how could snps contribute to gene regulation?
Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. 46, 881885 (2014). 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. Notably, transcript levels for genes within this pathway were not significantly affected by ASD-eQTLs within adult cortex tissues (2170years of age). Med. For example, rs4481150 eQTL is present in both fetal and adult eQTL databases. Functional gene ontology enrichment analysis identified immune-related processes (e.g. government site. Studies have previously reported associations between ASD and: (1) schizophrenia36; (2) depression37; (3) ADHD38,39; (4) bipolar disorder40; and other co- and multimorbidities24,41,42. How far from the SNP may the causative genes be?. PubMed 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. To obtain 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. *_merged_nodups.txt files) were processed to obtain Hi-C chromatin interaction libraries in the following format: read name, str1, chr1, pos1, frag1 mapq1, str2, chr2, pos2, frag2, mapq2 (str=strand, chr=chromosome, pos=position, frag=restriction site fragment, mapq=mapping quality score, 1 and 2 correspond to read ends in a pair). Roles for these component gene expression processes in ASD are supported by existing studies (e.g. In Psychopathology in Adolescents and Adults with Autism Spectrum Disorders (ed. Genet. Mottron, L. & Bzdok, D. Autism spectrum heterogeneity: Fact or artifact?. Nasser, J. et al. 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. J. M. OSullivan. 193-e22B-3 (Academic Press, 2016). cortical plate and germinal zone neurons)19 and one adult cortex-specific (i.e. All annotated human genes were chosen as the statistical domain scope. The existence of changes within fetal cortex pathways for endogenous antigens (e.g. ISSN 1061-4036 (print). 16, 551563 (2015). 1). Eleven genes (i.e. Rev. Only Hi-C libraries that contain >90% alignable unique read pairs, and >50% unique contacts (<40% duplication rate) within the total sequenced read pairs were included in the analysis. A large number of genes associated with various cancer types contain single nucleotide polymorphisms (SNPs). ASD-eQTLs within the fetal cortex PPI aminoacyl-tRNA biosynthesis cluster are associated with: (a) increases in transcript levels for five genes (i.e. Pedapati, E. V. et al. Gene expression variation can be seen across all levels of organismal organization (i.e. FOIA After 10,000 iterations we counted those instances where the number of shared items in the bootstrapped overlap is greater than or equal to the number of shared items in the observed overlap. Eur. The resulting expression (GTEx_Analysis_v8_eQTL_expression_matrices.tar) and covariates (GTEx_Analysis_v8_eQTL_covariates.tar.gz) data were downloaded from GTEx website (https://www.gtexportal.org/home/datasets, 01/05/2020). Imputed genotypes were filtered for HardyWeinberg equilibrium p<1106, variant missing genotype rate 0.05 and minor allele frequency 0.01. PubMed Adv. Bootstrapping analysis (n=10,000 iterations) was performed to test if observed overlaps were non-random. Synaptic Neurosci. 51, 11601169 (2019). Behav. PubMed Central Buniello, A. et al. Secondly, common SNPs only account for ~20% to the ASD risk6, suggesting that other genetic (e.g., rare variants, structural variation) and environmental factors also contribute to ASD etiology65,66. 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 ). This will revolutionize the medical field in the future. 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. 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. Article 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. Nature 516, 349354 (2014). Drug Metab Dispos. & Kellis, M. Chromatin-state discovery and genome annotation with ChromHMM. 45, 984994 (2013). Enhancer elements are functional segments of DNA located in noncoding regions that play an important role in regulating gene expression. Genet. All datasets and software used in the analysis are listed in Supplementary Table 1. J. Med. Sample-level gene read and TPM (Transcripts Per kilobase Million) counts were concatenated using combine_GCTs.py. Google Scholar. 37, D832D836 (2009). Secondly, in our manuscript we focused on cortex-specific eQTL-gene connections. Psychiatry 10, 77 (2020). Aguet, F. et al. SNPs may change the encoded amino acids (nonsynonymous) or can be silent (synonymous) or simply occur in the noncoding regions. Nature 538, 523527 (2016). 