STRING v11: Proteinprotein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. FOIA Estes, M. L. & McAllister, A. K. Maternal immune activation: Implications for neuropsychiatric disorders. 57, 580594 (2015). Collectively, these observations are consistent with changes in the regulation of subsets of stable and remodelled spatial eQTLs, over the course of brain development, being associated with a predisposition to ASD. By contrast, in the adult cortex they largely affect immune pathways. Article Bauer, D. E. et al. There is no fundamental reason why the same regulatory elements must or must not impact on the same gene in different tissues, or at different stages of development. These simple changes can be of transition or transversion type and they occur throughout the genome at a frequency of about one in 1,000 bp. Moreover, this approach is not tissue or disease specific and is capable of identifying previously unknown tissue-specific contributions to ASD etiology and its interactions with multimorbid conditions. Nasser, J. et al. Single nucleotide polymorphisms (SNPs) are one of the most common types of genetic variations in the human genome. There are studies connecting cortical dysfunctions and ASD using imaging14, cortical architecture15, or gene expression16. 3, 9598 (2016). Tissue-wide cell-specific proteogenomic modeling reveals novel candidate risk genes in autism spectrum disorders, Integrative analyses indicate an association between ITIH3 polymorphisms with autism spectrum disorder, A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles, Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks, Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism, Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD, Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes, Rare coding variants as risk modifiers of the 22q11.2 deletion implicate postnatal cortical development in syndromic schizophrenia, Convergent and distributed effects of the 3q29 deletion on the human neural transcriptome, http://autism.mindspec.org/autdb/Welcome.do, https://github.com/broadinstitute/gtex-pipeline/tree/master/rnaseq, https://github.com/broadinstitute/gtex-pipeline/tree/master/qtl, https://github.com/broadinstitute/gtex-pipeline/tree/master/genotype, https://www.well.ox.ac.uk/~wrayner/strand/, ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/technical/reference/, https://github.com/broadinstitute/tensorqtl, https://egg2.wustl.edu/roadmap/data/byFileType/chromhmmSegmentations/ChmmModels/coreMarks/jointModel/final/, https://github.com/Genome3d/genetic_regulation_in_ASD, https://doi.org/10.1038/s41380-020-0773-x, http://creativecommons.org/licenses/by/4.0/, Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism, The tRNA regulome in neurodevelopmental and neuropsychiatric disease, Investigation of Genetic Polymorphism in Autism Spectrum Disorder: a Pathogenesis of the Neurodevelopmental Disorder, Cancel Provided by the Springer Nature SharedIt content-sharing initiative, Nature Genetics (Nat Genet) Of 454 ASD-associated SNPs, 344 SNPs were represented in both fetal and adult cortex eQTL databases, and were run through the CoDeS3D pipeline (Fig. Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. A. Sey, Benxia Hu, Hyejung Won, Anja Barei, Alexander Jolyon Nash, Boris Lenhard, Gokul Ramaswami, Hyejung Won, Daniel H. Geschwind, Michael J. Gandal, Jillian R. Haney, Daniel H. Geschwind, Mirolyuba Ilieva, Blanca Irene Aldana, Tanja Maria Michel, Jhih-Rong Lin, Yingjie Zhao, Zhengdong D. Zhang, Esra Sefik, Ryan H. Purcell, Jennifer G. Mulle, Scientific Reports SNP selection and data report Vannucchi, G., Perugi, G. & Masi, G. Bipolar disorder and ASD. As eQTL patterns are tissue-specific, we are unable to extrapolate the results of this study to these tissues. Genet. Collectively, our results provide insight into potential cortex-specific regulatory mechanisms and pathways through which ASD-associated SNPs can contribute to the development and maintenance of ASD. As such, the genes we identified need not directly overlap those that have been previously curated as being involved in ASD through deletion or mutation studies. MeSH Five genes within this cluster (i.e. Porokhovnik, L. Individual copy number of ribosomal genes as a factor of mental retardation and autism risk and severity. and C.W. Physiol. 51, 11601169 (2019). 48, 552555 (2016). dorsolateral prefrontal cortex cells) cortex-specific Hi-C libraries. Our results support a dual role for Polycombas both a repressor and enhancer of transcriptionin the development of ASD risk. This will revolutionize the medical field in the future. Gao Z, Liang Y, Wang Y, Xiao Y, Chen J, Yang X, Shi T. Front Plant Sci. Raw RNA-seq fastq files 20 were downloaded from dbGaP (05/06/2020), merged across lanes from the same sample (final dataset of 219 individuals) and analysed using FastQC (v0.11.9; default parameters). SNPs are located in different regions of genes such as promoters, exons, introns, and 5 and 3 untranslated regions (UTR) and may affect gene expression and regulation. Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: A systematic review. 8 from fetal cortex: DDHD2, HLA-DRB1, PCCB, PCDH15, SF3B1, SNX19, TBL1X, VWA7; and 7 from adult cortex: DDHD2, GALNT10, PBX1, PCCB, RERE, SF3B1, SNX19) had been previously linked to ASD (Fig. However, the remaining 15 eQTLs are associated with different eGenes in adult and fetal cortical tissues (Supplementary Table 4). The .gov means its official. This data-driven approach enables the discovery of SNPs whose alleles impact gene regulation by miRNAs, with functional consequences for tumor biology. https://doi.org/10.1038/s41588-022-01093-0. Disclaimer. 4). What are SNPs and Why Are They Important? - Gene Food Transl. Google Scholar. As we observed for other pathways, there was a developmental separation in the immune pathways that were affected in the fetal and adult cortical tissues. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. Science 342, 253257 (2013). de la Torre-Ubieta, L., Won, H., Stein, J. L. & Geschwind, D. H. Advancing the understanding of autism disease mechanisms through genetics. Google Scholar. 28, 2730 (2000). Cold Spring Harb. & Crawford, D. A. Abnormalities in lipid metabolism may affect the proper functioning of the nervous system and, thus can contribute to ASD etiology48,49,50. There are several reasons for this apparent discrepancy. ASD-associated eQTLs regulate 81 genes in fetal and 44 genes in adult cortical tissues (Fig. Briefly, merged fastq files were aligned to the GRCh38 reference genome (Homo_sapiens_assembly38_noALT_noHLA_noDecoy.fasta, gs://gtex-resources) using STAR (v2.5.3a). & Pritchard, J. K. Cell 169, 11771186 (2017). Cross-Disorder Group of the Psychiatric Genomics Consortium et al. 44, 60466054 (2016). regioneR: An R/Bioconductor package for the association analysis of genomic regions based on permutation tests. TAP1 and TAP2); (b) decreased (HLA-DQB1); or (c) both increased and decreased depending on specific ASD-eQTLs (HLA-DMA; Fig. 2009 Apr 15;18(R1):R9-17. Each SNP represents a difference in a single DNA building block, called a "nucleotide." For example, an SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA. Interacting fragments that overlapped annotated genes (GENCODE transcript model version 26) were subsequently identified (hereafter referred to as SNP-gene pairs). The site is secure. When SNPs are located near a gene, then it is postulated that the gene contributes to the variation under investigation. PubMed and co-wrote the manuscript. In order to study spatial regulatory interactions in fetal and adult cortical tissues, we analysed two fetal brain-specific (i.e. Google Scholar. Python (version 3.6.9), R (version 4.0.2) and RStudio (version 1.2.5033) were used for data analysis and visualisation. Tolerance to loss-of-function (LoF) variants was measured using the probability-of-being-LoF-intolerant (pLI) method and gene LoF metrics were obtained from gnomAD (v2.1.1, https://gnomad.broadinstitute.org/)32. viral) lends some support the hypothesis that the risk of ASD may be greater among children whose mothers suffered from infectious or immune-related diseases during pregnancywhen the infant brain is developing60,61,62,63. Common genetic variants, acting additively, are a major source of risk for autism. The proteinprotein interaction (PPIs) network serves as a foundation for cellular signalling circuitry, which mediates cellular responses to environmental and genetic cues. Therefore, identification of numerous variations in genes and analysis of their effects may lead to a better understanding of their impact on gene function and health of an individual. The Gene module within AutDB is a manually curated reference set of ASD-linked genes that was first released in 2007. The proportions of eQTL and non-eQTL SNPs are significantly different in fetal and adult cortical tissues (Fishers exact test, p=0.04531). von Schimmelmann, M. et al. Applications of computational tools to predict functional SNPs effects in human ErbB genes. As such, our results only represent snap-shots within the plastic neurodevelopmental trajectory69,70. These spatial interactions are dynamic, developmentally and temporally dependent13. Chromosome conformation elucidates regulatory relationships in developing human brain. 20, 467484 (2019). Here, we integrated four distinct levels of biological information (GWAS, eQTL, spatial genome organization and proteinprotein interactions) to identify potential regulatory impacts of ASD-associated SNPs (p<5108) on biological pathways within fetal and adult cortical tissues. Article The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Gandal, M. J. et al. RNA-seq data) were mapped to Ensembl gene identifiers. 86, 885898 (2019). Diagnostic and Statistical Manual of Mental Disorders (DSM-5 (R)) (American Psychiatric Association Publishing, 2013). The size of each node depends on the protein expression levels (no missing values and minimum expression level >0 TPM) in the corresponding cortical tissue.

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