DiStasio, M. M., Nagakura, I., Nadler, M. J. Cells 8, 1151 (2019). 47, 12281235 (2015). Genet. Fetal and adult ASD-associated eQTLs were also associated with schizophrenia, unipolar depression, ADHD, bipolar disorder, anorexia nervosa and obsessivecompulsive disorder (Supplementary Fig. 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. By contrast, 9 fetal cortex-specific genes (i.e. Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health (NiPPeR): Study protocol for a randomised controlled trial. Polycomb proteins are known to be involved in transcriptional silencing43,44. What are single nucleotide polymorphisms (SNPs)? - MedlinePlus co-supervised E.G. 37, D832D836 (2009). We contend that our approach represents a valuable strategy to identify potential ASD candidate genes. Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: A systematic review. They may be responsible for the diversity among individuals, genome evolution, the most common familial traits such as curly hair, interindividual differences in drug response, and complex and common diseases such as diabetes, obesity, hypertension, and psychiatric disorders. 2f). Article Thank you for visiting nature.com. Briefly, the human genome reference (hg38) was fragmented at HindIII sites (A/AGCTT), the restriction enzyme that was used in the preparation of the Hi-C libraries. 20, 327348 (2010). 1). Science 376, eabf1970 (2022). Formulate hypotheses. Louvain clustering analysis identified seven highly connected PPI modules within fetal cortex. *Gene transcript levels are associated with the same eQTL in both the fetal and adult cortical tissues. The majority of ASD-associated SNPs are located within the non-coding components of the genome. Firstly, there was a significant enrichment of ASD-eQTLs within loci that are annotated as being regulated by PolyComb within the fetal, but not adult, cortex. trans-acting eQTLs)71. 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. Chiang, H.-L., Wu, J.-Y. 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. 51, 11601169 (2019). 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. PubMed Edges are only present if both interacting proteins are expressed in the cortical tissue. Internet Explorer). 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. 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. We also found that immune pathways were affected both in fetal and adult cortical tissues. 2022 Sep 23;13:973347. doi: 10.3389/fpls.2022.973347. Google Scholar. Transl. National Library of Medicine McCarthy, S. et al. 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). These differences can underlie susceptibility to common diseases, human traits, and differential responses to drugs. Nat. genes, whose expression levels are associated with a SNP). 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. The fetal immune PPI cluster contains both MHC class I (i.e. Blondel, V. D., Guillaume, J.-L., Lambiotte, R. & Lefebvre, E. Fast unfolding of communities in large networks. Rev. rSNPBase 3.0: an updated database of SNP-related regulatory elements & Jernigan, T. L. The basics of brain development. Res. ASD-associated eQTLs regulate 81 genes in fetal and 44 genes in adult cortical tissues (Fig. Explaining the disease phenotype of intergenic SNP through - PubMed PMC Dysregulation of fatty acid metabolism in early brain development may be a risk factor or marker for early-onset of ASD48. These mechanisms depend on the role o T.L. Nat. Klei, L. et al. Provided by the Springer Nature SharedIt content-sharing initiative, Nature Genetics (Nat Genet) Article Transcriptome-wide fetal and adult cortex-specific PPIs (CSPPIs) were constructed by combining the STRING PPI network with cortex-specific expression data from GTEx v8 or fetal brain datasets (Fig. Mountjoy, E. et al. ASD-associated SNPs are enriched within non-coding putative regulatory regions. 3). Notably, eQTLs involving rs13218591 and rs2237234 regulate different butyrophilin alleles (i.e. Internet Explorer). To obtain 47, D1005D1012 (2019). You are using a browser version with limited support for CSS. Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation. Next, the CoDeS3D algorithm identified the restriction fragments interacting with the SNP-containing restriction fragments. Psychiatry https://doi.org/10.1038/s41380-020-0773-x (2020). volume11, Articlenumber:15867 (2021) The proportions of eQTL and non-eQTL SNPs are significantly different in fetal and adult cortical tissues (Fishers exact test, p=0.04531). Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. SNP alleles in human disease and evolution. & Vasan, R. S. Next-generation genome-wide association studies: Time to focus on phenotype?. Usui, N. et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Integrative analysis of 111 reference human epigenomes. Rau, S. et al. 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). 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. Behav. Genet. Nature 516, 349354 (2014). Nat. 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. HHS Vulnerability Disclosure, Help Cardiovasc. Science 342, 253257 (2013). Nat. Article associated with an increase or reduction in transcript levels; 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 Google Scholar. One step closer to linking GWAS SNPs with the right genes Front. 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. Nucleic Acids Res. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. 3). VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction. Rev. Only SNPs associated with ASD with a p<5108 were included in downstream analyses. The PPI clusters with unknown functions (Fig. This site needs JavaScript to work properly. 