The site is secure. Article An AUTS2-Polycomb complex activates gene expression in the CNS. SNPs: impact on gene function and phenotype - PubMed 51, 11601169 (2019). Autism 3, 9 (2012). 12, 230 (2018). Eleven genes (i.e. Nat. 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. (d) 15 and 18 ASD-associated eQTLs affect at least one transcription factor binding sites within the fetal and adult cortical tissues, respectively. Mechanism of HPSE Gene SNPs Function: From Normal Processes - Springer and C.W. cerebellum68) or non-brain regions implicated in ASD may identify additional candidate genes. Fetal and adult ASD-associated eQTLs were also associated with schizophrenia, unipolar depression, ADHD, bipolar disorder, anorexia nervosa and obsessivecompulsive disorder (Supplementary Fig. SF3B1 and THOC7 were also associated with ASD-eQTLs within the adult cortex. how could snps contribute to gene regulation? Ann. 359, 6585 (2015). T.F. Common genetic variants, acting additively, are a major source of risk for autism. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Finally a number of fetal (n=50) and adult (n=28) cortex-specific eQTLs were observed (Supplementary Table 3). The SNP2TFBS27 database was queried to identify eQTLs that are predicted to alter the affinity of transcription factor binding sites (TFBSs). Single-nucleotide polymorphism - Wikipedia doi: 10.1093/hmg/ddp003. volume11, Articlenumber:15867 (2021) All annotated human genes were chosen as the statistical domain scope. To evaluate possible commonalities among ASD and other phenotypes at the eQTL level in the fetal and adult cortex, we intersected the identified ASD-associated eQTLs with SNPs associated with other traits in the GWAS catalog (p<5108, assessed on 26/08/2020). How could SNPs contribute to gene regulation quizlet? 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. The majority of ASD-associated SNPs are located within the non-coding components of the genome. Desai, D. & Pethe, P. Polycomb repressive complex 1: Regulators of neurogenesis from embryonic to adult stage. Knuesel, I. et al. 2f). ADS 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. Google Scholar. Bauer, D. E. et al. Bioinformatics 32, 289291 (2016). Vannucchi, G., Perugi, G. & Masi, G. Bipolar disorder and ASD. 19, 13211330 (2016). 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. We define a well-powered list of 2,320 sex-het SNPs showing sex-heterogeneity across multiple traits. We contend that our approach represents a valuable strategy to identify potential ASD candidate genes. J. Eur. https://doi.org/10.1038/s41588-022-01087-y (2022). MacArthur, J. et al. Front. Understanding the impact of SNPs associated with autism - Nature 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. Genotype data quality control was performed using PLINK (v2.0). the effects of rs7432375 and rs7618871 on PCCB gene transcript levels are not collinear; Supplementary Fig. Cell Tissue Res. 6, a019331 (2014). Here, we integrated ASD-associated GWAS SNPs with cortex-specific 3D genome structure and eQTL information to identify genes that are spatially regulated in fetal (1421 postconceptional weeks) and adult (2170years of age) cortical tissues. Dev. Psychiatry 25, 31783185 (2020). antigen processing and presentation) as being enriched in the ASD-eQTL associated gene sets for both fetal and adult cortical tissues (Supplementary Fig. Cell. Simply assigning function to the adjacent gene increases the number of false positive gene associations73. Genet. Genet. Transl. Increasing role of maternal immune activation in neurodevelopmental disorders. However, it is not the only mechanism by which changes in the DNA sequence can contribute to ASD. Louvain clustering identified seven PPI modules within the fetal cortex that were enriched for immune pathways, fatty acid metabolism, aminoacyl-tRNA biosynthesis, spliceosome, ribosome biogenesis in eukaryotes and two unknown modules. CAS TAP1 and TAP2); (b) decreased (HLA-DQB1); or (c) both increased and decreased depending on specific ASD-eQTLs (HLA-DMA; Fig. Article Identifying comorbid ADHD in autism: Attending to the inattentive presentation. VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction. 45, D896D901 (2017). Neurosci. Formulate hypotheses. Abell, N. S. et al. Lettre, G. One step closer to linking GWAS SNPs with the right genes. To obtain 10, 643660 (2014). & Zhang, Z. 2008 Sep 11;128(17):1951-5. Science 337, 11901195 (2012). 