and association with brain structure. A higher score in the CFG approach suggested that more evidence supported this gene as an ASD risk gene. We screened genes with higher CFG scores for candidate functional single nucleotide polymorphisms (SNPs). A genotyping experiment (602 ASD children and 604 healthy sex-matched children) and the dual-luciferase reporter gene assay were followed to validate the effects of SNPs. We identified three genes (MAPT, ZNF285, and TIGD5) as candidate causal genes using the CFG approach. The genotyping experiment showed that TIGD5 rs75547282 was associated with an increased risk of ASD under the dominant model (OR = 1.37, 95% CI = 1.09-1.72, P = 0.006) though the statistical power was limited (5.2%). The T allele of rs75547282 activated the expression of TIGD5 compared with the C allele in the dual-luciferase reporter assay. Our study indicates that such comprehensive integrative analyses may be an effective way to explore promising ASD susceptibility variants and needs to be further investigated in future research. Genotyping experiments should, however, be based on a larger population sample to increase statistical power. LAY SUMMARY: We set out to pinpoint the potential causal genes of ASD and explore the possible susceptibility and mechanism by combining lines of evidence from different analyses. Our results show that TIGD5 rs75547282 is associated with the risk of ASD in the Han Chinese population. In addition, a similar framework to seek promising ASD risk variants could be further investigated in future research Autism Res 2021, 14: 631-644. © 2021 International Society for Autism Research and Wiley Periodicals LLC., (© 2021 International Society for Autism Research, Wiley Periodicals LLC.)

It is challenge to pinpoint the functional variants among numerous genetic variants. Investigating the spatial dynamics of the human brain transcriptome for genes and exploring the expression quantitative trait loci data may provide the potential direction to identify the functional variants among autism spectrum disorders (ASD) patients. In order to explore the association of ITIH3 with ASD, the present study included three components: identifying the spatial-temporal expression of ITIH3 in the developing human brain using the expression data from the Allen Institute for Brain Science; examining the cis-acting regulatory effect of SNPs on the ITIH3 expression using UK Brain Expression Consortium database; validating the effect of identified SNPs using a case-control study with samples of 602 cases and 604 controls. The public expression data showed that ITIH3 may have a role in the development of human brain and suggested a cis-eQTL effect for rs2535629 and rs3617 on ITIH3 in the hippocampus. Genetic analysis of the above two SNPs suggested that the over-dominant model of rs2535629 was significantly associated with decreased risk of ASD. Convergent lines of evidence supported ITIH3 rs25352629 as a susceptibility variant for ASD.

Autism spectrum disorder (ASD) is associated with altered gut microbiota. However, there has been little consensus on the altered bacterial species and studies have had small sample sizes. We aimed to identify the taxonomic composition and evaluate the changes in the fecal microbiota in Chinese children with ASD by using a relatively large sample size. We conducted a case–control study of 101 children with ASD and 103 healthy controls in China. Demographic information and fecal samples were collected, and the V3‐V4 hypervariable regions of the bacterial 16S ribosomal RNA (rRNA) gene were sequenced. The alpha and beta diversities between the two groups were significantly different. After correcting for multiple comparisons, at the phylum level the relative abundances of Actinobacteria and Proteobacteria in the case group were significantly higher than those in the control group. The relative abundance of the Escherichia‐Shigella genus in the case group was significantly higher than that of the control group, and the relative abundance of Blautia and unclassified_f__Lachnospiraceae in the control group were higher than that of the case group. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis showed that children with ASD may have disturbed functional pathways, such as amino acid metabolism, cofactor and vitamin metabolism, and the AMP‐activated protein kinase signaling pathway. This study revealed the characteristics of the intestinal flora of Chinese children with ASD and provided further evidence of gut microbial dysbiosis in ASD. Lay Summary: This study characterized the gut microbiota composition of 101 children with ASD and 103 healthy controls in China. The altered gut microbiota may contribute significantly to the risk of ASD, including significant increases in the relative abundances of Actinobacteria, Proteobacteria and Escherichia‐Shigella and significant decrease of Blautia and unclassified_f__Lachnospiraceae. This study provided further evidence of gut microbial dysbiosis in ASD. [ABSTRACT FROM AUTHOR]

