We functionally annotated the ASD-associated eQTLs to understand the potential regulatory mechanisms of the regions they tagged (Supplementary Table 5). regQTLs: Single nucleotide polymorphisms that modulate microRNA - PLOS You are using a browser version with limited support for CSS. Juicer provides a one-click system for analyzing loop-resolution Hi-C experiments. Nineteen eGenes are regulated by Polycomb-repressed eQTL SNPs, and seven eGenesby trans-acting eQTL SNPs in fetal cortex (Fig. Nat. We identified shared and development-specific changes to transcript levels for spatially regulated genes within immune pathways. 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. Mech. Rev. Abstract. Brandler, W. M. et al. Finally, beyond changes in the DNA sequence, changes in gene regulation - for example, by sRNAs and epigenetic factors - can play a key role in disease. Science 375, 12471254 (2022). Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Eur. Before 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. Notably, 6 genes are associated with multiple eQTLs which exhibit opposing effects on transcript levels (Fig. However, despite having the same effects in fetal and adult tissues, some eQTLs had opposite direction of effects on the gene of interest (e.g. Yazar, S. et al. Lancet 383, 896910 (2014). Genet. Genetic variants were filtered based on HardyWeinberg equilibrium p<1106, minor allele frequency 0.01 and variant missing genotype rate 0.05. & Deptua, W. Butyrophilins: An important new element of resistance. Genes were inverse normal transformed across samples. Maurano, M. T. et al. SNP selection and data report Blondel, V. D., Guillaume, J.-L., Lambiotte, R. & Lefebvre, E. Fast unfolding of communities in large networks. Grove, J. et al. 49, 433436 (2012). The butyrophilin genes encode proteins that belong to the immunoglobulin superfamily and help modulate the immune system23. volume11, Articlenumber:15867 (2021) Therefore, characterizing the functional impacts (i.e. This data-driven approach enables the discovery of SNPs whose alleles impact gene regulation by miRNAs, with functional consequences for tumor biology. We detail the method, apply it to data from The Cancer Genome Atlas, and provide a tool to explore the findings. Science 362,eaat8127 (2018). The PPI clusters with unknown functions (Fig. 3). CAS As expected, the majority of identified eQTLs were located within intronic and intergenic regions (Fig. At the same time, ASD-eQTLs are also associated with regulation of fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome pathways in fetal cortex. HHS Vulnerability Disclosure, Help Normalized vcf files were further validated using VCFtools (v0.1.15). 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. LoF analysis revealed that 59% (fetal) and 77% (adult) of the eGenes are tolerant to variation that alters the gene sequence. Author summary Risk for many diseases and related manifestations differs by sex. Accessibility Schmitt, A. D. et al. Sex-heterogeneous SNPs disproportionately influence gene - PLOS Lombardo, M. V. Ribosomal protein genes in post-mortem cortical tissue and iPSC-derived neural progenitor cells are commonly upregulated in expression in autism. These differences can underlie susceptibility to common diseases, human traits, and differential responses to drugs. Lettre, G. One step closer to linking GWAS SNPs with the right genes. 3). Unauthorized use of these marks is strictly prohibited. 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 ). Nat. Genom. Increasing the number and sample sizes of the ASD GWAS studies will identify additional genetic variants which may help explain some of this missing heritability67. Book Single-nucleotide polymorphism - Wikipedia 28, 2730 (2000). Unable to load your collection due to an error, Unable to load your delegates due to an error. These eQTLs were also linked to other psychiatric disorders (e.g. Nucleic Acids Res. Introduction. 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). An official website of the United States government. National Library of Medicine 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. 1, Supplementary Table 3). This is further complicated by tissue averaging across the complex cellular organization and composition which is also different in early development and adulthood. 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. Google Scholar. Thousands of disease-associated SNPs (daSNPs) are located in intergenic regions (IGR), making it difficult to understand their association with disease phenotypes. In the meantime, to ensure continued support, we are displaying the site without styles 10, 643660 (2014). There are studies connecting cortical dysfunctions and ASD using imaging14, cortical architecture15, or gene expression16. Sign up for the Nature Briefing: Translational Research newsletter top stories in biotechnology, drug discovery and pharma. Nature 593, 238243 (2021). 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. Vannucchi, G., Perugi, G. & Masi, G. Bipolar disorder and ASD. Science 366, 11341139 (2019). 48, 12791283 (2016). Cell. https://doi.org/10.1038/s41588-022-01093-0, DOI: https://doi.org/10.1038/s41588-022-01093-0. 1). 4). Previous research has reported shared neurobiological and cellular processes associated with differences in cortical thickness across six psychiatric disorders (i.e. Phenotypes were defined as the mapped traits associated with the SNP in the GWAS Catalog. