how could snps contribute to gene regulation?

Modules that were enriched with ASD-eQTL associated genes were identified in the fetal and adult cortical tissues. Article Cells 8, 1151 (2019). 52, 13551363 (2020). Blondel, V. D., Guillaume, J.-L., Lambiotte, R. & Lefebvre, E. Fast unfolding of communities in large networks. 1). A reference panel of 64,976 haplotypes for genotype imputation. 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. reviewed in29). 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. Science 342, 253257 (2013). Breastfeed. 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. In total, 663,956 variants passed QC filters. In Psychopathology in Adolescents and Adults with Autism Spectrum Disorders (ed. Cell. 44, 60466054 (2016). Bethesda, MD 20894, Web Policies Sunwoo, M. et al. 47, D1005D1012 (2019). Dysregulation of fatty acid metabolism in early brain development may be a risk factor or marker for early-onset of ASD48. Gene expression is the outcome of numerous processes including transcription, co-transcriptional splicing, mRNA export, and translation. Scientific Reports (Sci Rep) 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. 2f). Musunuru, K. et al. Ann. ZSCAN23 and LY6G5C) whose transcript levels increase or decrease, dependent upon specific eQTL. Psychiatry https://doi.org/10.1038/s41380-020-0773-x (2020). Autism Spectr. Science 337, 11901195 (2012). Google Scholar. How far from the SNP may the causative genes be?. The majority of ASD-associated SNPs are located within the non-coding components of the genome. Golovina, E., Fadason, T., Lints, T.J. et al. 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. MacRae, C. A. We detail the method, apply it to data from The Cancer Genome Atlas, and provide a tool to explore the findings. 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. Corley, M. & Kroll, K. L. The roles and regulation of Polycomb complexes in neural development. By submitting a comment you agree to abide by our Terms and Community Guidelines. Notably, these regulatory elements are only associated with the expression (eQTL or expression quantitative trait locus) of the adjacent gene in ~40% of cases11. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. Nat. 45, D139D144 (2017). Collectively these results could indicate the existence of a window of tolerable variation within gene expressionoutside of which there is risk of developing ASD through changes in global gene expression. Karczewski, K. J. et al. 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. However, our study also has several limitations. How could SNPs contribute to gene regulation? Science 366, 11341139 (2019). STRING v11: Proteinprotein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 2008 Sep 11;128(17):1951-5. EBioMedicine 58, 102917 (2020). Here, we focused on roles for changes within cortical tissue. 4, 334336 (2011). Nucleic Acids Res. By contrast, the adult PPI gene set contained three highly connected modules, two of which were not associated with specific pathway, and one of which was enriched for immune pathways. performed the analyses and wrote the manuscript. As such, the three-dimensional (3D) genome organization, which emerges from the sum of the biophysical interactions within the nucleus, includes tissue-specific spatial interactions between eQTL regions and the genes that they control (hereafter eGenes)12. van Arensbergen, J. et al. SF3B1 and THOC7 were also associated with ASD-eQTLs within the adult cortex. 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. In our study eQTL data represent composite datasets across critical periods of development (e.g. If you are reading a news story where it says, for example, scientists find the genetic contributors to diabetes or some other condition or trait, you're probably reading about SNPS. Psychiatry 11, 71 (2021). 20, 327348 (2010). J Recept Signal Transduct Res. The GTEx Consortium atlas of genetic regulatory effects across human tissues. We identified changes within multiple key component pathways of gene expression (i.e. Circ. We extracted 2,000,451 proteinprotein interactions (with a combined score 400) between a total of 19,258 unique human proteins (Fig. You are using a browser version with limited support for CSS. contributed to the eQTL analysis and commented on the manuscript. A new study highlights a strategy to link SNPs implicated in human complex traits and diseases with probable causal genes. 