Although recent genome‐wide association studies have identified risk loci that strongly associates with autism spectrum disorder (ASD), how to pinpoint the causal genes remains a challenge. We aimed to pinpoint the potential causal genes and explore the possible susceptibility and mechanism. A convergent functional genomics (CFG) method was used to prioritize the candidate genes by combining lines of evidence, including Sherlock analysis, spatio‐temporal expression patterns, expression analysis, protein–protein interactions, co‐expression and association with brain structure. A higher score in the CFG approach suggested that more evidence supported this gene as an ASD risk gene. We screened genes with higher CFG scores for candidate functional single nucleotide polymorphisms (SNPs). A genotyping experiment (602 ASD children and 604 healthy sex‐matched children) and the dual‐luciferase reporter gene assay were followed to validate the effects of SNPs. We identified three genes (MAPT, ZNF285, and TIGD5) as candidate causal genes using the CFG approach. The genotyping experiment showed that TIGD5 rs75547282 was associated with an increased risk of ASD under the dominant model (OR = 1.37, 95% CI = 1.09–1.72, P = 0.006) though the statistical power was limited (5.2%). The T allele of rs75547282 activated the expression of TIGD5 compared with the C allele in the dual‐luciferase reporter assay. Our study indicates that such comprehensive integrative analyses may be an effective way to explore promising ASD susceptibility variants and needs to be further investigated in future research. Genotyping experiments should, however, be based on a larger population sample to increase statistical power. Lay Summary: We set out to pinpoint the potential causal genes of ASD and explore the possible susceptibility and mechanism by combining lines of evidence from different analyses. Our results show that TIGD5 rs75547282 is associated with the risk of ASD in the Han Chinese population. In addition, a similar framework to seek promising ASD risk variants could be further investigated in future research Autism Res 2021, 14: 631–644. © 2021 International Society for Autism Research and Wiley Periodicals LLC [ABSTRACT FROM AUTHOR]

The intestinal dysbiosis can be observed in patients with autism spectrum disorder (ASD), partly explained by the alteration in gut microbiota composition. Our study aims to screen ASD causal variants and explore the potential interaction between variants and gut microbiota. We conducted the expression quantitative trait loci (eQTL) analysis to identify variations that regulated the expression of the ASD risk gene XRN2 , and then validated genetic susceptibility to ASD risk in the case-control study among 627 ASD children and 606 healthy controls. The fecal samples were analyzed by 16S rRNA sequencing. Logistic regression model analysis was conducted to examine the interaction. We identified that rs2295412 was a cis-eQTL of XRN2 in brain tissues (P < 0.0005), And individuals with rs2295412 TC genotypes had decreased ASD risks compared to the TT genotype (OR = 0.42, 95 % CI: 0.19–0.94, P = 0.036). And rs2295412 genotypes and the abundance of f__Monoglobaceae showed the interaction on the ASD risks (P mul = 0.049). Compared to the children with a higher abundance of f__Monoglobaceae and rs2295412 CT+CC genotype, the children with a lower abundance and TT genotype might have higher ASD risks. These findings suggested the potential interaction between genetic variation and gut microbiota on ASD risks, which enhanced the understanding of pathogenic mechanisms and the underlying etiology of ASD, and provided clues for future investigations. • This study identified the XRN2 mutation in ASD GWAS region and predicted the possible function. • This study found that there was an interaction between XRN2 mutation and gut microbiota on ASD risks. • This study enhanced the understanding of pathogenic mechanisms and the underlying ASD etiology. [ABSTRACT FROM AUTHOR]