1, Supplementary Table 3). Raudvere, U. et al. Most genetic risk for autism resides with common variation. b, Epigenomic sequencing reads (ChIP-seq and ATAC-seq) are merged on a per-individual basis and used to impute. Nat. Tidsskr Nor Laegeforen. Randomised controlled trials involving pre- and post-conception interventions with different lipids are currently being undertaken or followed up (e.g.51)opening the possibility of post-hoc analyses for ASD risk. We find that sex-het SNPs influence a large set of diseases and health-related . Hum. By contrast, 9 fetal cortex-specific genes (i.e. Cells 8, 1151 (2019). We contend that changing the transcription levels of these genes, alters biological pathways that modify an individuals predisposition to develop ASD. 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). However, rs4481150 is only associated with increased transcript levels for ITIH4 in adult cortex. 22, 2126 (2014). 2023 Jan 28;257(3):47. doi: 10.1007/s00425-023-04073-8. 1). Neurosci. 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. Enrichment analyses were performed using R package regioneR79 (permutation test: 1000). Gentile, C. et al. Rare genetic susceptibility variants assessment in autism spectrum disorder: Detection rate and practical use. Clipboard, Search History, and several other advanced features are temporarily unavailable. Genet. and transmitted securely. Single nucleotide polymorphism (SNP) is the simplest form of DNA variation among individuals. We also found that immune pathways were affected both in fetal and adult cortical tissues. Perez, R. K. et al. Google Scholar. *The same eQTL is associated with transcription levels for the gene in both the fetal and adult cortical tissues. 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. For example, identical samples were not used in the ChromHMM, eQTL and Hi-C analyses of the fetal and adult cortical tissues. We identified 21 and 23 eQTLs that reduce the affinity of at least one TFBS in fetal and adult cortical tissues, respectively (Fig. However, in noncoding regions, the mechanism of how SNPs contribute to disease susceptibility remains unclear. 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. Ernst, J. Federal government websites often end in .gov or .mil. Nat. PubMed Central Neuron 83, 518532 (2014). The proteinprotein interaction (PPIs) network serves as a foundation for cellular signalling circuitry, which mediates cellular responses to environmental and genetic cues. 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. ASD, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, unipolar depression, obsessivecompulsive disorder and schizophrenia), implicating common mechanisms underlying cortical development24. Identification of positional candidate genes for the skin fat phenotype in ducks. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Moreover, we identified development stage-specific eQTLs that were associated with gene transcript levels in either fetal, or adult cortical tissue (Supplementary Fig. Usui, N. et al. WDR73 encodes the WD Repeat-containing protein 73 that is linked to microtubule organization and dynamics. 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). non-coding RNAs); (2) ASD is a spectrum . 370, 12091219 (2014). 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. Transl. In total, 663,956 variants passed QC filters. 45, 984994 (2013). All genomic positions and SNP annotations were obtained for human genome reference build hg38 (GRCh38) release 75. Genes were inverse normal transformed across samples. Front. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 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. Paternally inherited cis-regulatory structural variants are associated with autism. Genet. Genet. 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). Nat. SNPs are plotted based on the reference duck genome chromosome (x-axis).The horizontal solid line is the threshold for the . 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. Solution 5 (1 Ratings ) Solved Biology 3 Years Ago 40 Views This Question has Been Answered! When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene's function. 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. Willsey, A. J. et al. They may influence promoter activity (gene expression), messenger RNA (mRNA) conformation (stability), and subcellular localization of mRNAs and/or proteins and hence may produce disease. Blondel, V. D., Guillaume, J.