how could snps contribute to gene regulation?

Would you like email updates of new search results? Dynamics and stage-specificity of between-population gene expression 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. 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. Previous research has reported shared neurobiological and cellular processes associated with differences in cortical thickness across six psychiatric disorders (i.e. Nature 599, 628634 (2021). Clipboard, Search History, and several other advanced features are temporarily unavailable. Wang, S.S.-H., Kloth, A. D. & Badura, A. These mechanisms depend on the role o This data-driven approach enables the discovery of SNPs whose alleles impact gene regulation by miRNAs, with functional consequences for tumor biology. Mol. Genes were inverse normal transformed across samples. The neurobiology of lipid metabolism in autism spectrum disorders. For example, rs4647903, rs2535629, rs221902, rs7743252, rs832190 eQTLs were associated with increased transcript levels of DDHD2, ITIH4, PCNX1, TAP2, THOC7 genes both in fetal and adult cortical tissues. The resulting vcf file was converted to plink format and information on sample sex included. Fetal and adult cortical tissue-specific PPI networks with immune and growth related phenotypes are affected by ASD-associated eQTLs. You are using a browser version with limited support for CSS. The CSPPIs represents subnetworks of the STRING PPI network, in which a protein/node is only present if it is expressed in the cortical tissue (adult or fetal). Finally, we tested for enrichment of ASD-associated eQTLs within active regulatory elements and histone modification marks, using ChromHMM28 15-state models for adult dorsolateral prefrontal cortex and fetal brain. Diagnostic and Statistical Manual of Mental Disorders (DSM-5 (R)) (American Psychiatric Association Publishing, 2013). Article performed the analyses and wrote the manuscript. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. The p value was calculated as the sum of these instances divided by the total number of iterations n. If the p<0.01 we assume that the observed relationship is non-random. Notably, 6 genes are associated with multiple eQTLs which exhibit opposing effects on transcript levels (Fig. Genet. Firstly, there is a great phenotypic heterogeneity within autism spectrum disorders, which has led to question their classification into a single diagnostic category64. associated with an increase or reduction in transcript levels; Supplementary Fig. Introduction. 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. In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. Duplicated mapped reads were marked using Picard MarkDuplicates module (v2.21.4). 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. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. Enrichment within active regulatory elements and histone modification marks was identified using the Roadmap Epigenomics Project 15-state ChromHMM models28,78 for adult dorsolateral prefrontal cortex (E073_15_coreMarks_hg38lift_mnemonics.bed.gz) and fetal brain (E081_15_coreMarks_hg38lift_mnemonics.bed.gz) (downloaded from https://egg2.wustl.edu/roadmap/data/byFileType/chromhmmSegmentations/ChmmModels/coreMarks/jointModel/final/, 22/11/2020) (Supplementary Table 1). The dynamic 3D genome in gametogenesis and early embryonic development. J. Med. doi: 10.1093/hmg/ddp003. Nat. Bourgeron, T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. PubMed 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. Med. & Chen, Y.-T. Our findings highlight potential mechanisms through which ASD-associated variants potentially contribute to ASD development (fetal) and onset/maintenance (adult). PubMed Studies of non-coding disease-associated SNPs have demonstrated that they can mark regulatory elements that alter gene expression9,10. expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. BTN2A2 and BTN3A1 in the adult and fetal cortex, respectively). 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. The .gov means its official. Article The CoDeS3D algorithm then identified the restriction fragments containing the SNPs within fetal (i.e. 