22, 345361 (2016). Schmitt, A. D. et al. 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). Files containing cleaned Hi-C contacts locations (i.e. 1). Rev. Nat. View Solution Related Answers how could SNP's contribute to gene regulation?. contributed to the eQTL analysis and commented on the manuscript. Gentile, C. et al. 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). 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. PubMed Nat. Neurosci. You are using a browser version with limited support for CSS. Provided by the Springer Nature SharedIt content-sharing initiative, Nature Genetics (Nat Genet) Nat. [Structural variation in the human genome contributes to variation of traits]. Get the most important science stories of the day, free in your inbox. One step closer to linking GWAS SNPs with the right genes 2009;29(5):286-91. doi: 10.1080/10799890902911948. Proteins that were not annotated in the expression datasets were also removed from the CSPPI network. 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. 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. Psychiatry 10, 77 (2020). How do SNPs occur? Single-nucleotide polymorphism - Wikipedia Chiang, H.-L., Wu, J.-Y. Science 353, 772777 (2016). 48, 12791283 (2016). Rev. 2a, Supplementary Table 3). These mechanisms are not limited to impacts on gene regulation and can affect the splicing activity (so called sQTL SNPs 35), or trans-acting factors (e.g. Adult PPIs form three modules that were enriched in immune pathways and two unknown modules. 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. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Prevalence and outcomes of young people with concurrent autism spectrum disorder and first episode of psychosis. https://doi.org/10.1038/s41588-022-01093-0, DOI: https://doi.org/10.1038/s41588-022-01093-0. Explaining the disease phenotype of intergenic SNP through - PubMed Bookshelf Nat. 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. Genet. Internet Explorer). 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). PPI data was retrieved from STRING33 (version 11.0; 24/09/2020). Bootstrapping analysis (n=10,000 iterations) was performed to test if observed overlaps were non-random. By contrast, the rs1518367 eQTL is associated with reduced transcript levels for SF3B1 only in fetal cortex. doi: 10.1093/hmg/ddp003. Universit de Montral, Montreal, Quebec, Canada, Institut de Cardiologie de Montral, Montreal, Quebec, Canada, You can also search for this author in CAS We identified ASD-associated eQTLs that mark putative regulatory regions in fetal (n=80) and/or adult (n=80) cortical tissues. Using proteinprotein interaction (PPI) networks to explore interactions between proteins encoded by known disease-associated genes is a powerful approach to study the etiology of complex diseases, including psychiatric disorders17,18. Psychiatry 25, 31783185 (2020). government site. cortical plate and germinal zone neurons), or adult (i.e. Neurosci. & Anderson, M. P. T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains. Schizophr. Thirdly, the brain regions that are involved in the etiology of ASD remain difficult to determine. Finucane, H. K. et al. Frontiers | From GWAS to Function: Using Functional Genomics to doi: 10.1136/bmjdrc-2022-003164. Front. Understanding the mechanisms underlying the effects of SNPs that . Identifying Liver Cancer-Related Enhancer SNPs by Integrating - PubMed Brown, C. M., Austin, D. W. & Busija, L. Observable essential fatty acid deficiency markers and autism spectrum disorder. Careers. PDF GENETIC ASSOCIATION STUDIES OF COMPLEX DISEASES ByYen - arXiv Correspondence to PGBD1, ZKSCAN7, MPHOSPH9, TCF19 and VWA7); (b) decreases in transcript levels for VARS2; and (c) two genes (i.e. Identification of positional candidate genes for the skin fat phenotype in ducks. Understanding the impact of SNPs associated with autism - Nature By contrast, the rs3129968 minor allele is associated with a reduction in transcript levels for HLA-DRB1, which is expressed at low levels (TPM<1.25) within fetal cortex. ISSN 1546-1718 (online) Rev. (c) All ASD-associated eQTLs in adult cortex (n=58) and approximately 78 (97.5%) of the ASD-associated eQTLs within the fetal cortex are located within non-coding genomic regions (Supplementary Table 5). By contrast, the majority of ASD-associated eQTLs, that were identified in the adult cortex, are located within quiescent/low transcribed and weak transcription regions. J. Abnorm. J. Psychiatry 175, 359369 (2018). Question: how could SNP's contribute to gene regulation? - Chegg eCollection 2022. 