-L., Lambiotte, R. & Lefebvre, E. Fast unfolding of communities in large networks. Sci Rep 11, 15867 (2021). 4). Collectively, our results provide insight into potential cortex-specific regulatory mechanisms and pathways through which ASD-associated SNPs can contribute to the development and maintenance of ASD. Google Scholar. eQTL datasets for fetal and adult cortex were obtained from Walker et al.20 and GTEx v821, correspondingly. 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. These mechanisms depend on the role o Google Scholar. contracts here, Sign up for Nature Briefing: Translational Research. 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. However, it is likely that additional regions of the brain (e.g. Nat. 3, Supplementary Table 4). Klei, L. et al. & Crawford, D. A. 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. Keller, R.) 89110 (Springer International Publishing, 2019). by chromatin immunoprecipitation); and (c) identify the Polycomb subunits that differentiate those sites that enhance or repress transcription within the developing cortex. Neurosci. Schizophr. 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. In the meantime, to ensure continued support, we are displaying the site without styles Nat. A common two-phase adipogenesis process is described: early determination and terminal differentiation phases, involving an intricate integration of cytoarchitecture, transcription factors and co-regulators, and signaling pathways. Applications of computational tools to predict functional SNPs effects in human ErbB genes. CAS To identify existing and novel gene associations, we intersected our lists of genes, from fetal and adult cortical tissues, with a curated list of 1237 genes that had been previously implicated in autism development (AutDB31, accessed on 16/11/2020). Corley, M. & Kroll, K. L. The roles and regulation of Polycomb complexes in neural development. What are some common examples of known SNPs used in Prevalence and outcomes of young people with concurrent autism spectrum disorder and first episode of psychosis. Imputed genotypes were filtered for HardyWeinberg equilibrium p<1106, variant missing genotype rate 0.05 and minor allele frequency 0.01. 3, 9598 (2016). Genome-wide association study of traits in sacred lotus uncovers MITE-associated variants underlying stamen petaloid and petal number variations. They can act as biological markers, helping scientists locate genes that are associated with disease. Science 362,eaat8127 (2018). A large number of genes associated with various cancer types contain single nucleotide polymorphisms (SNPs). eCollection 2022. Brandler, W. M. et al. Genet. Fadason, T., Schierding, W., Lumley, T. & OSullivan, J. M. Chromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities. & Anderson, M. P. T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains. 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. BTN2A2 and BTN3A1 in the adult and fetal cortex, respectively). Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. Autism, early psychosis, and social anxiety disorder: Understanding the role of social cognition and its relationship to disability in young adults with disorders characterized by social impairments. Adv. J. Med. Boulanger-Bertolus, J., Pancaro, C. & Mashour, G. A. Disclaimer. Ensembl protein (STRING)33 and transcript identifiers (GTEx and Walker et al. 46, 881885 (2014). 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. Slider with three articles shown per slide. The significance level was determined using the BH algorithm (FDR<0.05). Louis S, Busch RM, Lal D, Hockings J, Hogue O, Morita-Sherman M, Vegh D, Najm I, Ghosh C, Bazeley P, Eng C, Jehi L, Rotroff DM. ADS Trials 18, 131 (2017). Overall, our findings highlight potential regulatory mechanisms and pathways important for the etiology of ASD in early brain development and adulthood. Res. 86, 885898 (2019). Nat. 3). The expression level in an indivisual is measured by the measuring the Trascribed mRNA, by the method of Northern blot . A. Sey, Benxia Hu, Hyejung Won, Anja Barei, Alexander Jolyon Nash, Boris Lenhard, Gokul Ramaswami, Hyejung Won, Daniel H. Geschwind, Michael J. Gandal, Jillian R. Haney, Daniel H. Geschwind, Mirolyuba Ilieva, Blanca Irene Aldana, Tanja Maria Michel, Jhih-Rong Lin, Yingjie Zhao, Zhengdong D. Zhang, Esra Sefik, Ryan H. Purcell, Jennifer G. Mulle, Scientific Reports Integrative analysis of 111 reference human epigenomes. 