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. FastQC reports were visually inspected and there were no samples that did not pass the quality check (no failures for Per base sequence quality, Per sequence quality scores, Per base N content and Sequence Length Distribution metrics). Article Finally, our approach focuses on identifying changes in gene regulation that are associated with and may contribute to ASD. J. Immunol. All datasets and software used in the analysis are listed in Supplementary Table 1. Eleven genes (i.e. PubMed Central However, this would require randomised control trials in animals prior to testing in humans. https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. 16, 469486 (2015). Nature 518, 317330 (2015). The mapping is shown for A the 1D linear genome and B the 3D genome structure constructed at the Hi-C resolution of 10 kbp. 1). Yazar, S. et al. on gene regulation) of the ASD-associated SNPs and translating them to the affected biological pathways in fetal and adult cortical tissues may provide mechanistic insights into the etiology of ASD during neurodevelopment. Genom. 57, 580594 (2015). CAS Nott, A. et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. From these CSPPI networks we identified 42 ASD-associated PPIs within the fetal gene set, and 10 ASD-associated PPIs from the adult cortical tissue gene set (Fig. Nucleic Acids Res. Synaptic Neurosci. Transl. Boyle, E. A., Li, Y. I. There are several reasons for this apparent discrepancy. Genetic and molecular features of seizure-freedom following surgical resections for focal epilepsy: A pilot study. Genes depleted for null variants were defined as having pLI>0.9. 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. Single nucleotide polymorphism (SNP) is the simplest form of DNA variation among individuals. These mechanisms depend on the role o Science 353, 772777 (2016). cortical plate and germinal zone neurons)19 and one adult cortex-specific (i.e. Wang, S.S.-H., Kloth, A. D. & Badura, A. antigen processing and presentation) as being enriched in the ASD-eQTL associated gene sets for both fetal and adult cortical tissues (Supplementary Fig. 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 Neurosci. We identified 80 eQTLs that are involved in 131 significant spatial eQTL-eGene interactions in fetal cortex; and 58 eQTLs that are associated with 67 significant spatial eQTL-eGene interactions in adult cortex (Fig. Nat. An official website of the United States government. This site needs JavaScript to work properly. Numerous genome-wide eQTL analyses have been reported to comprehensively capture such a DNA-RNA (i.e . Similar approaches, in combination with existing and future clinical studies of ASD will contribute to individualized mechanistic understanding of ASD etiology in early brain development and adulthood. [34] Genome-wide genetic data can be generated by multiple technologies, including SNP array and whole genome sequencing. Van Rooij, D. et al. Cis-eQTL SNPs are the SNPs that are within or around the corresponding gene, and trans-eQTL SNPs are those that are far away or even on dierent chromosomes. regioneR: An R/Bioconductor package for the association analysis of genomic regions based on permutation tests. Virtual histology of cortical thickness and shared neurobiology in 6 psychiatric disorders. 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. 48, 552555 (2016). Secondly, the finding that these ASD-eQTLs are associated with both increases and decreases in transcript levels is consistent with the up- and downregulation of the target genes. Applications of computational tools to predict functional SNPs effects in human ErbB genes. Desai, D. & Pethe, P. Polycomb repressive complex 1: Regulators of neurogenesis from embryonic to adult stage. Nucleic Acids Res. 47, 165175 (2019). spliceosome and splicing, aminoacyl-tRNA biosynthesis, and ribosome biogenesis) in the fetal cortex. GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. Autism 3, 9 (2012). SNPs can also be used to track the inheritance of disease genes within families. There was significant enrichment (p<0.01, permutation test: 1000) of ASD-associated eQTLs within loci repressed by Polycomb proteins in the fetal cortex when compared to the adult cortex. Roles for these component gene expression processes in ASD are supported by existing studies (e.g. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Firstly, there is a great phenotypic heterogeneity within autism spectrum disorders, which has led to question their classification into a single diagnostic category64. 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. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). miRNA) or by spatial associations of the regulatory element and target gene. Lancet 383, 896910 (2014). We found 80 and 58 SNPs that mark regulatory regions (i.e. Louvain clustering analysis identified seven highly connected PPI modules within fetal cortex. PubMedGoogle Scholar. These SNPs mostly locate within a gene or in a regulatory region near a gene and can affect the gene's function to Asthma-associated SNPs and genes from GWAS catalog. Google Scholar. Clipboard, Search History, and several other advanced features are temporarily unavailable. Here, we build on prior work to study a large set of anthropometric and biometric traits that could inform health differences by sex. Author summary Risk for many diseases and related manifestations differs by sex. Rev. BCFtools (v1.10.2) was used to exclude genetic variants on chromosome 0 (omitted due to mapping to multiple locations) and chromosome 25 (XY pseudoautosomal region), to rename chromosomes 23 (X), 24 (Y) and 26 (MT), to fix REF allele, to check samples sex and to normalize the output vcf file to the GRCh37 reference genome (human_g1k_v37.fasta.gz, downloaded from ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/technical/reference/, 01/07/2020). Perspect. We obtained ASD-associated SNPs from nine GWAS studies that were performed in cohorts containing individuals of mostly European ancestry (Supplementary Table 2). 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. Unauthorized use of these marks is strictly prohibited. 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. Data access was approved by the dbGaP (https://www.ncbi.nlm.nih.gov/gap/) Data Access Committee(s) for: (1) cortical plate and germinal zone neuron Hi-C datasets (project #16489: "Finessing predictors of cognitive development", accession: phs001190.v1.p1)19; (2) total RNA-seq and WGS datasets across GTEx v8 tissues (project #22937: Untangling the genetics of disease multimorbidity, accession: phs000424.v8.p2)21; and (3) total RNA-seq and genotyping datasets for fetal brain cortical tissue from 14 to 21 postconceptional weeks (PCWs) (project #25321: "Gene regulatory networks in Autism", accession: phs001900.v1.p1)20 (Supplementary Table 1). 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. Sign up for the Nature Briefing: Translational Research newsletter top stories in biotechnology, drug discovery and pharma. The expression level in an indivisual is measured by the measuring the Trascribed mRNA, by the method of Northern blot . Chapter 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. Autism, early psychosis, and social anxiety disorder: Understanding the role of social cognition and its relationship to disability in young adults with disorders characterized by social impairments. 28, 2730 (2000). Westra, H.-J. 2, Supplementary Table 5). 370, 12091219 (2014). 3). Neurosci. Abstract. Bauer, D. E. et al. 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). Neuron 83, 518532 (2014). 19, 13211330 (2016). PubMed Central Increasing role of maternal immune activation in neurodevelopmental disorders. Gazal, S. et al. Nature 593, 238243 (2021). 12, 24782492 (2017). Google Scholar. NMB encodes the neuromedin B peptide that regulates physiological processes including cell growth, exocrine and endocrine secretion22; and (2) downregulates WDR73 in adult cortex. Systematic localization of common disease-associate variation in regulatorty DNA. Slider with three articles shown per slide. Hum. Files containing cleaned Hi-C contacts locations (i.e. For example, rs35828350: (1) upregulates NMB in fetal cortex. Repeating similar analysis in other brain (e.g. PubMed ASD-eQTLs within the fetal cortex PPI aminoacyl-tRNA biosynthesis cluster are associated with: (a) increases in transcript levels for five genes (i.e. Cell 179, 750-771.e22 (2019). The resulting CSPPI networks contained 1,784,342 PPIs between 17,156 unique proteins in the adult brain, and 1,690,571 PPIs between 16,519 unique proteins in the fetal brain. Grove, J. et al. As such, we do not yet fully understand how to translate information on ASD-associated SNPs into specific biological mechanisms that can be therapeutically targeted to alleviate the symptoms and complications of ASD. 49, 433436 (2012). Until recently, there has been little if any functional follow-up of the actual role a given SNP or gene plays in the trait variation under study ( 22 ). dorsolateral prefrontal cortex cells)12 Hi-C chromatin interaction libraries (Supplementary Table 1). By contrast, the adult cortical gene set was largely related to immune pathways. Google Scholar. . SNP. 359, 6585 (2015). Functional annotation of ASD-associated eQTLs revealed that they are involved in diverse regulatory processes. Sci Rep 11, 15867 (2021). Lai, M.