359, 6585 (2015). Rare genetic susceptibility variants assessment in autism spectrum disorder: Detection rate and practical use. Disord. In our study eQTL data represent composite datasets across critical periods of development (e.g. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. Estes, M. L. & McAllister, A. K. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. 2a, Supplementary Table 3). Exploring the effects of genetic variation on gene regulation in cancer 2023 Apr;11(2):e003164. Nature 581, 434443 (2020). the effects of rs7432375 and rs7618871 on PCCB gene transcript levels are not collinear; Supplementary Fig. The Gene module within AutDB is a manually curated reference set of ASD-linked genes that was first released in 2007. ASD-associated eQTLs mark loci that spatially regulate the expression of genes involved in the fetal brain, in the adult brain, or both. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database34 was used to query the most impacted biological pathways. 3). PDF GENETIC ASSOCIATION STUDIES OF COMPLEX DISEASES ByYen - arXiv Psychiatry 8, 233 (2018). Tam, V. et al. Gene expression is the outcome of numerous processes including transcription, co-transcriptional splicing, mRNA export, and translation. PubMed Google Scholar. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Recent analysis found that non-coding daSNPs were frequently located in or approximate to regulatory elements, inspiring us to try to explain the disease phenotypes of IGR . 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). There are several reasons for this: (1) there are multiple potential mechanisms through which a genetic variant can impact on a phenotype. By contrast, incorporating data on spatial chromatin organization (i.e. Finally, protein identifiers (STRING)33 and transcript identifiers (GTEx and Walker et al. 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. Modules that were enriched with ASD-eQTL associated genes were identified in the fetal and adult cortical tissues. What are some common examples of known SNPs used in Buniello, A. et al. Thank you for visiting nature.com. Liggins Institute, University of Auckland, Auckland, New Zealand, E. Golovina,T. Fadason,M. H. Vickers&J. M. OSullivan, Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand, T. Fadason,M. H. Vickers&J. M. OSullivan, School of Medical Science, University of Auckland, Auckland, New Zealand, School of Population Health, University of Auckland, Auckland, New Zealand, Brain Research New Zealand, University of Auckland, Auckland, New Zealand, MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK, Garvan Institute of Medical Research, Sydney, Australia, You can also search for this author in 4), contained genes (i.e. Robinson, E. B. et al. All genomic positions and SNP annotations were obtained for human genome reference build hg38 (GRCh38) release 75. SNPs can also be used to track the inheritance of disease genes within families. Walker, R. L. et al. Nat. Patches of disorganization in the neocortex of children with autism. The resulting SNP-gene pairs were then used to query adult cortex, or fetal cortex eQTL databases to identify cis- and trans-acting eQTL-eGene interactions (i.e. and C.W. expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. 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). dorsolateral prefrontal cortex cells) cortex-specific Hi-C libraries. SNP. As such, our results only represent snap-shots within the plastic neurodevelopmental trajectory69,70. Genet. Transcript levels for 15 spatially regulated genes were altered by ASD-associated eQTLs in both the fetal and adult cortical tissues, 66 genes were specific to fetal cortex, and 29 eGenes were specific to the adult cortex. 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. & Kellis, M. Chromatin-state discovery and genome annotation with ChromHMM. Perspect. 3). The integration of spatial and functional data represents a significant difference from other approaches where functional assignments for phenotype-associated SNPs are typically made to the gene that is closest to the phenotype-associated SNP72. single nucleotide polymorphism / SNP | Learn Science at Scitable - Nature Aguet, F. et al. viral) lends some support the hypothesis that the risk of ASD may be greater among children whose mothers suffered from infectious or immune-related diseases during pregnancywhen the infant brain is developing60,61,62,63. antigen processing and presentation) as being enriched in the ASD-eQTL associated gene sets for both fetal and adult cortical tissues (Supplementary Fig. The SNP2TFBS27 database was queried to identify eQTLs that are predicted to alter the affinity of transcription factor binding sites (TFBSs). Secondly, in our manuscript we focused on cortex-specific eQTL-gene connections. 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. Again transcript levels for 12 genes are reduced. In the adult cortex, the known functions of the impacted genes were enriched in immune pathways. Python (version 3.6.9), R (version 4.0.2) and RStudio (version 1.2.5033) were used for data analysis and visualisation. cortical plate and germinal zone neurons), or adult (i.e. MacRae, C. A. Sign up for the Nature Briefing: Translational Research newsletter top stories in biotechnology, drug discovery and pharma. View Solution Related Answers how could SNP's contribute to gene regulation?. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). 