4). For gene analysis, we resampled eGenes from the list of all genes in the genome (GENCODE transcript model version 26). PubMed Nat. dorsolateral prefrontal cortex cells)12 Hi-C chromatin interaction libraries (Supplementary Table 1). 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. & Kellis, M. Chromatin-state discovery and genome annotation with ChromHMM. APOPT1, AS3MT) with the ASD-eQTL. Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. . Porokhovnik, L. Individual copy number of ribosomal genes as a factor of mental retardation and autism risk and severity. 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. Google Scholar. Bethesda, MD 20894, Web Policies 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. Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. A functional SNP in the promoter region of TCOF1 is associated - PubMed https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. rs10791097-SNX19, rs11191419-AS3MT, rs7085104-AS3MT, rs174592-FADS1; Supplementary Table 4). 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. Genet. Nature 593, 238243 (2021). Cold Spring Harb. Brown, C. M., Austin, D. W. & Busija, L. Observable essential fatty acid deficiency markers and autism spectrum disorder. FOIA Our finding that a subset of the identified ASD-associated eQTLs were linked to psychiatric phenotypes highlights the existence of potential shared regulatory mechanisms contributing to the risk of developing these multimorbid conditions. Article Bootstrapping analysis (n=10,000 iterations) was performed to test if observed overlaps were non-random. Here, we build on prior work to study a large set of anthropometric and biometric traits that could inform health differences by sex. 193-e22B-3 (Academic Press, 2016). The author declares no competing interests. Article As eQTL patterns are tissue-specific, we are unable to extrapolate the results of this study to these tissues. 3). 48, 552555 (2016). 20, 467484 (2019). Gazal, S. et al. EBioMedicine 58, 102917 (2020). & Vasan, R. S. Next-generation genome-wide association studies: Time to focus on phenotype?. Nature 518, 317330 (2015). 1). Polycomb proteins are known to be involved in transcriptional silencing43,44. 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. Firstly, SNPs can mark regulatory regions that affect distant genes (i.e. Moreover, Trlungeanu et al. This method prioritizes genes for functional characterization and helps address questions about the architecture of human phenotypes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database34 was used to query the most impacted biological pathways. Chiang, H.-L., Wu, J.-Y. 2e). Google Scholar. Hi-C chromatin interactions represent all captured pairs of interacting restriction fragments in the genome. 2 How could SNPs contribute to gene regulation? Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Karczewski, K. J. et al. 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. Universit de Montral, Montreal, Quebec, Canada, Institut de Cardiologie de Montral, Montreal, Quebec, Canada, You can also search for this author in *Gene transcript levels are associated with the same eQTL in both the fetal and adult cortical tissues. 1, e1500737 (2015). Lai, M.-C., Lombardo, M. V. & Baron-Cohen, S. Autism. 4, 334336 (2011). 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. Nat. What are single nucleotide polymorphisms (SNPs)? - MedlinePlus 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. 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. However, our study also has several limitations. Here, we focused on roles for changes within cortical tissue. Nucleic Acids Res. 216, 310315 (2020). Westra, H.-J. Nat. The authors declare no competing interests. Commun. Lancet 383, 896910 (2014). We identified shared and development-specific changes to transcript levels for spatially regulated genes within immune pathways. We obtained ASD-associated SNPs from nine GWAS studies that were performed in cohorts containing individuals of mostly European ancestry (Supplementary Table 2). Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. 57, 580594 (2015). However, this would require randomised control trials in animals prior to testing in humans. For example, PRC1.5 is recruited to activate genes47 and in combination with AUTS2 (autism susceptibility candidate 2) activates gene expression in neurons47. PubMed Modules that were enriched with ASD-eQTL associated genes were identified in the fetal and adult cortical tissues. Author summary Risk for many diseases and related manifestations differs by sex.