The significance of these associations in the developing cortex and how they contribute to the etiology of ASD remains to be empirically determined. A SNP is a one-letter place where your genome varies from another genome sequence. However, we contend that these results are consistent with the growing evidence that the vertical approach to connecting genetic variation to phenotype does not adequately account for the multimorbid nature of conditions within the typical variation that is present in humans. Changes to genes within the immune-related processes within adult cortex mostly affect the processing of exogenous antigen. & Zhang, Z. Collectively, these findings are consistent with a subset of ASD-associated eQTLs acting in a combinatorial and development stage specific manner to affect the risk of developing ASD. Interacting fragments that overlapped annotated genes (GENCODE transcript model version 26) were subsequently identified (hereafter referred to as SNP-gene pairs). PMC We observed that schizophrenia has the largest significant overlap with ASD-associated eQTLs both in fetal (78 out of 80, bootstrapping p<0.01, n=10,000) and adult (57 out of 58, bootstrapping p<0.01, n=10,000) cortical tissues (Supplementary Fig. Future studies of the roles of these genes in ASD will be important for understanding the full impact of ASD-associated genetic variation in the cortex. Tamiji, J. Firstly, there was a significant enrichment of ASD-eQTLs within loci that are annotated as being regulated by PolyComb within the fetal, but not adult, cortex. https://doi.org/10.1038/s41588-022-01087-y (2022). These differences can underlie susceptibility to common diseases, human traits, and differential responses to drugs. Finucane, H. K. et al. 47, D1005D1012 (2019). Nasser, J. et al. In our study eQTL data represent composite datasets across critical periods of development (e.g. These mechanisms are not limited to impacts on gene regulation and can affect the splicing activity (so called sQTL SNPs 35), or trans-acting factors (e.g. 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. Here, we build on prior work to study a large set of anthropometric and biometric traits that could inform health differences by sex. Before The results of our study should be interpreted in view of its strengths and limitations. Both HLA-DQB1 and HLA-DMA are examples of the MHC class II genes that are associated with processing of exogenous antigen. You'll get a detailed solution from a subject matter expert that helps you learn core concepts. Wang J, Su W, Zhang T, Zhang S, Lei H, Ma F, Shi M, Shi W, Xie X, Di C. Cell Death Dis. 46, 881885 (2014). dorsolateral prefrontal cortex cells) cortex-specific Hi-C libraries. Cite this article. Variants that do not have strand information for HumanOmni25-8v1-2_A1 and HumanOmni2-5Exome-8-v1-1-A genotyping chips were excluded (strand files and update_build.sh script were downloaded from https://www.well.ox.ac.uk/~wrayner/strand/, 01/07/2020, Supplementary Table 1). 2002;47(11):561-6. doi: 10.1007/s100380200086. PubMed Trlungeanu, D. C. et al. Transcriptome-wide fetal and adult cortex-specific PPIs (CSPPIs) were constructed by combining the STRING PPI network with cortex-specific expression data from GTEx v8 or fetal brain datasets (Fig. 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. Introduction. Bioinformatics 32, 289291 (2016). 45, D139D144 (2017). Abnormalities in lipid metabolism may affect the proper functioning of the nervous system and, thus can contribute to ASD etiology48,49,50. Wang, S.S.-H., Kloth, A. D. & Badura, A. 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. J. Stat. Google Scholar. Enrichment of the eQTLs within transcription factor binding sites was determined using SNP2TFBS (https://ccg.epfl.ch//snp2tfbs/, 07/09/2020)27. Stiles, J. A Dockerfile (including the CoDeS3D pipeline and downstream analyses), all findings, scripts and reproducibility report are available on github at https://github.com/Genome3d/genetic_regulation_in_ASD. Applications of computational tools to predict functional SNPs effects in human ErbB genes. For a specific TF-gene pair, detailed information could be observed in the rSNP report page using a link from the SNP in the 'element-gene-related SNPs . By contrast, in the fetal cortex changes in gene transcript levels occurred in immune pathways that were related to the processing of both endogenous and exogenous antigens. Since the output is an easily manipulated spreadsheet, the user can sort the SNPs to highlight different SNP features. & Pritchard, J. K. Cell 169, 11771186 (2017). eGene enrichment was tested within the biological process, molecular function and cellular component GO terms. The transcript levels of the genes within the two unknown adult cortex PPI clusters increased (i.e. Rev. We contend that changing the transcription levels of these genes, alters biological pathways that modify an individuals predisposition to develop ASD. Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. et al. SNP selection and data report The proteinprotein interaction (PPIs) network serves as a foundation for cellular signalling circuitry, which mediates cellular responses to environmental and genetic cues. This is a preview of subscription content, access via your institution, Receive 12 print issues and online access, Get just this article for as long as you need it, Prices may be subject to local taxes which are calculated during checkout. 4). contracts here, Sign up for Nature Briefing: Translational Research. [Structural variation in the human genome contributes to variation of traits]. Musunuru, K. et al. In total, 663,956 variants passed QC filters. Get the most important science stories of the day, free in your inbox. Genet. Nature Genetics Cell Syst. Virtual histology of cortical thickness and shared neurobiology in 6 psychiatric disorders. 1). Gene expression variation can be seen across all levels of organismal organization (i.e. Genes were inverse normal transformed across samples. A common two-phase adipogenesis process is described: early determination and terminal differentiation phases, involving an intricate integration of cytoarchitecture, transcription factors and co-regulators, and signaling pathways. 4). 4). By contrast, in the adult cortex they largely affect immune pathways. This network illustrates potential evidence for gene regulation related to RA-associated SNPs, and may provide comprehensive information for subsequent functional analyses and experiments. Res. A reference panel of 64,976 haplotypes for genotype imputation. We extracted 2,000,451 proteinprotein interactions (with a combined score 400) between a total of 19,258 unique human proteins (Fig. 4, 334336 (2011). To identify existing and novel gene associations, we intersected our lists of genes, from fetal and adult cortical tissues, with a curated list of 1237 genes that had been previously implicated in autism development (AutDB31, accessed on 16/11/2020). Science 376, eabf3041 (2022). Neurol. Polycomb proteins are known to be involved in transcriptional silencing43,44. Louvain clustering analysis identified seven highly connected PPI modules within fetal cortex. Mahfouz, A., Ziats, M. N., Rennert, O. M., Lelieveldt, B. P. F. & Reinders, M. J. T. Shared pathways among autism candidate genes determined by co-expression network analysis of the developing human brain transcriptome. Backman, J. D. et al. VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction. Raw Hi-C data were downloaded from dbGaP (accession: phs001190.v1.p1) and GEO (https://www.ncbi.nlm.nih.gov/geo/, accession: GSE87112) and analyzed using Juicer (v1.5)75 (https://github.com/aidenlab/juicer) pipeline to generate Hi-C libraries. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Neurosci. 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. JOS was also funded by a Royal Society of New Zealand Marsden Fund [Grant 16-UOO-072]. Federal government websites often end in .gov or .mil. Integrating datasets across biological levels enables us to predict how genetic variation impacts on biological pathways and their involvement in the etiology of ASD. SNPs are located in gene promoters, exons, introns as well as 5'- and 3'- untranslated regions (UTRs) and affect gene expression by different mechanisms. McCarthy, S. et al. doi: 10.1093/hmg/ddp003. Thank you for visiting nature.com. Dysregulation of fatty acid metabolism in early brain development may be a risk factor or marker for early-onset of ASD48. Unable to load your collection due to an error, Unable to load your delegates due to an error. Google Scholar. ISSN 1061-4036 (print). Bethesda, MD 20894, Web Policies DiStasio, M. M., Nagakura, I., Nadler, M. J. Google Scholar. 2b). CoDeS3D11 (https://github.com/Genome3d/codes3d-v2) was used to identify genes that spatially interact with putative regulatory regions tagged by ASD-associated SNPs (Fig. 