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. Breastfeed. Nature 593, 238243 (2021). Bioinformatics 32, 289291 (2016). van Arensbergen, J. et al. 2, Supplementary Table 5). Thereby, SNPs contribute to disease susceptibility, various responses to medication treatment and differences in outcomes within a disease population [8, 9]. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). Google Scholar. Get the most important science stories of the day, free in your inbox. Szklarczyk, D. et al. Nucleic Acids Res. Our results support a dual role for Polycombas both a repressor and enhancer of transcriptionin the development of ASD risk. This is further complicated by tissue averaging across the complex cellular organization and composition which is also different in early development and adulthood. Since the output is an easily manipulated spreadsheet, the user can sort the SNPs to highlight different SNP features. 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. Psychiatry 9, 298 (2019). Nineteen eGenes are regulated by Polycomb-repressed eQTL SNPs, and seven eGenesby trans-acting eQTL SNPs in fetal cortex (Fig. Schmitt, A. D. et al. and JavaScript. chr1_61170_C_T_b38 where chr1 is chromosome name, 61170 is variant position on the chromosome, C is reference allele, T is alternate allele and b38 is genome build 38). Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Cell Tissue Res. Lombardo, M. V. Ribosomal protein genes in post-mortem cortical tissue and iPSC-derived neural progenitor cells are commonly upregulated in expression in autism. [Structural variation in the human genome contributes to variation of traits]. Nucleic Acids Res. & Visscher, P. M. Cell 173, 15731580 (2018). Nat. contributed to the eQTL analysis and commented on the manuscript. Google Scholar. The GTEx Consortium atlas of genetic regulatory effects across human tissues. ASD-eQTLs were also associated with increases in HCG27 (TPM=3) and NDUFA6 (TPM=116.31) transcript levels within fetal cortex. Smith, R. M. & Sadee, W. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders. doi: 10.1136/bmjdrc-2022-003164. (a) Of 344 ASD-associated SNPs represented in both fetal and adult cortex-specific eQTL databases, more SNPs (n=80) are involved in spatial eQTL-gene interactions in the fetal cortex than in the adult cortex (n=58). Lastly, tensorQTL (https://github.com/broadinstitute/tensorqtl) algorithm was used to perform cis- and trans-QTL mapping. 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. Fifteen of these shared eQTLs control the same eGenes in fetal and adult cortex (e.g. We identified changes within multiple key component pathways of gene expression (i.e. Synaptic Neurosci. 51, 431444 (2019). 12, 24782492 (2017). Enrichment analyses were performed using R package regioneR79 (permutation test: 1000). Understanding the mechanisms underlying the effects of SNPs that . how could snps contribute to gene regulation? 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). Trials 18, 131 (2017). Guillaume Lettre. 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. GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. Numerous genome-wide eQTL analyses have been reported to comprehensively capture such a DNA-RNA (i.e . Cell Syst. https://doi.org/10.1038/s41588-022-01087-y (2022). This network illustrates potential evidence for gene regulation related to RA-associated SNPs, and may provide comprehensive information for subsequent functional analyses and experiments. Solved 1. In which ways can the individual steps of this - Chegg They can act as biological markers, helping scientists locate genes that are associated with disease. Wang J, Su W, Zhang T, Zhang S, Lei H, Ma F, Shi M, Shi W, Xie X, Di C. Cell Death Dis. PubMed Central Cell Rep. 17, 20422059 (2016). Unable to load your collection due to an error, Unable to load your delegates due to an error. 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. 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. Genet. Article Author summary Risk for many diseases and related manifestations differs by sex. von Schimmelmann, M. et al. Abell, N. S. et al. Neurosci. PubMed JOS was also funded by a Royal Society of New Zealand Marsden Fund [Grant 16-UOO-072]. Genetic variants were filtered based on HardyWeinberg equilibrium p<1106, minor allele frequency 0.01 and variant missing genotype rate 0.05. All annotated human genes were chosen as the statistical domain scope. Would you like email updates of new search results? 78, 4763 (2021). ADS How could SNPs contribute to gene regulation? Bootstrapping analysis (n=10,000 iterations) was performed to test if observed overlaps were non-random. 44, 60466054 (2016). cerebellum68) or non-brain regions implicated in ASD may identify additional candidate genes. Genom. Brown, C. M., Austin, D. W. & Busija, L. Observable essential fatty acid deficiency markers and autism spectrum disorder. 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. 3). Science 353, 772777 (2016). 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. ZSCAN23 and LY6G5C) whose transcript levels increase or decrease, dependent upon specific eQTL. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. 2 How could SNPs contribute to gene regulation? BTN2A2 and BTN3A1 in the adult and fetal cortex, respectively). Question : How could SNPs contribute to gene regulation? Formulate In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. 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). Mol. 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. SNPs) among conditions was counted for each bootstrap iteration. 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. 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. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide.
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