Firstly, there is a great phenotypic heterogeneity within autism spectrum disorders, which has led to question their classification into a single diagnostic category64. PubMed The main strength of this study is the integration of independent data sets, across distinct biological levels, that include cortex-specific 3D genome structure, eQTL and PPI data with ASD-associated GWAS SNPs. Transcript levels for these genes are associated with 65 eQTLs in fetal cortex and 39 eQTLs in adult cortex (Supplementary Table 3). Proteins that were not annotated in the expression datasets were also removed from the CSPPI network. Neuron 83, 518532 (2014). By contrast, the rs3129968 minor allele is associated with a reduction in transcript levels for HLA-DRB1, which is expressed at low levels (TPM<1.25) within fetal cortex. Within-family IDs were used as sample IDs in the output vcf file (recode vcf-iid bgz). cortical plate and germinal zone neurons)19 and one adult cortex-specific (i.e. In total, 663,956 variants passed QC filters. cerebellum68) or non-brain regions implicated in ASD may identify additional candidate genes. Nature 538, 523527 (2016). Google Scholar. 4). 42, 399403 (2017). Article Aguet, F. et al. Huang C, Guo Y, Li W, Xiang B, Zeng J, Zhou F, She L, Zhang P, Wang S, Liu B, Dai Q, Yang M. BMJ Open Diabetes Res Care. https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. Despite the existence of 15 genes in eQTL with ASD-associated SNPs in both fetal and adult cortical tissues, the majority of the changes in gene transcript levels were specific to either fetal (n=66), or adult (n=29) cortical tissue (Fig. Fadason, T., Schierding, W., Lumley, T. & OSullivan, J. M. Chromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities. genes, whose expression levels are associated with a SNP). Eur. Roles for immune dysfunction in ASD etiology are increasingly being identified57,58,59. Finally, protein identifiers (STRING)33 and transcript identifiers (GTEx and Walker et al. However, the remaining 15 eQTLs are associated with different eGenes in adult and fetal cortical tissues (Supplementary Table 4). Nat. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database34 was used to query the most impacted biological pathways. 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). Science 337, 11901195 (2012). Five genes within this cluster (i.e. Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. RNA-seq data)20,21 were mapped to gene identifiers, thus there was a potential loss of data specificity, since genes typically produce multiple transcripts and protein variants due to alternative splicing. PubMed PubMed bioRxiv https://doi.org/10.1101/787903 (2019). Recall that the DNA sequence is formed from a chain of . Functional gene ontology enrichment analysis identified immune-related processes (e.g. Karczewski, K. J. et al. The results of our study should be interpreted in view of its strengths and limitations. Genet. Genet. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. Rev. Introduction. Using proteinprotein interaction (PPI) networks to explore interactions between proteins encoded by known disease-associated genes is a powerful approach to study the etiology of complex diseases, including psychiatric disorders17,18. How do SNPs occur? Notably, we found that ASD-eQTL associated changes in transcript levels occurred in adult cortex immune pathways that were associated with processing of exogenous antigen. SNP selection and data report Nucleic Acids Res. Mountjoy, E. et al. By contrast, the ASD-eQTL associations within the fetal cortex PPI fatty acid metabolism and spliceosome clusters are less complex (decreases: FADS1, TBL1X, SF3B1, or increases: FADS2, DHX38 and THOC7; Fig. Interestingly, most of the genes within immune-related pathways in fetal cortex are associated with Polycomb-repressed ASD-eQTLs. spliceosome and splicing, aminoacyl-tRNA biosynthesis, and ribosome biogenesis) in the fetal cortex. Science 342, 253257 (2013). Edges are only present if both interacting proteins are expressed in the cortical tissue. Numerous genome-wide eQTL analyses have been reported to comprehensively capture such a DNA-RNA (i.e . & Paro, R. Transcriptional silencing by polycomb-group proteins. 3). Please enable it to take advantage of the complete set of features! Notably, the significant difference (p=0.04531) in numbers of fetal cortical eQTLs, when compared to adult cortical eQTLs is consistent with a developmental origin for ASD risk. Mol. How could SNPs contribute to gene regulation quizlet? In this manuscript we integrated data on cortex-specific spatial chromatin interactions (i.e. By contrast, immune-related genes that are associated with ASD-eQTLs within the fetal cortex have been implicated in the processing of both endogenous and exogenous antigens (Supplementary Table 7). CAS Dysregulation of fatty acid metabolism in early brain development may be a risk factor or marker for early-onset of ASD48. Eleven genes (i.e. Thank you for visiting nature.com. Science 353, 772777 (2016). Genet. enhancer reporter assays); (b) confirm that the Polycomb complexes are responsible for the observed activity (e.g. The author declares no competing interests. dorsolateral prefrontal cortex cells)12 Hi-C chromatin interaction libraries (Supplementary Table 1). 