12, 230 (2018). 3). 47, W191W198 (2019). 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 butyrophilin genes encode proteins that belong to the immunoglobulin superfamily and help modulate the immune system23. non-coding RNAs); (2) ASD is a spectrum . SNPs represent an important class of genetic variant, defined as a single-base change in the DNA sequence. 3). Transcript levels for four genes: (a) increased (i.e. 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. Basically, SNPs are copying errors. 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. We identified shared and development-specific changes to transcript levels for spatially regulated genes within immune pathways. Autism Spectr. *Hi-C datasets for cortical plate and germinal zone neurons (phs001190.v1.p1) were obtained from Won et al.19, Hi-C datasets for adult dorsolateral prefrontal cortex cells were obtained from Schmitt et al.12. Science 376, eabf3041 (2022). Changes to genes within the immune-related processes within adult cortex mostly affect the processing of exogenous antigen. Single nucleotide polymorphism (SNP) is the simplest form of DNA variation among individuals. For gene analysis, we resampled eGenes from the list of all genes in the genome (GENCODE transcript model version 26). Article spliceosome and splicing, aminoacyl-tRNA biosynthesis, and ribosome biogenesis) in the fetal cortex. 84% of the genes we identified were not present in AutDB. Nat. Cold Spring Harb. Most of these fetal ASD-associated eQTLs located within the Polycomb-repressed eQTLs were not identified as eQTLs in the adult cortex (Fig. EBioMedicine 58, 102917 (2020). Introduction. 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. The resulting vcf file was converted to plink format and information on sample sex included. 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. A Manhattan plot of association results from genome-wide association analysis.Y axis shows log 10 (P-value) of the association result for each SNP.Each SNP is indicated by a colored dot. & Wang, K. wANNOVAR: Annotating genetic variants for personal genomes via the web. Ensembl protein (STRING)33 and transcript identifiers (GTEx and Walker et al. We define a well-powered list of 2,320 sex-het SNPs showing sex-heterogeneity across multiple traits. Drug Metab Dispos. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database34 was used to query the most impacted biological pathways. It is estimated that the human genome contains more than 10 million different SNPs. antigen processing and presentation), protein kinase C signalling and regulation of cellcell adhesion processes (Supplementary Table 8). https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. HLA-DMA and BAG6 gene transcript levels are associated with distinct sets of eQTLs in both fetal and adult cortical tissues (Supplementary Fig. 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. Article Gao, Z. et al. 4). The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Szklarczyk, D. et al. & Paro, R. Transcriptional silencing by polycomb-group proteins. (e) Most of the fetal ASD-associated eQTLs are located within quiescent/low transcribed, week repressed PolyComb, repressed PolyComb and weak transcription regions. 42, 399403 (2017). fetal samples were aged from 14 to 21 postconceptional weeks and the adult samples were from individuals aged 2170years). 3, 1 (2011). However, this would require randomised control trials in animals prior to testing in humans. 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). GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. 37, D832D836 (2009). Correspondence to Nucleic Acids Res. 3). To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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. Mol. 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. 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. and co-wrote the manuscript. We extracted 2,000,451 proteinprotein interactions (with a combined score 400) between a total of 19,258 unique human proteins (Fig. CAS PubMed Article Trials 18, 131 (2017). Author summary Risk for many diseases and related manifestations differs by sex. Aguet, F. et al. There are studies connecting cortical dysfunctions and ASD using imaging14, cortical architecture15, or gene expression16. Nucleic Acids Res. Buniello, A. et al. ASD is widely considered to be a neurodevelopmental disorder resulting from functional changes within the brain. 1). These spatial interactions are dynamic, developmentally and temporally dependent13. Variants that do not have strand information for HumanOmni25-8v1-2_A1 and HumanOmni2-5Exome-8-v1-1-A genotyping chips were excluded (strand files and update_build.sh script were downloaded from https://www.well.ox.ac.uk/~wrayner/strand/, 01/07/2020, Supplementary Table 1). 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. In our study eQTL data represent composite datasets across critical periods of development (e.g. Transl. Res. 2009;29(5):286-91. doi: 10.1080/10799890902911948. Fetal and adult cortical tissue-specific PPI networks with immune and growth related phenotypes are affected by ASD-associated eQTLs. Perspect. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Karczewski, K. J. et al. Proteins that were not annotated in the expression datasets were also removed from the CSPPI network. *_merged_nodups.txt files) were processed to obtain Hi-C chromatin interaction libraries in the following format: read name, str1, chr1, pos1, frag1 mapq1, str2, chr2, pos2, frag2, mapq2 (str=strand, chr=chromosome, pos=position, frag=restriction site fragment, mapq=mapping quality score, 1 and 2 correspond to read ends in a pair). by chromatin immunoprecipitation); and (c) identify the Polycomb subunits that differentiate those sites that enhance or repress transcription within the developing cortex. 