Cell 167, 1481-1494.e18 (2016). 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. Studies of non-coding disease-associated SNPs have demonstrated that they can mark regulatory elements that alter gene expression9,10. Author summary Risk for many diseases and related manifestations differs by sex. 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. Motor cortex facilitation: A marker of attention deficit hyperactivity disorder co-occurrence in autism spectrum disorder. 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. An AUTS2-Polycomb complex activates gene expression in the CNS. These eQTLs were also linked to other psychiatric disorders (e.g. The CoDeS3D algorithm then identified the restriction fragments containing the SNPs within fetal (i.e. The patterns of transcript changes in the adult cortex PPI network were similar to those observed in the fetal cortex. doi: 10.1136/bmjdrc-2022-003164. Most of these fetal ASD-associated eQTLs located within the Polycomb-repressed eQTLs were not identified as eQTLs in the adult cortex (Fig. KLC1, ZSCAN31 and TRIM26), or decreased (i.e. and transmitted securely. 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. 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. Klei, L. et al. For gene analysis, we resampled eGenes from the list of all genes in the genome (GENCODE transcript model version 26). Functional annotation of ASD-associated eQTLs revealed that they are involved in diverse regulatory processes. Phenotypes were defined as the mapped traits associated with the SNP in the GWAS Catalog. 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. Google Scholar. 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. Brandler, W. M. et al. Pedapati, E. V. et al. Trials 18, 131 (2017). Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. 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). 2e). regioneR: An R/Bioconductor package for the association analysis of genomic regions based on permutation tests. This will revolutionize the medical field in the future. N. Engl. How could SNPs contribute to gene regulation quizlet? Molecular genetics of human pigmentation diversity. Basu, S. N., Kollu, R. & Banerjee-Basu, S. AutDB: A gene reference resource for autism research. Mottron, L. & Bzdok, D. Autism spectrum heterogeneity: Fact or artifact?. HLA-DRB1, HLA-DMB and HLA-DMA; associated with exogenous peptide processing) genes. 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). Systematic localization of common disease-associate variation in regulatorty DNA. Nat. 1, e1500737 (2015). For example, rs35828350: (1) upregulates NMB in fetal cortex. (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. The butyrophilin genes encode proteins that belong to the immunoglobulin superfamily and help modulate the immune system23. https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. Sunwoo, M. et al. 2023 Jan 28;257(3):47. doi: 10.1007/s00425-023-04073-8. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). 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. 3). The significance of these associations in the developing cortex and how they contribute to the etiology of ASD remains to be empirically determined. Circ. The remaining read pairs we refer to as contacts. Finally, our approach focuses on identifying changes in gene regulation that are associated with and may contribute to ASD. 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). By contrast, the ASD-eQTL associations within the fetal cortex PPI fatty acid metabolism and spliceosome clusters are less complex (decreases: FADS1, TBL1X, SF3B1, or increases: FADS2, DHX38 and THOC7; Fig. & Vasan, R. S. Next-generation genome-wide association studies: Time to focus on phenotype?. We also found that immune pathways were affected both in fetal and adult cortical tissues. Rev. Adult and fetal cortex-specific PPIs (CSPPI) were generated. 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. datasets) to construct tissue-specific transcriptome-wide PPI networks. 47, D607D613 (2019). Article One of main contributions of SNPs in clinical research is genome-wide association study (GWAS). 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. Front. Golovina, E., Fadason, T., Lints, T.J. et al. Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health (NiPPeR): Study protocol for a randomised controlled trial. PMC Hi-C libraries) and cortex-specific eQTLs to identify how ASD-associated SNPs impact cortex-specific gene expression. 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. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. 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. 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. associated with an increase or reduction in transcript levels; Supplementary Fig. Nucleic Acids Res. Google Scholar. J. As such, our results only represent snap-shots within the plastic neurodevelopmental trajectory69,70. 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. The existence of changes within fetal cortex pathways for endogenous antigens (e.g. https://doi.org/10.1038/s41588-022-01087-y, Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity. 3, 1 (2011). Neurosci. 370, 12091219 (2014). Unable to load your collection due to an error, Unable to load your delegates due to an error. Gel, B. et al. Nature 466, 714719 (2010). Python (version 3.6.9), R (version 4.0.2) and RStudio (version 1.2.5033) were used for data analysis and visualisation. 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. Article Enhancer elements are functional segments of DNA located in noncoding regions that play an important role in regulating gene expression. Federal government websites often end in .gov or .mil. Genetic control of expression and splicing in developing human brain informs disease mechanisms. PubMed Central PubMed Central ADS Of the 80 fetal and 58 adult eQTLs, 30 were observed in both fetal and adult cortical tissues (Fig. (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). 19, 13211330 (2016). Previous research has reported shared neurobiological and cellular processes associated with differences in cortical thickness across six psychiatric disorders (i.e. Neurosci. High-throughput identification of human SNPs affecting regulatory element activity. 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). Maternal immune activation and abnormal brain development across CNS disorders. In Handbook of Hormones (eds Takei, Y. et al.) Hi-C chromatin interactions represent all captured pairs of interacting restriction fragments in the genome. SNPs represent an important class of genetic variant, defined as a single-base change in the DNA sequence. Commun. Perspect. TAP1 and TAP2); (b) decreased (HLA-DQB1); or (c) both increased and decreased depending on specific ASD-eQTLs (HLA-DMA; Fig. 49, 433436 (2012). Google Scholar. Hudson, C. C., Hall, L. & Harkness, K. L. Prevalence of depressive disorders in individuals with autism spectrum disorder: A meta-analysis. SNPs can also be used to track the inheritance of disease genes within families. Adv. In our study eQTL data represent composite datasets across critical periods of development (e.g. How could so-called altruistic behaviors arise through natural selection? Neurosci. Cent. The PPI clusters with unknown functions (Fig. Article We identified shared and development-specific changes to transcript levels for spatially regulated genes within immune pathways. Cell. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Google Scholar. Nat. Normalized vcf files were further validated using VCFtools (v0.1.15). Porokhovnik, L. Individual copy number of ribosomal genes as a factor of mental retardation and autism risk and severity. 2e). Duplicated mapped reads were marked using Picard MarkDuplicates module (v2.21.4). However, we contend that these results are consistent with the growing evidence that the vertical approach to connecting genetic variation to phenotype does not adequately account for the multimorbid nature of conditions within the typical variation that is present in humans. Adult PPIs form three modules that were enriched in immune pathways and two unknown modules. We functionally annotated the ASD-associated eQTLs to understand the potential regulatory mechanisms of the regions they tagged (Supplementary Table 5). Nature 516, 349354 (2014). We identified 42 PPIs in the fetal and 10 PPIs in the adult cortical tissues. 44, 60466054 (2016). Weissbrod, O. et al. Within-family IDs were used as sample IDs in the output vcf file (recode vcf-iid bgz). T.L. Synaptic Neurosci. Epidemiological studies estimate that approximately 1% of people worldwide have ASD2. 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 . We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. Article The CSPPIs represents subnetworks of the STRING PPI network, in which a protein/node is only present if it is expressed in the cortical tissue (adult or fetal). 45, D139D144 (2017). 1). Nature 593, 238243 (2021). ASD, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, unipolar depression, obsessivecompulsive disorder and schizophrenia), implicating common mechanisms underlying cortical development24.

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