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. E.G. As such, our results only represent snap-shots within the plastic neurodevelopmental trajectory69,70. Transl. Nasser, J. et al. g:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update). Genet. In order to study spatial regulatory interactions in fetal and adult cortical tissues, we analysed two fetal brain-specific (i.e. T.L. They may be responsible for the diversity among individuals, geno SNPs: impact on gene function and phenotype 48, 552555 (2016). Musunuru, K. et al. Notably, transcript levels for genes within this pathway were not significantly affected by ASD-eQTLs within adult cortex tissues (2170years of age). 3). Cells 8, 1151 (2019). 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. doi: 10.1136/bmjdrc-2022-003164. fetal samples were aged from 14 to 21 postconceptional weeks and the adult samples were from individuals aged 2170years). 4). In the adult cortex, the known functions of the impacted genes were enriched in immune pathways. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). J Recept Signal Transduct Res. Godfrey, K. M. et al. Genetic and molecular features of seizure-freedom following surgical resections for focal epilepsy: A pilot study. PubMed 45, 12381243 (2013). Nucleic Acids Res. 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. The https:// ensures that you are connecting to the Rev. An AUTS2-Polycomb complex activates gene expression in the CNS. Thacker, S., Sefyi, M. & Eng, C. Alternative splicing landscape of the neural transcriptome in a cytoplasmic-predominant Pten expression murine model of autism-like Behavior. 8600 Rockville Pike ISSN 1061-4036 (print). Applications of computational tools to predict functional SNPs effects in human ErbB genes. eCollection 2022. 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. and C.W. Secondly, in our manuscript we focused on cortex-specific eQTL-gene connections. Identification of functional single nucleotide polymorphisms in the branchpoint site. Firstly, SNPs can mark regulatory regions that affect distant genes (i.e. All genomic positions and SNP annotations were obtained for human genome reference build hg38 (GRCh38) release 75. 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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). (d) 15 and 18 ASD-associated eQTLs affect at least one transcription factor binding sites within the fetal and adult cortical tissues, respectively. 3). Next, the CoDeS3D algorithm identified the restriction fragments interacting with the SNP-containing restriction fragments. We have shown that the transcript levels of genes, whose encoded proteins are known to contribute to immune pathways, fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome are affected in the fetal cortex. This site needs JavaScript to work properly. Lai, M.-C., Lombardo, M. V. & Baron-Cohen, S. Autism. 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. Article Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation. PubMed 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. Keller, R.) 89110 (Springer International Publishing, 2019). The transcript levels of the genes within the two unknown adult cortex PPI clusters increased (i.e. Google Scholar. Ensembl protein (STRING)33 and transcript identifiers (GTEx and Walker et al. However, it is likely that additional regions of the brain (e.g. Both HLA-DQB1 and HLA-DMA are examples of the MHC class II genes that are associated with processing of exogenous antigen. Nat. Regulatory roles and mechanisms of alternative RNA splicing in Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. Disord. Mechanism of HPSE Gene SNPs Function: From Normal Processes - Springer . 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. expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. What are single nucleotide polymorphisms (SNPs)? - MedlinePlus 370, 12091219 (2014). Proteins that were not annotated in the expression datasets were also removed from the CSPPI network. Hum Mol Genet. Clipboard, Search History, and several other advanced features are temporarily unavailable. Cell. 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. Question: how could SNP's contribute to gene regulation? - Chegg 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). Thereby, SNPs contribute to disease susceptibility, various responses to medication treatment and differences in outcomes within a disease population [8, 9]. 4, Supplementary Table 9). 4). 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. Genes that have essential functions show a decreased tolerance for loss-of-function (LoF) mutations32. Therefore, identification of numerous variations in genes and analysis of their effects may lead to a better understanding of their impact on gene function and health of an individual. We obtained ASD-associated SNPs from nine GWAS studies that were performed in cohorts containing individuals of mostly European ancestry (Supplementary Table 2). Google Scholar. SNPs: impact on gene function and phenotype - PubMed CAS Westra, H.-J. ASD-associated SNPs are enriched within non-coding putative regulatory regions. 2022 Sep 16;13:942643. doi: 10.3389/fneur.2022.942643. Neuron 83, 518532 (2014). 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. Science 376, eabf3041 (2022). Boyle, E. A., Li, Y. I. Article The cerebellum, sensitive periods, and autism. 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. ASD-associated eQTLs mark loci that spatially regulate the expression of genes involved in the fetal brain, in the adult brain, or both. Provided by the Springer Nature SharedIt content-sharing initiative, Nature Genetics (Nat Genet) Imputed genotypes were filtered for HardyWeinberg equilibrium p<1106, variant missing genotype rate 0.05 and minor allele frequency 0.01. ASD-associated eQTLs regulate 81 genes in fetal and 44 genes in adult cortical tissues (Fig. Tidsskr Nor Laegeforen. Gene expression variation can be seen across all levels of organismal organization (i.e. Golovina, E., Fadason, T., Lints, T.J. et al. The caveat of this is that the first approach can select the wrong gene and does not account for the effects of . how could SNP's contribute to gene regulation? Since the output is an easily manipulated spreadsheet, the user can sort the SNPs to highlight different SNP features. Google Scholar. Nucleic Acids Res. By contrast, in the adult cortex they largely affect immune pathways. Desai, D. & Pethe, P. Polycomb repressive complex 1: Regulators of neurogenesis from embryonic to adult stage. Transcript levels for these genes are associated with 65 eQTLs in fetal cortex and 39 eQTLs in adult cortex (Supplementary Table 3). 