dorsolateral prefrontal cortex cells)12 Hi-C chromatin interaction libraries (Supplementary Table 1). volume54,pages 748749 (2022)Cite this article. 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. This network illustrates potential evidence for gene regulation related to RA-associated SNPs, and may provide comprehensive information for subsequent functional analyses and experiments. One step closer to linking GWAS SNPs with the right genes We define a well-powered list of 2,320 sex-het SNPs showing sex-heterogeneity across multiple traits. Google Scholar. Within-family IDs were used as sample IDs in the output vcf file (recode vcf-iid bgz). Increasing role of maternal immune activation in neurodevelopmental disorders. Roles for immune dysfunction in ASD etiology are increasingly being identified57,58,59. 2a, Supplementary Table 3). Secondly, in our manuscript we focused on cortex-specific eQTL-gene connections. J.O.S. 2009 Apr 15;18(R1):R9-17. Google Scholar. Porokhovnik, L. Individual copy number of ribosomal genes as a factor of mental retardation and autism risk and severity. Again transcript levels for 12 genes are reduced. Musunuru, K. et al. A SNP is a one-letter place where your genome varies from another genome sequence. 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. A single nucleotide polymorphism, or SNP (pronounced "snip"), is a variation at a single position in a DNA sequence among individuals. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Kumar, S., Ambrosini, G. & Bucher, P. SNP2TFBSA database of regulatory SNPs affecting predicted transcription factor binding site affinity. Abnormalities in lipid metabolism may affect the proper functioning of the nervous system and, thus can contribute to ASD etiology48,49,50. Hormozdiari, F., Penn, O., Borenstein, E. & Eichler, E. E. The discovery of integrated gene networks for autism and related disorders. Breastfeed. 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). 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. Epub 2009 Feb 9. Before ADS Careers. 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. Google Scholar. Provided by the Springer Nature SharedIt content-sharing initiative, Advances in Neurodevelopmental Disorders (2022). https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. Article 2022 Sep 23;13:973347. doi: 10.3389/fpls.2022.973347. Different eQTLs are often associated with the gene transcript levels, although the effects of the minor allele are typically similar for the gene in question (i.e. Book Nucleic Acids Res. 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. 42, 399403 (2017). Normalized vcf files were further validated using VCFtools (v0.1.15). Genet. Nature Genetics Psychiatry 9, 298 (2019). 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. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. SNPs: impact on gene function and phenotype - PubMed ADS Cell Rep. 17, 20422059 (2016). RNA-seq data) were mapped to Ensembl gene identifiers. Nat. (b) Thirty ASD-associated SNPs are eQTLs in both fetal and adult cortical tissues. Backman, J. D. et al. The same reference genome and annotation files were used to calculate expression for fetal brain RNA-seq data. 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). PRC2-associated chromatin contacts in the developing limb reveal a possible mechanism for the atypical role of PRC2 in HoxA gene expression. 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. Hi-C libraries) and cortex-specific eQTLs to identify how ASD-associated SNPs impact cortex-specific gene expression. For SNPs analysis, we resampled SNPs from the list of all GWAS SNPs with gwas p<5108. Brown, C. M., Austin, D. W. & Busija, L. Observable essential fatty acid deficiency markers and autism spectrum disorder. SNPs and Disease We are all genetically different. Science 353, 772777 (2016). 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. The cerebellum, sensitive periods, and autism. Bourgeron, T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. The authors would like to thank the Genomics and Systems Biology Group (Liggins Institute) for useful discussions. 1). Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. 12, 230 (2018). 78, 4763 (2021). 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. Fetal and adult cortical tissue-specific PPI networks with immune and growth related phenotypes are affected by ASD-associated eQTLs. 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. CAS Tamiji, J. Systematic localization of common disease-associate variation in regulatorty DNA. fetal samples were aged from 14 to 21 postconceptional weeks and the adult samples were from individuals aged 2170years). Functional gene ontology enrichment analysis identified immune-related processes (e.g. DiStasio, M. M., Nagakura, I., Nadler, M. J. 216, 310315 (2020). Han, V. X. et al. Genetic determinants of chromatin reveal prostate cancer risk mediated PGBD1, ZKSCAN7, MPHOSPH9, TCF19 and VWA7); (b) decreases in transcript levels for VARS2; and (c) two genes (i.e. Adult PPIs form three modules that were enriched in immune pathways and two unknown modules. Mountjoy, E. 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). doi: 10.1136/bmjdrc-2022-003164. The Louvain clustering algorithm80 was further applied to identify ASD-specific clusters of functionally related proteins within the CSPPI networks. We detail the method, apply it to data from The Cancer Genome Atlas, and provide a tool to explore the findings. Cold Spring Harb. Schizophr. sharing sensitive information, make sure youre on a federal Disord. Perspect. Of 454 ASD-associated SNPs, 344 SNPs were represented in both fetal and adult cortex eQTL databases, and were run through the CoDeS3D pipeline (Fig. 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. Nasser, J. et al. and co-wrote the manuscript. Transl. Google Scholar. Cardiovasc. Firstly, there is a great phenotypic heterogeneity within autism spectrum disorders, which has led to question their classification into a single diagnostic category64. Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. This data-driven approach enables the discovery of SNPs whose alleles impact gene regulation by miRNAs, with functional consequences for tumor biology. PubMed Genet. Google Scholar. 11, 27 (2017). 370, 12091219 (2014). Article Van Rooij, D. et al. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. 