Cell type- and differentiation-specific gene expression is precisely controlled by genomic non-coding regulatory elements (NCREs), which include promoters, enhancers, silencers and insulators. PubMed Tamiji, J. Eleven genes (i.e. Transcript levels for four genes: (a) increased (i.e. Phenotypes were defined as the mapped traits associated with the SNP in the GWAS Catalog. By submitting a comment you agree to abide by our Terms and Community Guidelines. 2009 Apr 15;18(R1):R9-17. Maternal immune activation and abnormal brain development across CNS disorders. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Nucleic Acids Res. Google Scholar. 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. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). Brandler, W. M. et al. Previous research has reported shared neurobiological and cellular processes associated with differences in cortical thickness across six psychiatric disorders (i.e. We contend that our approach represents a valuable strategy to identify potential ASD candidate genes. Changes to genes within the immune-related processes within adult cortex mostly affect the processing of exogenous antigen. At the same time, ASD-eQTLs are also associated with regulation of fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome pathways in fetal cortex. However, more than 84% of the identified spatially regulated genes were novel and have not previously been linked to autism or curated in AutDB. Cells 8, 788 (2019). ADS 57, 580594 (2015). Careers. DiStasio, M. M., Nagakura, I., Nadler, M. J. J Hum Genet. Commun. Again transcript levels for 12 genes are reduced. Hi-C data) enables the identification of novel local and distal eQTL-gene connections. Backman, J. D. et al. Common genetic variants, acting additively, are a major source of risk for autism. 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. Secondly, common SNPs only account for ~20% to the ASD risk6, suggesting that other genetic (e.g., rare variants, structural variation) and environmental factors also contribute to ASD etiology65,66. Hi-C libraries) and cortex-specific eQTLs to identify how ASD-associated SNPs impact cortex-specific gene expression. The Gene module within AutDB is a manually curated reference set of ASD-linked genes that was first released in 2007. PubMed Author summary Risk for many diseases and related manifestations differs by sex. 3). 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). government site. Genome Res. 37, D832D836 (2009). 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). We find that sex-het SNPs influence a large set of diseases and health-related . The butyrophilin genes encode proteins that belong to the immunoglobulin superfamily and help modulate the immune system23. and commented on the manuscript. The fetal immune PPI cluster contains both MHC class I (i.e. 22, 2126 (2014). [34] Genome-wide genetic data can be generated by multiple technologies, including SNP array and whole genome sequencing. J Recept Signal Transduct Res. M.V. [Structural variation in the human genome contributes to variation of traits]. Thousands of disease-associated SNPs (daSNPs) are located in intergenic regions (IGR), making it difficult to understand their association with disease phenotypes. 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. Single Nucleotide Polymorphism (SNP) SNPs are variations that involve a change in just one nucleotide. The transcript levels of the genes within the two unknown adult cortex PPI clusters increased (i.e. Am. A new study highlights a strategy to link SNPs implicated in human complex traits and diseases with probable causal genes. PubMed Central Keller, R.) 89110 (Springer International Publishing, 2019). the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 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. Gaugler, T. et al. 28, 2730 (2000). PubMed 45, 12381243 (2013). CAS Genet. J. Immunol. Silbereis, J. C., Pochareddy, S., Zhu, Y., Li, M. & Sestan, N. The cellular and molecular landscapes of the developing human central nervous system. Overview of the analysis pipeline used in this study. Python (version 3.6.9), R (version 4.0.2) and RStudio (version 1.2.5033) were used for data analysis and visualisation. Genotype data quality control was performed using PLINK (v2.0). As such, the genes we identified need not directly overlap those that have been previously curated as being involved in ASD through deletion or mutation studies. 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. The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Genom. In conclusion, we have identified clinically relevant putative functional impacts for ASD-associated genetic variants within fetal and adult cortical tissues. How do SNPs occur? All RNA-seq data were processed according to the GTEx pipeline (https://github.com/broadinstitute/gtex-pipeline/tree/master/rnaseq) (Supplementary Fig. SNPs may change the encoded amino acids (nonsynonymous) or can be silent (synonymous) or simply occur in the noncoding regions. 3). Notably, Polycomb repressive complexes have distinct regulatory roles in identity, proliferation and differentiation of neuronal progenitor cells during development29,30. 359, 6585 (2015). 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. Perez, R. K. et al. 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. 45, 984994 (2013). Nat. 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. 3). Grove, J. et al. Virtual histology of cortical thickness and shared neurobiology in 6 psychiatric disorders. 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. The proteinprotein interaction (PPIs) network serves as a foundation for cellular signalling circuitry, which mediates cellular responses to environmental and genetic cues. fetal samples were aged from 14 to 21 postconceptional weeks and the adult samples were from individuals aged 2170years). Notably, eQTLs involving rs13218591 and rs2237234 regulate different butyrophilin alleles (i.e. Google Scholar. All annotated human genes were chosen as the statistical domain scope. contracts here, Sign up for Nature Briefing: Translational Research. We functionally annotated the ASD-associated eQTLs to understand the potential regulatory mechanisms of the regions they tagged (Supplementary Table 5). APOPT1, AS3MT) with the ASD-eQTL. Smith, R. M. & Sadee, W. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders. We obtained ASD-associated SNPs from nine GWAS studies that were performed in cohorts containing individuals of mostly European ancestry (Supplementary Table 2). Lancet 383, 896910 (2014). 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). How could SNPs contribute to gene regulation quizlet? Nat. This network illustrates potential evidence for gene regulation related to RA-associated SNPs, and may provide comprehensive information for subsequent functional analyses and experiments. Finally, we evaluated identified eQTL SNP associations with other phenotypes in the GWAS Catalog (downloaded on 26/08/2020) (Supplementary Table 4). Karczewski, K. J. et al. Patches of disorganization in the neocortex of children with autism. https://doi.org/10.1038/s41588-022-01087-y (2022). Slider with three articles shown per slide. GWAS has been commonly used in identifying SNPs associated with diseases or clinical phenotypes or traits. We identified 42 PPIs in the fetal and 10 PPIs in the adult cortical tissues. Cell 50, 184-196.e4 (2019). Enrichment analyses were performed using R package regioneR79 (permutation test: 1000). expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. Increasing role of maternal immune activation in neurodevelopmental disorders. Han, V. X. et al. 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. Cell 155, 9971007 (2013). Single nucleotide polymorphism (SNP) is the simplest form of DNA variation among individuals. Article 235, 40314045 (2020). MATH PubMedGoogle Scholar. & Kellis, M. Chromatin-state discovery and genome annotation with ChromHMM. By contrast, incorporating data on spatial chromatin organization (i.e. 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. genes, whose expression levels are associated with a SNP). Top five genotype principal components (calculated using compute_genotype_pcs.py script from https://github.com/broadinstitute/gtex-pipeline/tree/master/genotype), 30 PEER factors, sex and genotyping platform were used as covariates in the eQTL analysis. 44, 60466054 (2016). Nat. We identified 21 and 23 eQTLs that reduce the affinity of at least one TFBS in fetal and adult cortical tissues, respectively (Fig. co-supervised E.G. Bioinformatics 32, 289291 (2016). 4), contained genes (i.e. To obtain 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.

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