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. Both HLA-DQB1 and HLA-DMA are examples of the MHC class II genes that are associated with processing of exogenous antigen. This network illustrates potential evidence for gene regulation related to RA-associated SNPs, and may provide comprehensive information for subsequent functional analyses and experiments. Trials 18, 131 (2017). J Hum Genet. Physiol. Desai, D. & Pethe, P. Polycomb repressive complex 1: Regulators of neurogenesis from embryonic to adult stage. Schmitt, A. D. et al. Gentile, C. et al. HLA-C and HLA-F; associated with endogenous antigen processing) and MHC class II (i.e. Integrating datasets across biological levels enables us to predict how genetic variation impacts on biological pathways and their involvement in the etiology of ASD. 2c). Cell 50, 184-196.e4 (2019). Briefly, read counts were normalised using the TMM algorithm and genes were selected if they had counts of 0.1 TPM in 20% samples and 6 unnormalized reads in 20% samples. 22, 345361 (2016). Our findings highlight potential mechanisms through which ASD-associated variants potentially contribute to ASD development (fetal) and onset/maintenance (adult). eCollection 2022. Motor cortex facilitation: A marker of attention deficit hyperactivity disorder co-occurrence in autism spectrum disorder. cortical plate and germinal zone neurons), or adult (i.e. Future analyses that incorporate horizontal analyses of all genetic variants associated with ASD and its high-frequency multimorbid conditions will improve our ability to stratify autistic individuals and manage their complications. von Schimmelmann, M. et al. Gazal, S. et al. 3). 2008 Sep 11;128(17):1951-5. Thus, integrating biological measurements on developmental and tissue-specific spatial chromatin interactions with eQTL information could inform our understanding of the regulatory impacts of ASD-associated SNPs. Provided by the Springer Nature SharedIt content-sharing initiative, Advances in Neurodevelopmental Disorders (2022). A SNP is a one-letter place where your genome varies from another genome sequence. Furthermore, despite not having discussed them in detail, there are number of genes whose transcript levels are affected by ASD-eQTLs whose functions were not enriched within known pathways. Lastly, tensorQTL (https://github.com/broadinstitute/tensorqtl) algorithm was used to perform cis- and trans-QTL mapping. A single nucleotide polymorphism, or SNP (pronounced "snip"), is a variation at a single position in a DNA sequence among individuals. Genet. a, CWAS identify epigenomic features that are genetically associated with a trait. ASD-eQTLs were also associated with increases in HCG27 (TPM=3) and NDUFA6 (TPM=116.31) transcript levels within fetal cortex. Over the past decade, genome-wide association (GWAS) and genetic studies have identified increasing numbers of single nucleotide polymorphisms (SNPs)3,4 and other forms of variation (e.g., copy number variants, rare structural variants)5,6 that are associated with ASD. Aranda, S., Mas, G. & Di Croce, L. Regulation of gene transcription by Polycomb proteins. Diagnostic and Statistical Manual of Mental Disorders (DSM-5 (R)) (American Psychiatric Association Publishing, 2013). 2b). Husson, T. et al. 11, 27 (2017). Finally, our approach focuses on identifying changes in gene regulation that are associated with and may contribute to ASD. Python (version 3.6.9), R (version 4.0.2) and RStudio (version 1.2.5033) were used for data analysis and visualisation. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nancy Y. Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex, $$p\;value = \frac{\sum (bootstrapped \ge observed)}{n}$$, https://doi.org/10.1038/s41598-021-95447-z. Breastfeed. 86, 885898 (2019). These spatial interactions are dynamic, developmentally and temporally dependent13. Genet. The transcript levels of the genes within the two unknown adult cortex PPI clusters increased (i.e. Slider with three articles shown per slide. How could SNPs contribute to gene regulation? Chang, X. Hi-C libraries) and cortex-specific eQTLs to identify how ASD-associated SNPs impact cortex-specific gene expression. Previous research has reported shared neurobiological and cellular processes associated with differences in cortical thickness across six psychiatric disorders (i.e. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. These mechanisms are not limited to impacts on gene regulation and can affect the splicing activity (so called sQTL SNPs35), or trans-acting factors (e.g. Book eGene enrichment was tested within the biological process, molecular function and cellular component GO terms. 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. TYW5, FTCDNL1, and RTN1) whose transcript levels decrease with the ASD-eQTL and NDRG4, whose transcript levels increase or decrease dependent upon the ASD-eQTL. Cortical and subcortical brain morphometry differences between patients with autism spectrum disorder and healthy individuals across the lifespan: Results from the ENIGMA ASD Working Group. Polycomb proteins are known to be involved in transcriptional silencing43,44. Genome Res. When SNPs occur within a gene or in a regulatory region near a gene, they often play a more direct role in the disease by affecting the function of the gene, either causing it to make a protein that works too well, or has less activity than normal, or completely stops its production. The fetal immune PPI cluster contains both MHC class I (i.e. ASD, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, unipolar depression, obsessivecompulsive disorder and schizophrenia), implicating common mechanisms underlying cortical development24. associated with an increase or reduction in transcript levels; Supplementary Fig. & Wang, K. wANNOVAR: Annotating genetic variants for personal genomes via the web. Finally a number of fetal (n=50) and adult (n=28) cortex-specific eQTLs were observed (Supplementary Table 3). The existence of changes within fetal cortex pathways for endogenous antigens (e.g. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Drug Metab Dispos. Gene Ontology (GO) enrichment and pathways analyses for the eGenes within the ASD-specific CSPPI clusters were performed using the g:GOSt module of the g:Profiler tool81. The SNPs located in enhancer elements may affect gene expression and lead to disease. You'll get a detailed solution from a subject matter expert that helps you learn core concepts. HHS Vulnerability Disclosure, Help 78, 4763 (2021). The SNP2TFBS27 database was queried to identify eQTLs that are predicted to alter the affinity of transcription factor binding sites (TFBSs). To create a lookup table, genetic variants were annotated with rsIDs from dbSNP build 151 database. van Arensbergen, J. et al. Genet. Child Psychol. 3). Most commonly, SNPs are found in the DNA between genes. 370, 12091219 (2014). Therefore, characterizing the functional impacts (i.e. Accessibility Cell 179, 750-771.e22 (2019). and co-wrote the manuscript. SNPs may change the encoded amino acids (nonsynonymous) or can be silent (synonymous) or simply occur in the noncoding regions. Adult PPIs form three modules that were enriched in immune pathways and two unknown modules. ISSN 2045-2322 (online). The butyrophilin genes encode proteins that belong to the immunoglobulin superfamily and help modulate the immune system23. Internet Explorer). Chromosome conformation elucidates regulatory relationships in developing human brain. This observation is consistent with: (1) a comorbid association between ASD and schizophrenia25; or (2) a lack of resolution and precision in defining the ASD and schizophrenia phenotypes, and thus possible false positives in GWASs26. Therefore, with appropriate pre-natal genetic diagnosis of risk and patient stratification, it remains possible that targeted lipid supplementation could reduce the risk of ASD. Genetic variants were filtered based on HardyWeinberg equilibrium p<1106, minor allele frequency 0.01 and variant missing genotype rate 0.05. However, in noncoding regions, the mechanism of how SNPs contribute to disease susceptibility remains unclear. CAS and C.W. Unauthorized use of these marks is strictly prohibited. Genet. antigen processing and presentation), protein kinase C signalling and regulation of cellcell adhesion processes (Supplementary Table 8). Fetal and adult cortical tissue-specific PPI networks with immune and growth related phenotypes are affected by ASD-associated eQTLs. Article Boyle, E. A., Li, Y. I. 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 By submitting a comment you agree to abide by our Terms and Community Guidelines. SNPs are located in gene promoters, exons, introns as well as 5'- and 3'- untranslated regions (UTRs) and affect gene expression by different mechanisms. PubMed Maurano, M. T. et al. 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. Cardiovasc. dorsolateral prefrontal cortex cells) cortex-specific Hi-C libraries. Autism 3, 9 (2012). 45, 12381243 (2013). Disord.
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