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. 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. SNPs: impact on gene function and phenotype - PubMed Our results support a dual role for Polycombas both a repressor and enhancer of transcriptionin the development of ASD risk. (f) The majority of the fetal ASD-associated eQTLs that are located within weakly repressed PolyComb (ReprPCWk) and repressed PolyComb (ReprPC) regions were not identified as being eQTLs within the adult cortex. genes, whose expression levels are associated with a SNP). 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 compendium of chromatin contact maps reveals spatially active regions in the human genome. https://doi.org/10.1038/s41588-022-01093-0, DOI: https://doi.org/10.1038/s41588-022-01093-0. 28, 2730 (2000). Science 366, 11341139 (2019). In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Bookshelf Li, F., An, Z. Dynamics and stage-specificity of between-population gene expression To create a lookup table, genetic variants were annotated with rsIDs from dbSNP build 151 database. Lombardo, M. V. Ribosomal protein genes in post-mortem cortical tissue and iPSC-derived neural progenitor cells are commonly upregulated in expression in autism. 3). Frontiers | From GWAS to Function: Using Functional Genomics to & Jernigan, T. L. The basics of brain development. 2023 Apr 6;14(4):244. doi: 10.1038/s41419-023-05763-7. Fourthly, the human brain takes over two decades to build via precisely regulated cell type-specific molecular processes governed by both genetic blueprint and environmental factors. Nat. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. KEGG pathway analysis 34 of these modules revealed that they are associated with immune pathways, fatty acid metabolism, aminoacyl-tRNA biosynthesis, spliceosome, ribosome biogenesis in eukaryotes and two modules were not enriched for specific pathway (Fig. Genotype data quality control was performed using PLINK (v2.0). Neurosci. For example, if the user wants to find SNPs that might affect gene expression, he/she may choose to sort SNPs by regulatory potential score before sorting SNPs by function score. 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. life cycle [1,2], population [3-5], species [6-8], tissue [9,10], and cell [11,12]) and this variation drives phenotypic divergence among species and populations [13,14].A long-standing goal in population genetics and evolutionary biology has been to identify and characterize this . This observation is consistent with: (1) a comorbid association between ASD and schizophrenia25; or (2) a lack of resolution and precision in defining the ASD and schizophrenia phenotypes, and thus possible false positives in GWASs26. Of the 66 fetal cortex genes, transcript levels for 36 are upregulated in association with a change of the eQTL SNP to the minor allele, while 24 are reduced (Fig. (e) Most of the fetal ASD-associated eQTLs are located within quiescent/low transcribed, week repressed PolyComb, repressed PolyComb and weak transcription regions. Genet. In the meantime, to ensure continued support, we are displaying the site without styles HLA-C and HLA-F; associated with endogenous antigen processing) and MHC class II (i.e. 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. The SNPs located in enhancer elements may affect gene expression and lead to disease. https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. Provided by the Springer Nature SharedIt content-sharing initiative, Advances in Neurodevelopmental Disorders (2022). 20, 467484 (2019). SNPs represent an important class of genetic variant, defined as a single-base change in the DNA sequence. Am. PubMed Central 84% of the genes we identified were not present in AutDB. By submitting a comment you agree to abide by our Terms and Community Guidelines. 2009 May;37(5):977-91. doi: 10.1124/dmd.108.026047. The Louvain clustering algorithm80 was further applied to identify ASD-specific clusters of functionally related proteins within the CSPPI networks. Porokhovnik, L. Individual copy number of ribosomal genes as a factor of mental retardation and autism risk and severity. For example, rs35828350: (1) upregulates NMB in fetal cortex. Polycomb proteins are known to be involved in transcriptional silencing43,44. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. This will revolutionize the medical field in the future. Only SNP-phenotype associations with a p<5108 were included in the analysis. However, the functions of the genetic variants that are responsible for the association with ASD remain poorly characterized. Rev. Furthermore, we constructed fetal and adult cortex-specific proteinprotein interaction networks and identified that ASD-associated regulatory SNPs impact on immune pathways, fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome in the fetal cortex. E.G. volume11, Articlenumber:15867 (2021) Google Scholar. Gao Z, Liang Y, Wang Y, Xiao Y, Chen J, Yang X, Shi T. Front Plant Sci. 2009 Apr 15;18(R1):R9-17. sharing sensitive information, make sure youre on a federal Genotypes (derived by Whole Genome Sequencing) were processed by the Genotype-Tissue Expression (GTEx) project, and filtered genotypes (with minor allele frequency 0.1) for 838 tissue donors were downloaded from dbGaP (https://www.ncbi.nlm.nih.gov/gap/, 01/05/2020). Front. Modules that were enriched with ASD-eQTL associated genes were identified in the fetal and adult cortical tissues. Article By contrast, incorporating data on spatial chromatin organization (i.e. NMB encodes the neuromedin B peptide that regulates physiological processes including cell growth, exocrine and endocrine secretion22; and (2) downregulates WDR73 in adult cortex. Genet. 4). 3, 1 (2011). 1). The cerebellum, sensitive periods, and autism. By contrast, immune-related genes that are associated with ASD-eQTLs within the fetal cortex have been implicated in the processing of both endogenous and exogenous antigens (Supplementary Table 7). Science 362,eaat8127 (2018). & Kellis, M. Chromatin-state discovery and genome annotation with ChromHMM. Finucane, H. K. et al. aberrant splicing and ASD52,53; upregulation of ribosomal protein genes and a higher ribosomal gene dosage can be linked to ASD risk and severity54,55). Nucleic Acids Res. Cell Rep. 17, 20422059 (2016). TAP1 and TAP2); (b) decreased (HLA-DQB1); or (c) both increased and decreased depending on specific ASD-eQTLs (HLA-DMA; Fig. In Handbook of Hormones (eds Takei, Y. et al.) reviewed in29). 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. Genom. Therefore, the aims of the present study were to determine the TCOF1 gene's core promoter and to identify mutations in this region that could contribute to the phenotypic variation observed in this syndrome. Writing Committee for the Attention-Deficit/Hyperactivity Disorder et al. 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. Identifying comorbid ADHD in autism: Attending to the inattentive presentation. Psychiatry https://doi.org/10.1038/s41380-020-0773-x (2020). The regulatory effects can occur in trans (e.g. CAS MeSH Juicer provides a one-click system for analyzing loop-resolution Hi-C experiments. CAS 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. An official website of the United States government. Neurosci. Most of these fetal ASD-associated eQTLs located within the Polycomb-repressed eQTLs were not identified as eQTLs in the adult cortex (Fig. High-throughput identification of human SNPs affecting regulatory element activity. Rev. 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. Perez, R. K. et al. 78, 4763 (2021). cortical plate and germinal zone neurons)19 and one adult cortex-specific (i.e. Enrichment of the eQTLs within transcription factor binding sites was determined using SNP2TFBS (https://ccg.epfl.ch//snp2tfbs/, 07/09/2020)27. By contrast, the adult cortical gene set was largely related to immune pathways. Nature 593, 238243 (2021). Briefly, data were preprocessed to correct strand orientation and position of the variants on the GRCh37 reference genome (update_build.sh script). *The same eQTL is associated with transcription levels for the gene in both the fetal and adult cortical tissues. Both HLA-DQB1 and HLA-DMA are examples of the MHC class II genes that are associated with processing of exogenous antigen. Genet. 20, 327348 (2010). Nat. Previous research has reported shared neurobiological and cellular processes associated with differences in cortical thickness across six psychiatric disorders (i.e. Despite the existence of 15 genes in eQTL with ASD-associated SNPs in both fetal and adult cortical tissues, the majority of the changes in gene transcript levels were specific to either fetal (n=66), or adult (n=29) cortical tissue (Fig. 216, 310315 (2020). Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. These differences can underlie susceptibility to common diseases, human traits, and differential responses to drugs. Psychiatry 8, 233 (2018). Gaugler, T. et al. 16, 469486 (2015). Biol. 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. Increasing role of maternal immune activation in neurodevelopmental disorders. 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. 47, 12281235 (2015). Boulanger-Bertolus, J., Pancaro, C. & Mashour, G. A. 