-C., Lombardo, M. V. & Baron-Cohen, S. Autism. Enh enhancers, Het heterochromatin, Quies quiescent/low, ReprPC repressed PolyComb, ReprPCWk week repressed PolyComb, TssA active TSS, TssAFlnk flanking active TSS, Tx strong transcription, TxWk weak transcription. Physiol. This approach, in combination with clinical studies on ASD, will contribute to individualized mechanistic understanding of ASD development. Genet. ISSN 1546-1718 (online) 47, 12281235 (2015). Nat. Psychiatry 8, 233 (2018). 3). Nucleic Acids Res. Only SNP-phenotype associations with a p<5108 were included in the analysis. Front. We contend that empirical studies are required to (a) confirm the regulatory activity of the sites (e.g. ASD-eQTLs were also associated with increases in HCG27 (TPM=3) and NDUFA6 (TPM=116.31) transcript levels within fetal cortex. The proportions of eQTL and non-eQTL SNPs are significantly different in fetal and adult cortical tissues (Fishers exact test, p=0.04531). This improved knowledge may provide a starting point for the development of new, useful SNP markers for medical testing and a safer individualized medication to treat the most common devastating disorders. (c) All ASD-associated eQTLs in adult cortex (n=58) and approximately 78 (97.5%) of the ASD-associated eQTLs within the fetal cortex are located within non-coding genomic regions (Supplementary Table 5). Nat. 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. Overall, our findings highlight potential regulatory mechanisms and pathways important for the etiology of ASD in early brain development and adulthood. Science 362,eaat8127 (2018). 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. Within-family IDs were used as sample IDs in the output vcf file (recode vcf-iid bgz). T.F. cortical plate and germinal zone neurons), or adult (i.e. There are studies connecting cortical dysfunctions and ASD using imaging14, cortical architecture15, or gene expression16. Trlungeanu, D. C. et al. Google Scholar. TAP1 and TAP2); (b) decreased (HLA-DQB1); or (c) both increased and decreased depending on specific ASD-eQTLs (HLA-DMA; Fig. Mountjoy, E. et al. The fetal immune PPI cluster contains both MHC class I (i.e. Neurol. Cell Rep. 17, 20422059 (2016). 4). It is estimated that the human genome contains more than 10 million different SNPs. 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 16, 551563 (2015). This network illustrates potential evidence for gene regulation related to RA-associated SNPs, and may provide comprehensive information for subsequent functional analyses and experiments. 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. 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. View Solution Related Answers how could SNP's contribute to gene regulation?. The identified gene sets were enriched for immune pathways, fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and the spliceosome in the fetal cortex. Enrichment analyses were performed using R package regioneR79 (permutation test: 1000). Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. *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. 2a, Supplementary Table 3). PubMed Roles for immune dysfunction in ASD etiology are increasingly being identified57,58,59. PubMed Central 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. Schmitt, A. D. et al. & Pritchard, J. K. Cell 169, 11771186 (2017). Article 84% of the genes we identified were not present in AutDB. Brodie, A., Azaria, J. R. & Ofran, Y. Wang J, Su W, Zhang T, Zhang S, Lei H, Ma F, Shi M, Shi W, Xie X, Di C. Cell Death Dis. And by View the full answer Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. They can act as biological markers, helping scientists locate genes that are associated with disease. By contrast, adult ASD-associated eQTLs were located within quiescent/low transcribed (n=31) and weak transcription (n=15) regions (Fig. We functionally annotated the ASD-associated eQTLs to understand the potential regulatory mechanisms of the regions they tagged (Supplementary Table 5). Most commonly, SNPs are found in the DNA between genes. The .gov means its official. 22, 2126 (2014). We identified 42 PPIs in the fetal and 10 PPIs in the adult cortical tissues. In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. PDE10A, PBX1, SF3B1, BAG6 and RERE) were LoF intolerant (Supplementary Table 6). Next, the CoDeS3D algorithm identified the restriction fragments interacting with the SNP-containing restriction fragments. JOS was also funded by a Royal Society of New Zealand Marsden Fund [Grant 16-UOO-072]. HLA-DRB1, HLA-DMB and HLA-DMA; associated with exogenous peptide processing) genes. government site. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Roadmap Epigenomics Consortium et al.

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