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. However, it is likely that additional regions of the brain (e.g. SNP selection and data report 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. Interestingly, most of the genes within immune-related pathways in fetal cortex are associated with Polycomb-repressed ASD-eQTLs. Perspect. A compendium of chromatin contact maps reveals spatially active regions in the human genome. Single Nucleotide Polymorphisms (SNPs) - Genome.gov Furthermore, the Hi-C dataset used to inform the adult cortex analysis consisted of one sample (with one replicate), while two samples (each with three replicates) were used for the fetal cortex analysis (Supplementary Table 1). The Kyoto Encyclopedia of Genes and Genomes (KEGG) database34 was used to query the most impacted biological pathways. CAS Functional annotation of ASD-associated eQTLs revealed that they are involved in diverse regulatory processes. 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. Cell 167, 1481-1494.e18 (2016). https://doi.org/10.1038/s41588-022-01093-0. 2009;29(5):286-91. doi: 10.1080/10799890902911948. (b) Thirty ASD-associated SNPs are eQTLs in both fetal and adult cortical tissues. CAS Genet. 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. 235, 40314045 (2020). Exploring the effects of genetic variation on gene regulation in cancer An AUTS2-Polycomb complex activates gene expression in the CNS. Chapter Article Provided by the Springer Nature SharedIt content-sharing initiative, Nature Genetics (Nat Genet) Rau, S. et al. Fetal and adult ASD-associated eQTLs were also associated with schizophrenia, unipolar depression, ADHD, bipolar disorder, anorexia nervosa and obsessivecompulsive disorder (Supplementary Fig. The results of these experiments would be valuable in identifying novel therapeutic approaches to reduce the risk of full-blown ASD development, particularly given the strength of the evidence for Polycomb roles transcription control46 and increasing evidence for links to neuronal development (e.g. 25, 142154 (2015). Hum Mol Genet. Cite this article. Cell 155, 9971007 (2013). 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. dorsolateral prefrontal cortex cells) cortex-specific Hi-C libraries. Most commonly, SNPs are found in the DNA between genes. Karczewski, K. J. et al. SNP alleles in human disease and evolution. Of the 80 fetal and 58 adult eQTLs, 30 were observed in both fetal and adult cortical tissues (Fig. (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). Identifying Liver Cancer-Related Enhancer SNPs by Integrating - PubMed Regulatory roles and mechanisms of alternative RNA splicing in antigen processing and presentation) as being enriched in the ASD-eQTL associated gene sets for both fetal and adult cortical tissues (Supplementary Fig. SNPs are located in gene promoters, exons, introns as well as 5'- and 3'- untranslated regions (UTRs) and affect gene expression by different mechanisms. 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. Only SNPs associated with ASD with a p<5108 were included in downstream analyses. Weissbrod, O. et al. For gene analysis, we resampled eGenes from the list of all genes in the genome (GENCODE transcript model version 26). Phenotypes were defined as the mapped traits associated with the SNP in the GWAS Catalog. The remaining read pairs we refer to as contacts. Neurosci. 1). In Handbook of Hormones (eds Takei, Y. et al.) 46, 881885 (2014). 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. 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. 2a, Supplementary Table 3). Roadmap Epigenomics Consortium et al. JOS was also funded by a Royal Society of New Zealand Marsden Fund [Grant 16-UOO-072]. 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. Transl. Ann. For example, identical samples were not used in the ChromHMM, eQTL and Hi-C analyses of the fetal and adult cortical tissues. 2008 Sep 11;128(17):1951-5. 69, 101468 (2020). Of these genes, 15 are spatially regulated in both fetal and adult cortical tissues (Fig. We identified shared and development-specific changes to transcript levels for spatially regulated genes within immune pathways. Nancy Y. Careers. 19, 13211330 (2016). Guillaume Lettre. HLA-C and HLA-F; associated with endogenous antigen processing) and MHC class II (i.e. Proteins that were not annotated in the expression datasets were also removed from the CSPPI network. Gao, Z. et al. Neuropsychol. 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. Neurosci. 2, Supplementary Table 5). Malinowska, M., Tokarz-Deptua, B. 1). Over 11 million proteinprotein interactions (PPIs) were downloaded from STRING database (version 11.0) and combined with cortex-specific expression data (GTEx v8 or Walker et al. Boyle, E. A., Li, Y. I. Gazal, S. et al. 