1, e1500737 (2015). Won, H. et al. Psychiatry 8, 233 (2018). The size of each node depends on the protein expression levels (no missing values and minimum expression level >0 TPM) in the corresponding cortical tissue. Article PubMedGoogle Scholar. Epidemiological studies estimate that approximately 1% of people worldwide have ASD2. Gazal, S. et al. ISSN 1546-1718 (online) Autism 3, 9 (2012). schizophrenia, ADHD, bipolar disorder). Genet. Google Scholar. Simply assigning function to the adjacent gene increases the number of false positive gene associations73. Unauthorized use of these marks is strictly prohibited. To build ASD-specific fetal and adult CSPPIs, only interactions between ASD-associated genes we extracted from fetal and adult CSPPIs. Eleven genes (i.e. Rau, S. et al. The caveat of this is that the first approach can select the wrong gene and does not account for the effects of . 3). 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. Silbereis, J. C., Pochareddy, S., Zhu, Y., Li, M. & Sestan, N. The cellular and molecular landscapes of the developing human central nervous system. American Psychiatric Association. SNP. 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. Solution 5 (1 Ratings ) Solved Biology 3 Years Ago 40 Views This Question has Been Answered! 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. 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. Finally, our approach focuses on identifying changes in gene regulation that are associated with and may contribute to ASD. cerebellum68) or other organs are important in the pathophysiology of ASD. However, rs4481150 is only associated with increased transcript levels for ITIH4 in adult cortex. Cell. a, CWAS identify epigenomic features that are genetically associated with a trait. As such, restriction fragments were used to identify regulatory interactions between SNPs and genes (Fig. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). how could SNP's contribute to gene regulation? All datasets and software used in the analysis are listed in Supplementary Table 1. Transcript levels for these genes are associated with 65 eQTLs in fetal cortex and 39 eQTLs in adult cortex (Supplementary Table 3). 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 Louvain clustering algorithm80 was further applied to identify ASD-specific clusters of functionally related proteins within the CSPPI networks. Nat. Within-family IDs were used as sample IDs in the output vcf file (recode vcf-iid bgz). Book Bookshelf CAS 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. sharing sensitive information, make sure youre on a federal Genetic variants were filtered based on HardyWeinberg equilibrium p<1106, minor allele frequency 0.01 and variant missing genotype rate 0.05. Husson, T. et al. 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. When SNPs occur within a gene or in a regulatory region near a gene, they often play a more direct role in the disease by affecting the function of the gene, either causing it to make a protein that works too well, or has less activity than normal, or completely stops its production. These differences can underlie susceptibility to common diseases, human traits, and differential responses to drugs. 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. 1). 2002;47(11):561-6. doi: 10.1007/s100380200086. 52, 13551363 (2020). In conclusion, we have identified clinically relevant putative functional impacts for ASD-associated genetic variants within fetal and adult cortical tissues. . A reference panel of 64,976 haplotypes for genotype imputation. Nat. Cell 50, 184-196.e4 (2019). Google Scholar. Over 11 million proteinprotein interactions (PPIs) were downloaded from STRING database (version 11.0) and combined with cortex-specific expression data (GTEx v8 or Walker et al. Genet. Science 375, 12471254 (2022). We identified ASD-associated eQTLs that mark putative regulatory regions in fetal (n=80) and/or adult (n=80) 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. 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. 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 Genes that have essential functions show a decreased tolerance for loss-of-function (LoF) mutations32. 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, 9598 (2016). J. Med. and C.W. Slider with three articles shown per slide. Genet. performed the analyses and wrote the manuscript. 4, 334336 (2011). Article PubMed Central Duplicated mapped reads were marked using Picard MarkDuplicates module (v2.21.4). N. Engl. Gaugler, T. et al. Neurosci. HLA-C and HLA-F; associated with endogenous antigen processing) and MHC class II (i.e. Provided by the Springer Nature SharedIt content-sharing initiative, Advances in Neurodevelopmental Disorders (2022). Rev. Ann. Disclaimer. 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. Wray, N. R., Wijmenga, C., Sullivan, P. F., Yang, J. 2022 Sep 16;13:942643. doi: 10.3389/fneur.2022.942643. Systematic identification of trans eQTLs as putative drivers of known disease associations. & Kellis, M. Chromatin-state discovery and genome annotation with ChromHMM. Tam, V. et al. We identified 42 PPIs in the fetal and 10 PPIs in the adult cortical tissues. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Removal of HLA genes from analyses of the adult cortex gene set identified a retained enrichment for immune-related processes (e.g. government site. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. Finally, we tested for enrichment of ASD-associated eQTLs within active regulatory elements and histone modification marks, using ChromHMM28 15-state models for adult dorsolateral prefrontal cortex and fetal brain. However, studies have shown that Polycomb repressive complexes (PRC) can have a dual role in gene regulation during development45,46. Chang, X. The Sanger Imputation Service (https://imputation.sanger.ac.uk/, 02/07/2020)74 was used to: (1) pre-phase the validated genotypes with Eagle (v2.4.1); and (2) to impute them using the 1000 Genomes Phase 3 multi-ethnic reference panel and PBWT algorithm. 