Tidsskr Nor Laegeforen. Science 375, 12471254 (2022). 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. 69, 101468 (2020). (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). Basically, SNPs are copying errors. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. Briefly, data were preprocessed to correct strand orientation and position of the variants on the GRCh37 reference genome (update_build.sh script). Boyle, E. A., Li, Y. I. 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. We contend that empirical studies are required to (a) confirm the regulatory activity of the sites (e.g. Transl. Get what matters in translational research, free to your inbox weekly. Neurosci. Neurosignals 18, 98112 (2010). PubMed Central There are several reasons for this apparent discrepancy. Briefly, read counts were normalised using the TMM algorithm and genes were selected if they had counts of 0.1 TPM in 20% samples and 6 unnormalized reads in 20% samples. antigen processing and presentation), protein kinase C signalling and regulation of cellcell adhesion processes (Supplementary Table 8). GWAS has been commonly used in identifying SNPs associated with diseases or clinical phenotypes or traits. doi: 10.1093/hmg/ddp003. Single nucleotide polymorphisms, frequently called SNPs (pronounced "snips"), are the most common type of genetic variation. 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. Gaugler, T. et al. In conclusion, we have identified clinically relevant putative functional impacts for ASD-associated genetic variants within fetal and adult cortical tissues. Science 342, 253257 (2013). ISSN 1061-4036 (print). Nature 599, 628634 (2021). 4). This will revolutionize the medical field in the future. How far from the SNP may the causative genes be?. This approach, in combination with clinical studies on ASD, will contribute to individualized mechanistic understanding of ASD development. Hudson, C. C., Hall, L. & Harkness, K. L. Prevalence of depressive disorders in individuals with autism spectrum disorder: A meta-analysis. Drug Metab Dispos. Pedapati, E. V. et al. All datasets and software used in the analysis are listed in Supplementary Table 1. Notably, 6 genes are associated with multiple eQTLs which exhibit opposing effects on transcript levels (Fig. Yazar, S. et al. Nat. cortical plate and germinal zone neurons), or adult (i.e. Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. 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). Within-family IDs were used as sample IDs in the output vcf file (recode vcf-iid bgz). Author summary Risk for many diseases and related manifestations differs by sex. 4). BCFtools were used to set variant IDs according to the GTEx variant ID format (e.g. As such, our results only represent snap-shots within the plastic neurodevelopmental trajectory69,70. 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. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. 16, 469486 (2015). von Schimmelmann, M. et al. A compendium of chromatin contact maps reveals spatially active regions in the human genome. 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. Genet. We find that sex-het SNPs influence a large set of diseases and health-related . Of these genes, 15 are spatially regulated in both fetal and adult cortical tissues (Fig. Nucleic Acids Res. However, the functions of the genetic variants that are responsible for the association with ASD remain poorly characterized. Finally, protein identifiers (STRING)33 and transcript identifiers (GTEx and Walker et al. Identification of functional single nucleotide polymorphisms in the branchpoint site. Overall, our findings highlight potential regulatory mechanisms and pathways important for the etiology of ASD in early brain development and adulthood. Secondly, the finding that these ASD-eQTLs are associated with both increases and decreases in transcript levels is consistent with the up- and downregulation of the target genes. 1, Supplementary Fig. WDR73 encodes the WD Repeat-containing protein 73 that is linked to microtubule organization and dynamics. 53, 15271533 (2021). Brodie, A., Azaria, J. R. & Ofran, Y. 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. Only SNPs associated with ASD with a p<5108 were included in downstream analyses. PubMed Single nucleotide polymorphism, or SNP. Pepper, K. L. et al. Nat. Hi-C libraries) and cortex-specific eQTLs to identify how ASD-associated SNPs impact cortex-specific gene expression. Louvain clustering analysis identified seven highly connected PPI modules within fetal cortex. ASD-eQTLs within the fetal cortex PPI aminoacyl-tRNA biosynthesis cluster are associated with: (a) increases in transcript levels for five genes (i.e. Nat. 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. Article 51, 431444 (2019). Universit de Montral, Montreal, Quebec, Canada, Institut de Cardiologie de Montral, Montreal, Quebec, Canada, You can also search for this author in Neurosci. antigen processing and presentation) as being enriched in the ASD-eQTL associated gene sets for both fetal and adult cortical tissues (Supplementary Fig. Article 84% of the genes we identified were not present in AutDB. 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. 78, 4763 (2021). Szklarczyk, D. et al. 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. 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. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Husson, T. et al. 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. Res. Han, V. X. et al. & Wang, K. wANNOVAR: Annotating genetic variants for personal genomes via the web. Paternally inherited cis-regulatory structural variants are associated with autism. Google Scholar. There are several reasons for this: (1) there are multiple potential mechanisms through which a genetic variant can impact on a phenotype. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. identified a form of ASD resulting from a failure of the brain to properly import amino acidsa critical substrate in gene expression56. Nat. 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 . 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. Molecular genetics of human pigmentation diversity. Kumar, S., Ambrosini, G. & Bucher, P. SNP2TFBSA database of regulatory SNPs affecting predicted transcription factor binding site affinity. Duplicated mapped reads were marked using Picard MarkDuplicates module (v2.21.4). Schmitt, A. D. et al. Functional gene ontology enrichment analysis identified immune-related processes (e.g. 1). Integrative analysis of 111 reference human epigenomes. Internet Explorer). Gazal, S. et al. We also found that immune pathways were affected both in fetal and adult cortical tissues. Synaptic Neurosci. Westra, H.-J. Psychiatry 11, 71 (2021). Genet. 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 ). Consistent with this, we identified that ASD-associated genetic variants impact transcript levels for genes involved in fatty acid metabolism in the developing fetal cortex (1421 postconceptional weeks). Nott, A. et al. An AUTS2-Polycomb complex activates gene expression in the CNS. 359, 6585 (2015). 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. By contrast, the rs1518367 eQTL is associated with reduced transcript levels for SF3B1 only in fetal cortex. Blondel, V. D., Guillaume, J.-L., Lambiotte, R. & Lefebvre, E. Fast unfolding of communities in large networks. Boulanger-Bertolus, J., Pancaro, C. & Mashour, G. A. *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. The authors would like to thank the Genomics and Systems Biology Group (Liggins Institute) for useful discussions. Integrating datasets across biological levels enables us to predict how genetic variation impacts on biological pathways and their involvement in the etiology of ASD. Gentile, C. et al. https://doi.org/10.1038/s41588-022-01093-0. The same reference genome and annotation files were used to calculate expression for fetal brain RNA-seq data. 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. cerebellum68) or non-brain regions implicated in ASD may identify additional candidate genes. Abnormalities in lipid metabolism may affect the proper functioning of the nervous system and, thus can contribute to ASD etiology48,49,50. Science 366, 11341139 (2019). 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. Nat. Science 362,eaat8127 (2018). Gene expression is the outcome of numerous processes including transcription, co-transcriptional splicing, mRNA export, and translation. sharing sensitive information, make sure youre on a federal The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Dev. 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). 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. Hi-C data) enables the identification of novel local and distal eQTL-gene connections. Google Scholar. trans-acting eQTLs)71. Brown, C. M., Austin, D. W. & Busija, L. Observable essential fatty acid deficiency markers and autism spectrum disorder. The caveat of this is that the first approach can select the wrong gene and does not account for the effects of . 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. Science 376, eabf1970 (2022). SNP alleles in human disease and evolution. 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. Knuesel, I. et al. Article Applications of computational tools to predict functional SNPs effects in human ErbB genes. Schizophr. By submitting a comment you agree to abide by our Terms and Community Guidelines. & Jernigan, T. L. The basics of brain development. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in https://doi.org/10.1038/s41588-022-01087-y, Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity. Front. PubMed Of the 80 fetal and 58 adult eQTLs, 30 were observed in both fetal and adult cortical tissues (Fig. 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. 1, Supplementary Table 3). Writing Committee for the Attention-Deficit/Hyperactivity Disorder et al. 3, 1 (2011). Adult and fetal cortex-specific PPIs (CSPPI) were generated. Genet. Hum. Chiang, H.-L., Wu, J.-Y. STRING v11: Proteinprotein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Increasing the number and sample sizes of the ASD GWAS studies will identify additional genetic variants which may help explain some of this missing heritability67. N. Engl. Both HLA-DQB1 and HLA-DMA are examples of the MHC class II genes that are associated with processing of exogenous antigen. 216, 310315 (2020). For gene analysis, we resampled eGenes from the list of all genes in the genome (GENCODE transcript model version 26). For example, PRC1.5 is recruited to activate genes47 and in combination with AUTS2 (autism susceptibility candidate 2) activates gene expression in neurons47. Briefly, merged fastq files were aligned to the GRCh38 reference genome (Homo_sapiens_assembly38_noALT_noHLA_noDecoy.fasta, gs://gtex-resources) using STAR (v2.5.3a). 