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. This will revolutionize the medical field in the future. These findings indicate that there may be developmental stage-specific differences in the impact of the immune system on ASD risk and on-going severity. PubMed Central The number of shared items (e.g. Desai, D. & Pethe, P. Polycomb repressive complex 1: Regulators of neurogenesis from embryonic to adult stage. Hi-C chromatin interactions represent all captured pairs of interacting restriction fragments in the genome. PPI network analyses have been used to discover essential proteins, clusters of proteins with similar, overlapping or combinatorial functions, and associated pathways involved in tissue-specific contributions to ASD etiology17,18. J Recept Signal Transduct Res. The GTEx Consortium atlas of genetic regulatory effects across human tissues. SNPs in genes that regulate DNA mismatch repair, cell cycle regulation, metabolism and immunity are associated with genetic susceptibility to cancer [ 1 - 12 ]. ASD-associated eQTLs mark loci that spatially regulate the expression of genes involved in the fetal brain, in the adult brain, or both. 22, 345361 (2016). genes, whose expression levels are associated with a SNP). 51, 11601169 (2019). reviewed in29). Roles for these component gene expression processes in ASD are supported by existing studies (e.g. To obtain CrossMap (v0.2.6) was used to convert coordinates of genetic variants from genome build hg19 to hg38, resulting in ~54.8 million genetic variants. Google Scholar. 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. Szklarczyk, D. et al. PubMed TAP1 and TAP2); (b) decreased (HLA-DQB1); or (c) both increased and decreased depending on specific ASD-eQTLs (HLA-DMA; Fig. Polycomb proteins are known to be involved in transcriptional silencing43,44. Front. Ernst, J. Notably, these regulatory elements are only associated with the expression (eQTL or expression quantitative trait locus) of the adjacent gene in ~40% of cases11. Autism 3, 9 (2012). Neurol. 84% of the genes we identified were not present in AutDB. 48, 552555 (2016). NMB encodes the neuromedin B peptide that regulates physiological processes including cell growth, exocrine and endocrine secretion22; and (2) downregulates WDR73 in adult cortex. ADS Aranda, S., Mas, G. & Di Croce, L. Regulation of gene transcription by Polycomb proteins. Genet. Mottron, L. & Bzdok, D. Autism spectrum heterogeneity: Fact or artifact?. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). Cells 8, 1151 (2019). Res. how could snps contribute to gene regulation? Estes, M. L. & McAllister, A. K. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. 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. 3, Supplementary Table 4). Klei, L. et al. Smith, R. M. & Sadee, W. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders. Bookshelf ISSN 1061-4036 (print). ADS We identified 42 PPIs in the fetal and 10 PPIs in the adult cortical tissues. Google Scholar. 2022 Sep 23;13:973347. doi: 10.3389/fpls.2022.973347. & Deptua, W. Butyrophilins: An important new element of resistance. 11, 27 (2017). Lastly, tensorQTL (https://github.com/broadinstitute/tensorqtl) algorithm was used to perform cis- and trans-QTL mapping. Nature 593, 238243 (2021). 6, a019331 (2014). Here, we focused on roles for changes within cortical tissue. Eleven genes (i.e. [34] Genome-wide genetic data can be generated by multiple technologies, including SNP array and whole genome sequencing. Five genes within this cluster (i.e. Understanding how ASD-eQTLs affect fetal and adult cortex PPIs could lead to the identification of the pathways that affect cortical development and ASD susceptibility. We obtained ASD-associated SNPs from nine GWAS studies that were performed in cohorts containing individuals of mostly European ancestry (Supplementary Table 2). 3). Nature 581, 434443 (2020). Consistent with this, we identified that ASD-associated genetic variants impact transcript levels for genes involved in fatty acid metabolism in the developing fetal cortex (1421 postconceptional weeks). CAS Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Genetic control of expression and splicing in developing human brain informs disease mechanisms. Epub 2009 Feb 9. 