4). PHACTR3, BAG6, CSNK2B, SF3B1, PPP1R16B, FADS2, RTN1, TBL1X and ENAH) and 5 adult cortex-specific genes (i.e. CAS Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. https://doi.org/10.1038/s41588-022-01093-0. Won, H. et al. https://doi.org/10.1038/s41588-022-01087-y, Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity. Applications of computational tools to predict functional SNPs effects in human ErbB genes. Removal of HLA genes from analyses of the adult cortex gene set identified a retained enrichment for immune-related processes (e.g. Sign up for the Nature Briefing: Translational Research newsletter top stories in biotechnology, drug discovery and pharma. Article American Psychiatric Association. HHS Vulnerability Disclosure, Help Grossniklaus, U. We find that sex-het SNPs influence a large set of diseases and health-related . Nat. et al. An alternative explanation is that the existence of the shared eQTLs between the multimorbid conditions is due to ambiguity in the phenotyping that was used in the GWAS studies that characterised the phenotype associated-SNPs. SNP selection and data report 2d). Google Scholar. The STRING33 PPI network (version 11.0, protein.links.full.v11.0.txt.gz, https://string-db.org/) was downloaded on 24/09/2020. ASD-eQTLs were also associated with increases in HCG27 (TPM=3) and NDUFA6 (TPM=116.31) transcript levels within fetal cortex. To build ASD-specific fetal and adult CSPPIs, only interactions between ASD-associated genes we extracted from fetal and adult CSPPIs. However, switching the ASD-eQTL to the minor allele is associated with an increase in transcript levels for these genes within the fetal cortex (Fig. A single nucleotide polymorphism, or SNP (pronounced "snip"), is a variation at a single position in a DNA sequence among individuals. Google Scholar. Neurosignals 18, 98112 (2010). J. Psychiatry 175, 359369 (2018). MacArthur, J. et al. Article We contend that empirical studies are required to (a) confirm the regulatory activity of the sites (e.g. 51, 431444 (2019). SNPs are, of course, already routinely used in human studies to test individual genes or genomic regions for their association with disease phenotypes. JAMA Psychiat. This method prioritizes genes for functional characterization and helps address questions about the architecture of human phenotypes. This problem has been solved! How could SNPs contribute to gene regulation? Cell. Nat. Therefore, characterizing the functional impacts (i.e. 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. Estes, M. L. & McAllister, A. K. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. official website and that any information you provide is encrypted supervised E.G. Hi-C libraries) and cortex-specific eQTLs to identify how ASD-associated SNPs impact cortex-specific gene expression. 4, Supplementary Table 9). In order to study spatial regulatory interactions in fetal and adult cortical tissues, we analysed two fetal brain-specific (i.e. Smith, R. M. & Sadee, W. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders. 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. LoF analysis revealed that 59% (fetal) and 77% (adult) of the eGenes are tolerant to variation that alters the gene sequence. Internet Explorer). EG is the recipient of a Liggins Ph.D. scholarship and was supported by MBIE Catalyst Grant (The New ZealandAustralia LifeCourse Collaboration on Genes, Environment, Nutrition and Obesity (GENO); UOAX1611). Genet. Google Scholar. Single Nucleotide Polymorphism (SNP) SNPs are variations that involve a change in just one nucleotide. 47, D1005D1012 (2019). HLA-C and HLA-F; associated with endogenous antigen processing) and MHC class II (i.e. Scientific Reports (Sci Rep) 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. 47, 12281235 (2015). 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. 4). van Arensbergen, J. et al. 47, 165175 (2019). regioneR: An R/Bioconductor package for the association analysis of genomic regions based on permutation tests. 9, 5198 (2018). Szklarczyk, D. et al. 3). Stoner, R. et al. Nature 593, 238243 (2021). Identification of common genetic risk variants for autism spectrum disorder. The caveat of this is that the first approach can select the wrong gene and does not account for the effects of . 19, 13211330 (2016). Studies of non-coding disease-associated SNPs have demonstrated that they can mark regulatory elements that alter gene expression9,10. SNPs) among conditions was counted for each bootstrap iteration. PRC2-associated chromatin contacts in the developing limb reveal a possible mechanism for the atypical role of PRC2 in HoxA gene expression. Numerous genome-wide eQTL analyses have been reported to comprehensively capture such a DNA-RNA (i.e . They can act as biological markers, helping scientists locate genes that are associated with disease. ISSN 2045-2322 (online). miRNA) or by spatial associations of the regulatory element and target gene. Cell 167, 1481-1494.e18 (2016). Formulate hypotheses. Abstract. We found 80 and 58 SNPs that mark regulatory regions (i.e. Perspect. Different eQTLs are often associated with the gene transcript levels, although the effects of the minor allele are typically similar for the gene in question (i.e. 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. Google Scholar. Transl. Psychiatry 9, 298 (2019). 