51, 11601169 (2019). 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). 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. Stoner, R. et al. Fadason, T., Schierding, W., Lumley, T. & OSullivan, J. M. Chromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. As such, restriction fragments were used to identify regulatory interactions between SNPs and genes (Fig. 2f). Google Scholar. The significance of these associations in the developing cortex and how they contribute to the etiology of ASD remains to be empirically determined. There are studies connecting cortical dysfunctions and ASD using imaging14, cortical architecture15, or gene expression16. 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. Recall that the DNA sequence is formed from a chain of . However, it is not the only mechanism by which changes in the DNA sequence can contribute to ASD. These SNPs mostly locate within a gene or in a regulatory region near a gene and can affect the gene's function to Asthma-associated SNPs and genes from GWAS catalog. Nature 516, 349354 (2014). PRC2-associated chromatin contacts in the developing limb reveal a possible mechanism for the atypical role of PRC2 in HoxA gene expression. Cardiovasc. Cold Spring Harb. 4). Tamiji, J. The proportions of eQTL and non-eQTL SNPs are significantly different in fetal and adult cortical tissues (Fishers exact test, p=0.04531). Google Scholar. The resulting expression (GTEx_Analysis_v8_eQTL_expression_matrices.tar) and covariates (GTEx_Analysis_v8_eQTL_covariates.tar.gz) data were downloaded from GTEx website (https://www.gtexportal.org/home/datasets, 01/05/2020). Cells 8, 1151 (2019). SNPs are located in gene promoters, exons, introns as well as 5'- and 3'- untranslated regions (UTRs) and affect gene expression by different mechanisms. Aguet, F. et al. GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. Book 22, 345361 (2016). dorsolateral prefrontal cortex cells) cortex-specific Hi-C libraries. 47, W191W198 (2019). Imputed genotypes were filtered for HardyWeinberg equilibrium p<1106, variant missing genotype rate 0.05 and minor allele frequency 0.01. Trlungeanu, D. C. et al. ASD-associated SNPs (p<5108, n=454) were downloaded from the GWAS Catalog (Supplementary Tables 1 and 2). PubMed Central 3). American Psychiatric Association. Chang, X. and transmitted securely. TAP1 and TAP2); (b) decreased (HLA-DQB1); or (c) both increased and decreased depending on specific ASD-eQTLs (HLA-DMA; Fig. ZSCAN23 and LY6G5C) whose transcript levels increase or decrease, dependent upon specific eQTL. b, Epigenomic sequencing reads (ChIP-seq and ATAC-seq) are merged on a per-individual basis and used to impute. & Zhang, Z. Wray, N. R., Wijmenga, C., Sullivan, P. F., Yang, J. Chromosome conformation elucidates regulatory relationships in developing human brain. They may be responsible for the diversity among individuals, geno SNPs: impact on gene function and phenotype Psychiatry 10, 380 (2020). Single nucleotide polymorphism (SNP) is the simplest form of DNA variation among individuals. Nucleic Acids Res. 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. PPI data was retrieved from STRING33 (version 11.0; 24/09/2020). & Vasan, R. S. Next-generation genome-wide association studies: Time to focus on phenotype?. 22, 2126 (2014). 1). Lastly, tensorQTL (https://github.com/broadinstitute/tensorqtl) algorithm was used to perform cis- and trans-QTL mapping. Most commonly, SNPs are found in the DNA between genes. Bauer, D. E. et al. CAS 2e). Moreover, this approach is not tissue or disease specific and is capable of identifying previously unknown tissue-specific contributions to ASD etiology and its interactions with multimorbid conditions. Red stars are a SNPs highly associated with a disease at a p -value of 5 10 8. Bootstrapping analysis revealed that these overlaps are significant (p<0.01, n=10,000). Biol. Child Psychol. Maternal immune activation and abnormal brain development across CNS disorders. Genome-wide association study of traits in sacred lotus uncovers MITE-associated variants underlying stamen petaloid and petal number variations. Each bootstrap iteration generated samples of the same size as in the tested sample for tested condition. 16, 551563 (2015). Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Genetic variants were filtered based on HardyWeinberg equilibrium p<1106, minor allele frequency 0.01 and variant missing genotype rate 0.05. However, this would require randomised control trials in animals prior to testing in humans. Gene expression variation can be seen across all levels of organismal organization (i.e. The cerebellum, sensitive periods, and autism. Transl. 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. 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. PubMed Disord. CrossMap (v0.2.6) was used to convert coordinates of genetic variants from genome build hg19 to hg38, resulting in ~54.8 million genetic variants. However, the potential contributions of cortex-specific developmental changes to these networks in ASD development have yet to be investigated. Single nucleotide polymorphisms (SNPs) are one of the most common types of genetic variations in the human genome. 