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). Gene expression is the outcome of numerous processes including transcription, co-transcriptional splicing, mRNA export, and translation. Gandal, M. J. et al. 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. SNPs) among conditions was counted for each bootstrap iteration. PubMed & Zhang, Z. Nature 518, 317330 (2015). regQTLs: Single nucleotide polymorphisms that modulate microRNA - PLOS The caveat of this is that the first approach can select the wrong gene and does not account for the effects of . MacArthur, J. et al. Cell. 47, D607D613 (2019). Hudson, C. C., Hall, L. & Harkness, K. L. Prevalence of depressive disorders in individuals with autism spectrum disorder: A meta-analysis. Am. Juicer provides a one-click system for analyzing loop-resolution Hi-C experiments. Changes to genes within the immune-related processes within adult cortex mostly affect the processing of exogenous antigen. Science 360, 327331 (2018). Westra, H.-J. DiStasio, M. M., Nagakura, I., Nadler, M. J. Brain Basics: Genes At Work In The Brain | National Institute of 12, 405 (2018). The regulatory effects can occur in trans (e.g. contracts here, Sign up for Nature Briefing: Translational Research. 2f). Sex-heterogeneous SNPs disproportionately influence gene - PLOS Neuron 83, 518532 (2014). Edges are only present if both interacting proteins are expressed in the cortical tissue. Finally, significant cortex-specific eQTL-eGene interactions were identified using the Benjamini-Hochberg (BH) FDR correction to adjust the eQTL p values (FDR<0.05) (Supplementary Table 3). 3). 45, 984994 (2013). And by View the full answer 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. Bootstrapping analysis (n=10,000 iterations) was performed to test if observed overlaps were non-random. Genet. Within-family IDs were used as sample IDs in the output vcf file (recode vcf-iid bgz). The remaining 60% of the identified eQTLs involve interactions with non-adjacent genes that can be >1Mb away in the linear DNA sequence or even on a different chromosome. By contrast, the rs1518367 eQTL is associated with reduced transcript levels for SF3B1 only in fetal cortex. Transcript levels for these genes are associated with 65 eQTLs in fetal cortex and 39 eQTLs in adult cortex (Supplementary Table 3). Single-nucleotide polymorphisms (SNPs) associated with ASD (n=454) were downloaded from the GWAS Catalog (www.ebi.ac.uk/gwas/; 05/04/2020; Supplementary Table 2). Neurol. 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. Cell type- and differentiation-specific gene expression is precisely controlled by genomic non-coding regulatory elements (NCREs), which include promoters, enhancers, silencers and insulators. 4). They may be responsible for the diversity among individuals, geno SNPs: impact on gene function and phenotype Nucleic Acids Res. Genet. Kumar, S., Ambrosini, G. & Bucher, P. SNP2TFBSA database of regulatory SNPs affecting predicted transcription factor binding site affinity. Cell Syst. 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. Grossniklaus, U. By contrast, in the adult cortex they largely affect immune pathways. 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. & Anderson, M. P. T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains. ASD is widely considered to be a neurodevelopmental disorder resulting from functional changes within the brain. Increasing role of maternal immune activation in neurodevelopmental disorders. 10, 643660 (2014). This method prioritizes genes for functional characterization and helps address questions about the architecture of human phenotypes. Internet Explorer). The identified ASD-associated eQTLs were annotated using wANNOVAR tool77 (http://wannovar.wglab.org/, 10/08/2020) to obtain information about the locus they tagged (Supplementary Table 4). (d) 15 and 18 ASD-associated eQTLs affect at least one transcription factor binding sites within the fetal and adult cortical tissues, respectively. HLA-DRB1, HLA-DMB and HLA-DMA; associated with exogenous peptide processing) genes. T.F. Transl. Tamiji, J. ASD-eQTLs were also associated with increases in HCG27 (TPM=3) and NDUFA6 (TPM=116.31) transcript levels within fetal cortex. PubMed Genes that have essential functions show a decreased tolerance for loss-of-function (LoF) mutations32. A SNP is a one-letter place where your genome varies from another genome sequence.

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