2c). There are several reasons for this: (1) there are multiple potential mechanisms through which a genetic variant can impact on a phenotype. & Anderson, M. P. T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains. PubMed Central We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. Science 376, eabf1970 (2022). A Dockerfile (including the CoDeS3D pipeline and downstream analyses), all findings, scripts and reproducibility report are available on github at https://github.com/Genome3d/genetic_regulation_in_ASD. Single Nucleotide Polymorphism (SNP) SNPs are variations that involve a change in just one nucleotide. 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. GWAS has been commonly used in identifying SNPs associated with diseases or clinical phenotypes or traits. Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. 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. ASD-eQTLs within the fetal cortex PPI aminoacyl-tRNA biosynthesis cluster are associated with: (a) increases in transcript levels for five genes (i.e. Mahfouz, A., Ziats, M. N., Rennert, O. M., Lelieveldt, B. P. F. & Reinders, M. J. T. Shared pathways among autism candidate genes determined by co-expression network analysis of the developing human brain transcriptome. Nat. Nat. Willsey, A. J. et al. We found 80 and 58 SNPs that mark regulatory regions (i.e. 6, a019331 (2014). Furthermore, the Hi-C dataset used to inform the adult cortex analysis consisted of one sample (with one replicate), while two samples (each with three replicates) were used for the fetal cortex analysis (Supplementary Table 1). 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. J. SNPs may change the encoded amino acids (nonsynonymous) or can be silent (synonymous) or simply occur in the noncoding regions. volume11, Articlenumber:15867 (2021) Usui, N. et al. Finucane, H. K. et al. 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. Single nucleotide polymorphisms, frequently called SNPs (pronounced "snips"), are the most common type of genetic variation. Brodie, A., Azaria, J. R. & Ofran, Y. The mapping is shown for A the 1D linear genome and B the 3D genome structure constructed at the Hi-C resolution of 10 kbp. KLC1, ZSCAN31 and TRIM26), or decreased (i.e. The .gov means its official. https://doi.org/10.1038/s41588-022-01087-y (2022). The identified ASD-associated eQTLs were annotated using wANNOVAR tool77 (http://wannovar.wglab.org/, 10/08/2020) to obtain information about the locus they tagged (Supplementary Table 4). LoF analysis revealed that 59% (fetal) and 77% (adult) of the eGenes are tolerant to variation that alters the gene sequence. Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. Moreover, we identified development stage-specific eQTLs that were associated with gene transcript levels in either fetal, or adult cortical tissue (Supplementary Fig. Cells 8, 1151 (2019). Lai, M.-C., Lombardo, M. V. & Baron-Cohen, S. Autism. Mol. Kumar, S., Ambrosini, G. & Bucher, P. SNP2TFBSA database of regulatory SNPs affecting predicted transcription factor binding site affinity. 69, 101468 (2020). However, the remaining 15 eQTLs are associated with different eGenes in adult and fetal cortical tissues (Supplementary Table 4). 45, 984994 (2013). Nat. ASD-associated eQTLs mark loci that spatially regulate the expression of genes involved in the fetal brain, in the adult brain, or both. 25, 142154 (2015). The proportions of eQTL and non-eQTL SNPs are significantly different in fetal and adult cortical tissues (Fishers exact test, p=0.04531). Malinowska, M., Tokarz-Deptua, B. Identification of positional candidate genes for the skin fat phenotype in ducks. 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. Secondly, in our manuscript we focused on cortex-specific eQTL-gene connections. All genomic positions and SNP annotations were obtained for human genome reference build hg38 (GRCh38) release 75. PubMed Collectively, these findings are consistent with a subset of ASD-associated eQTLs acting in a combinatorial and development stage specific manner to affect the risk of developing ASD. Nat. Roles for immune dysfunction in ASD etiology are increasingly being identified57,58,59. Firstly, SNPs can mark regulatory regions that affect distant genes (i.e. Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. As such, our results only represent snap-shots within the plastic neurodevelopmental trajectory69,70. 2, Supplementary Table 5). Enrichment analyses were performed using R package regioneR79 (permutation test: 1000). We contend that changing the transcription levels of these genes, alters biological pathways that modify an individuals predisposition to develop ASD. associated with an increase or reduction in transcript levels; Supplementary Fig. 2d). Here, we focused on roles for changes within cortical tissue. 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. An AUTS2-Polycomb complex activates gene expression in the CNS. 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 ). Transl. For example, identical samples were not used in the ChromHMM, eQTL and Hi-C analyses of the fetal and adult cortical tissues. The authors declare no competing interests. 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. 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. Nat. 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. In Handbook of Hormones (eds Takei, Y. et al.) identified a form of ASD resulting from a failure of the brain to properly import amino acidsa critical substrate in gene expression56. The site is secure. 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. 1, Supplementary Table 3). Fetal ASD-associated eQTLs were located within quiescent/low transcribed (n=31), weak transcription (n=18), week repressed Polycomb (n=14) and repressed Polycomb (n=10) regions (Fig.
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