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. Liggins Institute, University of Auckland, Auckland, New Zealand, E. Golovina,T. Fadason,M. H. Vickers&J. M. OSullivan, Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand, T. Fadason,M. H. Vickers&J. M. OSullivan, School of Medical Science, University of Auckland, Auckland, New Zealand, School of Population Health, University of Auckland, Auckland, New Zealand, Brain Research New Zealand, University of Auckland, Auckland, New Zealand, MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK, Garvan Institute of Medical Research, Sydney, Australia, You can also search for this author in official website and that any information you provide is encrypted Since the output is an easily manipulated spreadsheet, the user can sort the SNPs to highlight different SNP features. 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). Bookshelf 28, 2730 (2000). Sample-level gene read and TPM (Transcripts Per kilobase Million) counts were concatenated using combine_GCTs.py. A new study highlights a strategy to link SNPs implicated in human complex traits and diseases with probable causal genes. PubMed Genet. 3). Genet. PubMed Central Gene expression variation can be seen across all levels of organismal organization (i.e. Reads where both ends had a mapq30 were included in the final library. 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A. Cell type- and differentiation-specific gene expression is precisely controlled by genomic non-coding regulatory elements (NCREs), which include promoters, enhancers, silencers and insulators. Notably, 6 genes are associated with multiple eQTLs which exhibit opposing effects on transcript levels (Fig. NMB encodes the neuromedin B peptide that regulates physiological processes including cell growth, exocrine and endocrine secretion22; and (2) downregulates WDR73 in adult cortex. and transmitted securely. WDR73 encodes the WD Repeat-containing protein 73 that is linked to microtubule organization and dynamics. Writing Committee for the Attention-Deficit/Hyperactivity Disorder et al. Thirdly, the brain regions that are involved in the etiology of ASD remain difficult to determine. Five genes within this cluster (i.e. 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. Wray, N. R., Wijmenga, C., Sullivan, P. F., Yang, J. PubMed Central Question: how could SNP's contribute to gene regulation? - Chegg Front. 3). Roadmap Epigenomics Consortium et al. 1, Supplementary Table 3). Paternally inherited cis-regulatory structural variants are associated with autism. Numerous genome-wide eQTL analyses have been reported to comprehensively capture such a DNA-RNA (i.e . The GTEx Consortium atlas of genetic regulatory effects across human tissues. 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. contributed to discussions that aided results interpretation and commented on the manuscript. Science 362,eaat8127 (2018). Science 375, 12471254 (2022). 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. Patches of disorganization in the neocortex of children with autism. 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. expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. 3, 1 (2011). CAS Google Scholar. Rev. 3, Supplementary Table 4). 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). Hi-C chromatin interactions represent all captured pairs of interacting restriction fragments in the genome. 69, 101468 (2020). Duplicated mapped reads were marked using Picard MarkDuplicates module (v2.21.4). 22, 2126 (2014). Sci. 1, e1500737 (2015). 47, D1005D1012 (2019). cortical plate and germinal zone neurons), or adult (i.e. For example, identical samples were not used in the ChromHMM, eQTL and Hi-C analyses of the fetal and adult cortical tissues. Cell 167, 1481-1494.e18 (2016). Psychiatry 8, 233 (2018). Mottron, L. & Bzdok, D. Autism spectrum heterogeneity: Fact or artifact?. T.L. Google Scholar. Weissbrod, O. et al. 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. 3). schizophrenia, ADHD, bipolar disorder). All genomic positions and SNP annotations were obtained for human genome reference build hg38 (GRCh38) release 75. However, the potential contributions of cortex-specific developmental changes to these networks in ASD development have yet to be investigated. Next, the CoDeS3D algorithm identified the restriction fragments interacting with the SNP-containing restriction fragments. Introduction. Ensembl protein (STRING)33 and transcript identifiers (GTEx and Walker et al. Chromosome conformation elucidates regulatory relationships in developing human brain. J. Med. Firstly, SNPs can mark regulatory regions that affect distant genes (i.e. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Nineteen eGenes are regulated by Polycomb-repressed eQTL SNPs, and seven eGenesby trans-acting eQTL SNPs in fetal cortex (Fig. Nat. 4). regQTLs: Single nucleotide polymorphisms that modulate microRNA - PLOS 19, 13211330 (2016). 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. The main strength of this study is the integration of independent data sets, across distinct biological levels, that include cortex-specific 3D genome structure, eQTL and PPI data with ASD-associated GWAS SNPs. by chromatin immunoprecipitation); and (c) identify the Polycomb subunits that differentiate those sites that enhance or repress transcription within the developing cortex. The Gene module within AutDB is a manually curated reference set of ASD-linked genes that was first released in 2007. Most of these fetal ASD-associated eQTLs located within the Polycomb-repressed eQTLs were not identified as eQTLs in the adult cortex (Fig. J. Mol. Genet. MacArthur, J. et al. Neurosci. Nature 599, 628634 (2021). Won, H. et al. These differences can underlie susceptibility to common diseases, human traits, and differential responses to drugs. If you are reading a news story where it says, for example, scientists find the genetic contributors to diabetes or some other condition or trait, you're probably reading about SNPS. 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. Genet. 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. PubMed Central 46, 881885 (2014). Hughes, H. K., Mills Ko, E., Rose, D. & Ashwood, P. immune dysfunction and autoimmunity as pathological mechanisms in autism spectrum disorders. 3). 2009 May;37(5):977-91. doi: 10.1124/dmd.108.026047. Thousands of disease-associated SNPs (daSNPs) are located in intergenic regions (IGR), making it difficult to understand their association with disease phenotypes. Simply assigning function to the adjacent gene increases the number of false positive gene associations73. PubMed 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. We contend that empirical studies are required to (a) confirm the regulatory activity of the sites (e.g. 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. 3). 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. Interacting fragments that overlapped annotated genes (GENCODE transcript model version 26) were subsequently identified (hereafter referred to as SNP-gene pairs).