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. We contend that our approach represents a valuable strategy to identify potential ASD candidate genes. Fetal and adult cortical tissue-specific PPI networks with immune and growth related phenotypes are affected by ASD-associated eQTLs. Functional annotation of ASD-associated eQTLs revealed that they are involved in diverse regulatory processes. The existence of changes within fetal cortex pathways for endogenous antigens (e.g. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. Transcript levels for four genes: (a) increased (i.e. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene's function. Bootstrapping analysis revealed that these overlaps are significant (p<0.01, n=10,000). Dev. In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. Thereby, SNPs contribute to disease susceptibility, various responses to medication treatment and differences in outcomes within a disease population [8, 9]. cerebellum68) or other organs are important in the pathophysiology of ASD. Nucleic Acids Res. This work was funded by a University of Auckland FRDF Grant (Confirming spatial connections to unravel how SNPs affect phenotype; 3714499) and a MBIE Catalyst grant (The New Zealand-Australia LifeCourse Collaboration on Genes, Environment, Nutrition and Obesity (GENO); UOAX1611) to JOS. PubMed Nat. Nucleic Acids Res. Google Scholar. Gene expression is the outcome of numerous processes including transcription, co-transcriptional splicing, mRNA export, and translation. Cold Spring Harb. *Hi-C datasets for cortical plate and germinal zone neurons (phs001190.v1.p1) were obtained from Won et al.19, Hi-C datasets for adult dorsolateral prefrontal cortex cells were obtained from Schmitt et al.12. Files containing cleaned Hi-C contacts locations (i.e. However, studies have shown that Polycomb repressive complexes (PRC) can have a dual role in gene regulation during development45,46. Five genes within this cluster (i.e. We identified shared and development-specific changes to transcript levels for spatially regulated genes within immune pathways. 1). Bauer, D. E. et al. View Solution Related Answers how could SNP's contribute to gene regulation?. ASD-associated SNPs are enriched within non-coding putative regulatory regions. Louis S, Busch RM, Lal D, Hockings J, Hogue O, Morita-Sherman M, Vegh D, Najm I, Ghosh C, Bazeley P, Eng C, Jehi L, Rotroff DM. Notably, the transcript levels for 6 genes in the fetal immune cluster (HCG27, TAP2, HLA-F, HLA-DMA, HLA-C and HLA-DMB) are associated with regulation by Polycomb-repressed ASD-eQTLs. In the adult cortex, the known functions of the impacted genes were enriched in immune pathways. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Transl. 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. fetal samples were aged from 14 to 21 postconceptional weeks and the adult samples were from individuals aged 2170years). Fetal and adult ASD-associated eQTLs were also associated with schizophrenia, unipolar depression, ADHD, bipolar disorder, anorexia nervosa and obsessivecompulsive disorder (Supplementary Fig. 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. Ann. & Wang, K. wANNOVAR: Annotating genetic variants for personal genomes via the web. Nat. Maurano, M. T. et al. Internet Explorer). and commented on the manuscript. 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. & Deptua, W. Butyrophilins: An important new element of resistance. Louvain clustering identified seven PPI modules within the fetal cortex that were enriched for immune pathways, fatty acid metabolism, aminoacyl-tRNA biosynthesis, spliceosome, ribosome biogenesis in eukaryotes and two unknown modules. 10, 643660 (2014). Sci Rep 11, 15867 (2021). Porokhovnik, L. Individual copy number of ribosomal genes as a factor of mental retardation and autism risk and severity. Nature 516, 349354 (2014). Genet. J. Psychiatry 175, 359369 (2018). Basically, SNPs are copying errors. Genomic and metabolic profiling of two tomato contrasting cultivars for tolerance to Tuta absoluta. A Manhattan plot of association results from genome-wide association analysis.Y axis shows log 10 (P-value) of the association result for each SNP.Each SNP is indicated by a colored dot. For example, identical samples were not used in the ChromHMM, eQTL and Hi-C analyses of the fetal and adult cortical tissues.
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