3). Finally, our approach focuses on identifying changes in gene regulation that are associated with and may contribute to ASD. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Google Scholar. Fetal and adult cortical tissue-specific PPI networks with immune and growth related phenotypes are affected by ASD-associated eQTLs. 3). Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Genetic control of expression and splicing in developing human brain informs disease mechanisms. Nucleic Acids Res. 1). supervised E.G. Backman, J. D. et al. ASD-eQTLs within the fetal cortex PPI aminoacyl-tRNA biosynthesis cluster are associated with: (a) increases in transcript levels for five genes (i.e. rSNPBase 3.0: an updated database of SNP-related regulatory elements and JavaScript. 235, 40314045 (2020). Motor cortex facilitation: A marker of attention deficit hyperactivity disorder co-occurrence in autism spectrum disorder. Reads where both ends had a mapq30 were included in the final library. Overview of the analysis pipeline used in this study. T.F. Trlungeanu, D. C. et al. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. For example, PRC1.5 is recruited to activate genes47 and in combination with AUTS2 (autism susceptibility candidate 2) activates gene expression in neurons47. Systematic identification of trans eQTLs as putative drivers of known disease associations. 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. Chiang, H.-L., Wu, J.-Y. How could so-called altruistic behaviors arise through natural selection? Transcript levels for four genes: (a) increased (i.e. 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. Brown, C. M., Austin, D. W. & Busija, L. Observable essential fatty acid deficiency markers and autism spectrum disorder. Integrative analysis of 111 reference human epigenomes. 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. Hormozdiari, F., Penn, O., Borenstein, E. & Eichler, E. E. The discovery of integrated gene networks for autism and related disorders. Klei, L. et al. 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. Psychiatry 11, 71 (2021). Similarly, the ribosome biogenesis in eukaryotes cluster contained ASD-eQTL associated genes whose transcripts were increased (n=5), decreased (n=4), and one that was subject to increases or decreases in transcript levels depending on specific ASD-eQTL. We found 80 and 58 SNPs that mark regulatory regions (i.e. SNPs are located in different regions of genes such as promoters, exons, introns, and 5 and 3 untranslated regions (UTR) and may affect gene expression and regulation. J. Abnorm. 2e). 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. HLA-DRB1, HLA-DMB and HLA-DMA; associated with exogenous peptide processing) genes. There are several reasons for this apparent discrepancy. and co-wrote the manuscript. 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). 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). Here, we focused on roles for changes within cortical tissue. non-coding RNAs); (2) ASD is a spectrum disorder not a single highly characterised phenotype; and (3) like all polygenic disorders, ASD is likely to be a whole of body disorder with important etiological contributions from discrete and distant organs within the body. Genes and environments, development and time | PNAS Adv. 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. 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). Gaugler, T. et al. Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: A systematic review. Nature 538, 523527 (2016). There is no fundamental reason why the same regulatory elements must or must not impact on the same gene in different tissues, or at different stages of development. 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. 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. PubMed 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. Interestingly, most of the genes within immune-related pathways in fetal cortex are associated with Polycomb-repressed ASD-eQTLs. Article Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. Nat. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database34 was used to query the most impacted biological pathways. Google Scholar. Slider with three articles shown per slide. RNA-seq data were processed by GTEx using RNA-seq analysis (https://github.com/broadinstitute/gtex-pipeline/tree/master/rnaseq) and eQTL discovery (https://github.com/broadinstitute/gtex-pipeline/tree/master/qtl) pipelines to calculate normalized gene expression and covariates. Bourgeron, T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. 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. official website and that any information you provide is encrypted 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. Enhancer elements are functional segments of DNA located in noncoding regions that play an important role in regulating gene expression. and JavaScript. 1). J.O.S. Article 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. Nat Genet 54, 748749 (2022). SNPs in genes that regulate DNA mismatch repair, cell cycle regulation, metabolism and immunity are associated with genetic susceptibility to cancer [ 1 - 12 ].
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