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. The same reference genome and annotation files were used to calculate expression for fetal brain RNA-seq data. 57, 580594 (2015). Bourgeron, T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. JOS was also funded by a Royal Society of New Zealand Marsden Fund [Grant 16-UOO-072]. Neurosci. 25, 142154 (2015). When arising in genes, SNPs can impact on mRNA splicing, nucleo-cytoplasmic export, stability, and translation. 193-e22B-3 (Academic Press, 2016). identified a form of ASD resulting from a failure of the brain to properly import amino acidsa critical substrate in gene expression56. How could so-called altruistic behaviors arise through natural selection? Nat. For gene analysis, we resampled eGenes from the list of all genes in the genome (GENCODE transcript model version 26). We identified changes within multiple key component pathways of gene expression (i.e. EG is the recipient of a Liggins Ph.D. scholarship and was supported by MBIE Catalyst Grant (The New ZealandAustralia LifeCourse Collaboration on Genes, Environment, Nutrition and Obesity (GENO); UOAX1611). Estes, M. L. & McAllister, A. K. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Wray, N. R., Wijmenga, C., Sullivan, P. F., Yang, J. The GWAS Catalog is a publicly available database of all published GWAS studies76. KLC1, ZSCAN31 and TRIM26), or decreased (i.e. 2c). [34] Genome-wide genetic data can be generated by multiple technologies, including SNP array and whole genome sequencing. Article Klei, L. et al. Notably, eQTLs involving rs13218591 and rs2237234 regulate different butyrophilin alleles (i.e. 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. All datasets and software used in the analysis are listed in Supplementary Table 1. 12, 24782492 (2017). The proteinprotein interaction (PPIs) network serves as a foundation for cellular signalling circuitry, which mediates cellular responses to environmental and genetic cues. Genes that have essential functions show a decreased tolerance for loss-of-function (LoF) mutations32. 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. Ernst, J. Article Golovina, E., Fadason, T., Lints, T.J. et al. Benefits and limitations of genome-wide association studies. 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. Only SNPs associated with ASD with a p<5108 were included in downstream analyses. 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. We also found that immune pathways were affected both in fetal and adult cortical tissues. Sci. 84% of the genes we identified were not present in AutDB. The GTEx eQTL discovery (https://github.com/broadinstitute/gtex-pipeline/tree/master/qtl) pipeline was further used to calculate normalized gene expression and covariates. The butyrophilin genes encode proteins that belong to the immunoglobulin superfamily and help modulate the immune system23. b, Epigenomic sequencing reads (ChIP-seq and ATAC-seq) are merged on a per-individual basis and used to impute. Breastfeed. What are some common examples of known SNPs used in 2f). 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). Article Accessibility Solution 5 (1 Ratings ) Solved Biology 3 Years Ago 40 Views This Question has Been Answered! Neurosci. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. Hum. Szklarczyk, D. et al. In Psychopathology in Adolescents and Adults with Autism Spectrum Disorders (ed. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. MeSH Trials 18, 131 (2017). 1, Supplementary Table 3). Rev. Would you like email updates of new search results? Molecular genetics of human pigmentation diversity. The caveat of this is that the first approach can select the wrong gene and does not account for the effects of . 47, 165175 (2019). Li, F., An, Z. Finally, protein identifiers (STRING)33 and transcript identifiers (GTEx and Walker et al. 344 ASD-associated SNPs (p<5108) represented in both fetal and adult cortex-specific eQTL datasets were run through the CoDeS3D pipeline to identify 81 and 44 spatially regulated genes in fetal and adult cortical tissues, correspondingly. Mottron, L. & Bzdok, D. Autism spectrum heterogeneity: Fact or artifact?. 12, 405 (2018). Identification of non-coding silencer elements and their regulation of
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