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. Nat. HCG27, TAP2, HLA-F, HLA-DMA and HLA-DMB) are not highly expressed (TPM<3) within fetal cortical tissue. 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. Similar changes occur in adult cortex where transcript levels for 15 genes are upregulated in association with a change to the minor allele at the eQTL SNP (Fig. Gao Z, Liang Y, Wang Y, Xiao Y, Chen J, Yang X, Shi T. Front Plant Sci. 12, 230 (2018). Notably, these regulatory elements are only associated with the expression (eQTL or expression quantitative trait locus) of the adjacent gene in ~40% of cases11. Article Nature 599, 628634 (2021). Genetic control of expression and splicing in developing human brain informs disease mechanisms. Sunwoo, M. et al. 1). Genotypes (derived by Whole Genome Sequencing) were processed by the Genotype-Tissue Expression (GTEx) project, and filtered genotypes (with minor allele frequency 0.1) for 838 tissue donors were downloaded from dbGaP (https://www.ncbi.nlm.nih.gov/gap/, 01/05/2020). A new study highlights a strategy to link SNPs implicated in human complex traits and diseases with probable causal genes. Finucane, H. K. et al. Gandal, M. J. et al. The fetal immune PPI cluster contains both MHC class I (i.e. 78, 4763 (2021). https://doi.org/10.1038/s41588-022-01087-y (2022). & Crawford, D. A. Duplicated mapped reads were marked using Picard MarkDuplicates module (v2.21.4). 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. Article By contrast, 9 fetal cortex-specific genes (i.e. Genet. Brown, C. M., Austin, D. W. & Busija, L. Observable essential fatty acid deficiency markers and autism spectrum disorder. Gel, B. et al. GWAS has been commonly used in identifying SNPs associated with diseases or clinical phenotypes or traits. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. Science 353, 772777 (2016). Genet. https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. 49, 433436 (2012). CAS DiStasio, M. M., Nagakura, I., Nadler, M. J. 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. Five genes within this cluster (i.e. Genotypes, expression matrices and covariates for fetal and adult brain were integrated into CoDeS3D11 (https://github.com/Genome3d/codes3d-v2) pipeline as two separate eQTL databases. 6, a019331 (2014). Porokhovnik, L. Individual copy number of ribosomal genes as a factor of mental retardation and autism risk and severity. 11, 27 (2017). 1, e1500737 (2015). These mechanisms depend on the role o When considering 25 experimentally validated SNP-gene pairs, the cS2G method had predictions for 16 of them and could assign 11 SNPs to the right genes (precision = 0.69, recall = 0.44). de la Torre-Ubieta, L., Won, H., Stein, J. L. & Geschwind, D. H. Advancing the understanding of autism disease mechanisms through genetics. Bookshelf Sci. contributed to the eQTL analysis and commented on the manuscript. Since the output is an easily manipulated spreadsheet, the user can sort the SNPs to highlight different SNP features. Nucleic Acids Res. Breastfeed. Hormozdiari, F., Penn, O., Borenstein, E. & Eichler, E. E. The discovery of integrated gene networks for autism and related disorders. Systematic identification of trans eQTLs as putative drivers of known disease associations. You are using a browser version with limited support for CSS. Next, the CoDeS3D algorithm identified the restriction fragments interacting with the SNP-containing restriction fragments. Thank you for visiting nature.com. View Solution Related Answers how could SNP's contribute to gene regulation?. For gene analysis, we resampled eGenes from the list of all genes in the genome (GENCODE transcript model version 26). Finally, we evaluated identified eQTL SNP associations with other phenotypes in the GWAS Catalog (downloaded on 26/08/2020) (Supplementary Table 4). Nucleic Acids Res. However, in noncoding regions, the mechanism of how SNPs contribute to disease susceptibility remains unclear. Moreover, Trlungeanu et al. (e) Most of the fetal ASD-associated eQTLs are located within quiescent/low transcribed, week repressed PolyComb, repressed PolyComb and weak transcription regions. Autism 3, 9 (2012). 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. Clipboard, Search History, and several other advanced features are temporarily unavailable. Correspondence to In this study, we integrated four distinct levels of biological information (GWAS, eQTL, genome organization [Hi-C] and proteinprotein interactions [PPI] networks) to translate genetic variation associated with ASD to the biological pathways that are affectedthrough alterations to the transcription levels of their component proteins in fetal and adult cortical tissues. eQTL datasets for fetal and adult cortex were obtained from Walker et al.20 and GTEx v821, correspondingly. In the meantime, to ensure continued support, we are displaying the site without styles Cite this article. Pepper, K. L. et al. Nat. PubMedGoogle Scholar. Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health (NiPPeR): Study protocol for a randomised controlled trial. CAS Nature Genetics Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. volume54,pages 748749 (2022)Cite this article. Trlungeanu, D. C. et al. J. Stat. Firstly, there is a great phenotypic heterogeneity within autism spectrum disorders, which has led to question their classification into a single diagnostic category64. SNPs can be viewed as the SNPs that are correlated with mRNA expres-sion of a gene. T.L. CAS Bauer, D. E. et al. Provided by the Springer Nature SharedIt content-sharing initiative, Advances in Neurodevelopmental Disorders (2022). Genome-wide association study of traits in sacred lotus uncovers MITE-associated variants underlying stamen petaloid and petal number variations. Roadmap Epigenomics Consortium et al. HLA-DRB1, HLA-DMB and HLA-DMA; associated with exogenous peptide processing) genes. 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. When present within a coding sequence and leading to an amino acid change (referred to as a non-synonymous SNP or mutation), they can modify the protein's activity. Genetic and molecular features of seizure-freedom following surgical resections for focal epilepsy: A pilot study. By contrast, the majority of ASD-associated eQTLs, that were identified in the adult cortex, are located within quiescent/low transcribed and weak transcription regions. Notably, Polycomb repressive complexes have distinct regulatory roles in identity, proliferation and differentiation of neuronal progenitor cells during development29,30. Nat. Abell, N. S. et al. Transl. It is estimated that the human genome contains more than 10 million different SNPs. Before We also identified two genes that had multiple eQTLs where substitution of the SNP with the minor allele had opposing associations with the genes transcript levels (Fig. Psychiatry 10, 380 (2020). Hughes, H. K., Mills Ko, E., Rose, D. & Ashwood, P. immune dysfunction and autoimmunity as pathological mechanisms in autism spectrum disorders. The proportion of ASD explained by SNPs has been estimated to be between 17 and 60%7,8, thus their contribution should not be neglected. CAS Article However, it is not the only mechanism by which changes in the DNA sequence can contribute to ASD. Cell Rep. 17, 20422059 (2016). Vannucchi, G., Perugi, G. & Masi, G. Bipolar disorder and ASD. Rev. Simply assigning function to the adjacent gene increases the number of false positive gene associations73. Perez, R. K. et al. To obtain For example, rs35828350: (1) upregulates NMB in fetal cortex. In the meantime, to ensure continued support, we are displaying the site without styles PGBD1, ZKSCAN7, MPHOSPH9, TCF19 and VWA7); (b) decreases in transcript levels for VARS2; and (c) two genes (i.e. eGene enrichment was tested within the biological process, molecular function and cellular component GO terms. Neurosci. Godfrey, K. M. et al. Transl. 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. Cell 179, 750-771.e22 (2019). ADS As such, restriction fragments were used to identify regulatory interactions between SNPs and genes (Fig. To create a lookup table, genetic variants were annotated with rsIDs from dbSNP build 151 database. 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. 20, 327348 (2010). Nat. These eQTLs were also linked to other psychiatric disorders (e.g. 12, 24782492 (2017). ASD, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, unipolar depression, obsessivecompulsive disorder and schizophrenia), implicating common mechanisms underlying cortical development24. Article (d) 15 and 18 ASD-associated eQTLs affect at least one transcription factor binding sites within the fetal and adult cortical tissues, respectively. 22, 345361 (2016). Google Scholar. Genotypes (derived by Array Genotyping) for 219 fetal brain donors20 were downloaded from dbGaP (05/06/2020), processed and prepared in the GTEx format (Supplementary Fig. sharing sensitive information, make sure youre on a federal Hum Mol Genet. Phenotypes were defined as the mapped traits associated with the SNP in the GWAS Catalog. Kumar, S., Ambrosini, G. & Bucher, P. SNP2TFBSA database of regulatory SNPs affecting predicted transcription factor binding site affinity. They may be responsible for the diversity among individuals, geno SNPs: impact on gene function and phenotype 359, 6585 (2015). Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation. We also found that immune pathways were affected both in fetal and adult cortical tissues. 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. 47, W191W198 (2019). PDE10A, PBX1, SF3B1, BAG6 and RERE) were LoF intolerant (Supplementary Table 6). 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. robert gordon secondary school fees,
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