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. The butyrophilin genes encode proteins that belong to the immunoglobulin superfamily and help modulate the immune system23. View Solution Related Answers how could SNP's contribute to gene regulation?. Single Nucleotide Polymorphism (SNP) SNPs are variations that involve a change in just one nucleotide. Article SNP selection and data report Cell Syst. contributed to discussions that aided results interpretation and commented on the manuscript. Psychiatry https://doi.org/10.1038/s41380-020-0773-x (2020). 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. Nat. 45, 984994 (2013). Federal government websites often end in .gov or .mil. Science 353, 772777 (2016). The .gov means its official. Rev. Nucleic Acids Res. All genomic positions and SNP annotations were obtained for human genome reference build hg38 (GRCh38) release 75. genes, whose expression levels are associated with a SNP). 2002;47(11):561-6. doi: 10.1007/s100380200086. CAS 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). Here, we build on prior work to study a large set of anthropometric and biometric traits that could inform health differences by sex. & Chen, Y.-T. Motor cortex facilitation: A marker of attention deficit hyperactivity disorder co-occurrence in autism spectrum disorder. 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. The GTEx eQTL discovery (https://github.com/broadinstitute/gtex-pipeline/tree/master/qtl) pipeline was further used to calculate normalized gene expression and covariates. 2e). 3). viral) lends some support the hypothesis that the risk of ASD may be greater among children whose mothers suffered from infectious or immune-related diseases during pregnancywhen the infant brain is developing60,61,62,63. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. 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. 47, D607D613 (2019). How could SNPs contribute to gene regulation? 12, 230 (2018). Thirdly, the brain regions that are involved in the etiology of ASD remain difficult to determine. Buniello, A. et al. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). Nucleic Acids Res. 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. J. Med. 1). The author declares no competing interests. By contrast, 9 fetal cortex-specific genes (i.e. & Visscher, P. M. Cell 173, 15731580 (2018). ASD-associated eQTLs regulate 81 genes in fetal and 44 genes in adult cortical tissues (Fig. Genes were inverse normal transformed across samples. CAS Wang J, Su W, Zhang T, Zhang S, Lei H, Ma F, Shi M, Shi W, Xie X, Di C. Cell Death Dis. When SNPs are located near a gene, then it is postulated that the gene contributes to the variation under investigation. CAS 2d). associated with an increase or reduction in transcript levels; Supplementary Fig. Finucane, H. K. et al. As expected, the majority of identified eQTLs were located within intronic and intergenic regions (Fig. Genes depleted for null variants were defined as having pLI>0.9. Therefore, characterizing the functional impacts (i.e. 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. Backman, J. D. et al. https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. 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. 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). Genet. MATH J. M. OSullivan. 2008, P10008 (2008). Dysregulation of fatty acid metabolism in early brain development may be a risk factor or marker for early-onset of ASD48. Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex. Neurosci. Rev. g:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update). Patches of disorganization in the neocortex of children with autism. Nature 518, 317330 (2015). Nat. E.G. . Bootstrapping analysis (n=10,000 iterations) was performed to test if observed overlaps were non-random. 370, 12091219 (2014). 2023 Apr 6;14(4):244. doi: 10.1038/s41419-023-05763-7. PubMed Am. We incorporated cortex-specific expression patterns and PPI networks to identify candidate genes and pathways that have putative roles in the etiology of ASD-associated changes in the cortex. Genetic and molecular features of seizure-freedom following surgical resections for focal epilepsy: A pilot study. PubMed J. Immunol. Unauthorized use of these marks is strictly prohibited. As eQTL patterns are tissue-specific, we are unable to extrapolate the results of this study to these tissues. 4). However, rs4481150 is only associated with increased transcript levels for ITIH4 in adult cortex. Moreover, we identified development stage-specific eQTLs that were associated with gene transcript levels in either fetal, or adult cortical tissue (Supplementary Fig. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. BTN2A2 and BTN3A1 in the adult and fetal cortex, respectively). A new study highlights a strategy to link SNPs implicated in human complex traits and diseases with probable causal genes. Commun. 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. By contrast, the adult PPI gene set contained three highly connected modules, two of which were not associated with specific pathway, and one of which was enriched for immune pathways. 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. Circ. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL.

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