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. Identification of functional single nucleotide polymorphisms in the branchpoint site. There are several reasons for this: (1) there are multiple potential mechanisms through which a genetic variant can impact on a phenotype. dorsolateral prefrontal cortex cells) cortex-specific Hi-C libraries. Cardiovasc. Mech. Lastly, tensorQTL (https://github.com/broadinstitute/tensorqtl) algorithm was used to perform cis- and trans-QTL mapping. Abell, N. S. et al. J. M. OSullivan. Cis-eQTL SNPs are the SNPs that are within or around the corresponding gene, and trans-eQTL SNPs are those that are far away or even on dierent chromosomes. Normalized vcf files were further validated using VCFtools (v0.1.15). PubMedGoogle Scholar. Science 342, 253257 (2013). Patches of disorganization in the neocortex of children with autism. Our findings highlight potential mechanisms through which ASD-associated variants potentially contribute to ASD development (fetal) and onset/maintenance (adult). Proteins that were not annotated in the expression datasets were also removed from the CSPPI network. National Library of Medicine Removal of HLA genes from analyses of the adult cortex gene set identified a retained enrichment for immune-related processes (e.g. J. Stat. cortical plate and germinal zone neurons), or adult (i.e. Res. 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). expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. Gazal, S. et al. Grossniklaus, U. 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. CAS 4, 334336 (2011). Only SNPs associated with ASD with a p<5108 were included in downstream analyses. 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. However, more than 84% of the identified spatially regulated genes were novel and have not previously been linked to autism or curated in AutDB. 47, D607D613 (2019). & Zhang, Z. 2 How could SNPs contribute to gene regulation? 51, 431444 (2019). Protoc. Cent. Quality control metrics and gene-level expression data were calculated using RNA-seQC (v2.3.6) on the basis of GENCODE v26 gene annotation (gencode.v26.GRCh38.genes.gtf, gs://gtex-resources). Enhancer elements are functional segments of DNA located in noncoding regions that play an important role in regulating gene expression. We find that sex-het SNPs influence a large set of diseases and health-related . co-supervised E.G. 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. Adv. Desai, D. & Pethe, P. Polycomb repressive complex 1: Regulators of neurogenesis from embryonic to adult stage. Article Notably, we found that ASD-eQTL associated changes in transcript levels occurred in adult cortex immune pathways that were associated with processing of exogenous antigen. 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. 46, 881885 (2014). 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. Would you like email updates of new search results? 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. 22, 2126 (2014). Behav. Article We contend that changing the transcription levels of these genes, alters biological pathways that modify an individuals predisposition to develop ASD. However, the potential contributions of cortex-specific developmental changes to these networks in ASD development have yet to be investigated. identified a form of ASD resulting from a failure of the brain to properly import amino acidsa critical substrate in gene expression56. 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. Kumar, S., Ambrosini, G. & Bucher, P. SNP2TFBSA database of regulatory SNPs affecting predicted transcription factor binding site affinity. Nat. When arising in genes, SNPs can impact on mRNA splicing, nucleo-cytoplasmic export, stability, and translation. Here, we focused on roles for changes within cortical tissue. Nat. 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. 2008, P10008 (2008). To obtain How could SNPs contribute to gene regulation quizlet? Edges are only present if both interacting proteins are expressed in the cortical tissue. How far from the SNP may the causative genes be?. Schmitt, A. D. et al. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). However, this would require randomised control trials in animals prior to testing in humans. Identification of non-coding silencer elements and their regulation of Med. Neurol. Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health (NiPPeR): Study protocol for a randomised controlled trial. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). Thank you for visiting nature.com. Nott, A. et al. The number of shared items (e.g. These spatial interactions are dynamic, developmentally and temporally dependent13. ADS 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. https://doi.org/10.1038/s41588-022-01093-0. Cold Spring Harb. 45, 984994 (2013). Get what matters in translational research, free to your inbox weekly. Article J.O.S. In order to study spatial regulatory interactions in fetal and adult cortical tissues, we analysed two fetal brain-specific (i.e. 3). Enrichment analyses were performed using R package regioneR79 (permutation test: 1000). 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. Python (version 3.6.9), R (version 4.0.2) and RStudio (version 1.2.5033) were used for data analysis and visualisation. Most commonly, SNPs are found in the DNA between genes. SNPs) among conditions was counted for each bootstrap iteration. Tidsskr Nor Laegeforen. Genet. Smith, R. M. & Sadee, W. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders. Removal of all HLA genes from the analysis, identified enrichments for genes involved in fatty acid metabolism and processes related to the endoplasmic-reticulum-associated protein degradation (ERAD) pathway within fetal cortex. Molecular genetics of human pigmentation diversity. As we observed for other pathways, there was a developmental separation in the immune pathways that were affected in the fetal and adult cortical tissues. 2a, Supplementary Table 3). The significance level was determined using the BH algorithm (FDR<0.05). Exploring the effects of genetic variation on gene regulation in cancer 51, 11601169 (2019). 3). 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. & Visscher, P. M. Cell 173, 15731580 (2018). Thirdly, the brain regions that are involved in the etiology of ASD remain difficult to determine. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. Grove, J. et al. McCarthy, S. et al. associated with an increase or reduction in transcript levels; Supplementary Fig. 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. Google Scholar. Bootstrapping analysis (n=10,000 iterations) was performed to test if observed overlaps were non-random. What are some common examples of known SNPs used in Gao, Z. et al. and C.W. J Hum Genet. Article 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. Neurol. 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. 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). schizophrenia, ADHD, bipolar disorder). MacArthur, J. et al. 2023 Jan 28;257(3):47. doi: 10.1007/s00425-023-04073-8. PubMedGoogle Scholar. Collectively, these observations are consistent with changes in the regulation of subsets of stable and remodelled spatial eQTLs, over the course of brain development, being associated with a predisposition to ASD. A SNP is a one-letter place where your genome varies from another genome sequence. CAS Durand, N. C. et al. The resulting vcf file was converted to plink format and information on sample sex included. eQTL datasets for fetal and adult cortex were obtained from Walker et al.20 and GTEx v821, correspondingly. Identification of positional candidate genes for the skin fat phenotype in ducks. PubMed However, switching the ASD-eQTL to the minor allele is associated with an increase in transcript levels for these genes within the fetal cortex (Fig. 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. By contrast, in the adult cortex they largely affect immune pathways. 1, e1500737 (2015). PDE10A, PBX1, SF3B1, BAG6 and RERE) were LoF intolerant (Supplementary Table 6). & Deptua, W. Butyrophilins: An important new element of resistance. FOIA 48, 12791283 (2016). 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. The authors would like to thank the Genomics and Systems Biology Group (Liggins Institute) for useful discussions. 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. The significance of these associations in the developing cortex and how they contribute to the etiology of ASD remains to be empirically determined. Prevalence and outcomes of young people with concurrent autism spectrum disorder and first episode of psychosis. They can act as biological markers, helping scientists locate genes that are associated with disease. Firstly, there is a great phenotypic heterogeneity within autism spectrum disorders, which has led to question their classification into a single diagnostic category64. 47, 165175 (2019). dorsolateral prefrontal cortex cells)12 Hi-C chromatin interaction libraries (Supplementary Table 1). You are using a browser version with limited support for CSS. Virtual histology of cortical thickness and shared neurobiology in 6 psychiatric disorders. Formulate hypotheses. We observed that schizophrenia has the largest significant overlap with ASD-associated eQTLs both in fetal (78 out of 80, bootstrapping p<0.01, n=10,000) and adult (57 out of 58, bootstrapping p<0.01, n=10,000) cortical tissues (Supplementary Fig. 3). Malinowska, M., Tokarz-Deptua, B. doi: 10.1136/bmjdrc-2022-003164. 16, 551563 (2015). 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. 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. 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. We identified shared and development-specific changes to transcript levels for spatially regulated genes within immune pathways. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. *Gene transcript levels are associated with the same eQTL in both the fetal and adult cortical tissues. 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). CAS American Psychiatric Association. SNPs are, of course, already routinely used in human studies to test individual genes or genomic regions for their association with disease phenotypes. Article ADS When SNPs are located near a gene, then it is postulated that the gene contributes to the variation under investigation. Science 376, eabf3041 (2022). Files containing cleaned Hi-C contacts locations (i.e. Sample-level gene read and TPM (Transcripts Per kilobase Million) counts were concatenated using combine_GCTs.py.