Hum Mol Genet. Finally, significant cortex-specific eQTL-eGene interactions were identified using the Benjamini-Hochberg (BH) FDR correction to adjust the eQTL p values (FDR<0.05) (Supplementary Table 3). Nineteen eGenes are regulated by Polycomb-repressed eQTL SNPs, and seven eGenesby trans-acting eQTL SNPs in fetal cortex (Fig. a, CWAS identify epigenomic features that are genetically associated with a trait. Fifthly, we are aware that the tools and datasets used in this study are potentially biased. Van Rooij, D. et al. Genet. What are some common examples of known SNPs used in J. Stat. Removal of HLA genes from analyses of the adult cortex gene set identified a retained enrichment for immune-related processes (e.g. Neuron 83, 518532 (2014). The majority of ASD-associated SNPs are located within the non-coding components of the genome. Enrichment of the eQTLs within transcription factor binding sites was determined using SNP2TFBS (https://ccg.epfl.ch//snp2tfbs/, 07/09/2020)27. 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. 2f). KLC1, ZSCAN31 and TRIM26), or decreased (i.e. 2009 Apr 15;18(R1):R9-17. Brain cell type-specific enhancer-promoter interactome maps and disease-risk association. Fifteen of these shared eQTLs control the same eGenes in fetal and adult cortex (e.g. Hudson, C. C., Hall, L. & Harkness, K. L. Prevalence of depressive disorders in individuals with autism spectrum disorder: A meta-analysis. volume11, Articlenumber:15867 (2021) Article 4). ISSN 1061-4036 (print). J.O.S. Cells 8, 788 (2019). Our results support a dual role for Polycombas both a repressor and enhancer of transcriptionin the development of ASD risk. Gene expression is the outcome of numerous processes including transcription, co-transcriptional splicing, mRNA export, and translation. Front Neurol. PubMed Central The authors would like to thank the Genomics and Systems Biology Group (Liggins Institute) for useful discussions. 6, a019331 (2014). The same reference genome and annotation files were used to calculate expression for fetal brain RNA-seq data. Thank you for visiting nature.com. However, it is likely that additional regions of the brain (e.g. The resulting vcf file was converted to plink format and information on sample sex included. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. Duplicated mapped reads were marked using Picard MarkDuplicates module (v2.21.4). We identified changes within multiple key component pathways of gene expression (i.e. Wang, S.S.-H., Kloth, A. D. & Badura, A. 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. When arising in genes, SNPs can impact on mRNA splicing, nucleo-cytoplasmic export, stability, and translation. An official website of the United States government. Nat. Frontiers | Exploring the Impact of Single-Nucleotide Polymorphisms on Genet. 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. Unauthorized use of these marks is strictly prohibited. Over the past decade, genome-wide association (GWAS) and genetic studies have identified increasing numbers of single nucleotide polymorphisms (SNPs)3,4 and other forms of variation (e.g., copy number variants, rare structural variants)5,6 that are associated with ASD. SNPs: impact on gene function and phenotype - PubMed EBioMedicine 58, 102917 (2020). Transcript levels for 15 spatially regulated genes were altered by ASD-associated eQTLs in both the fetal and adult cortical tissues, 66 genes were specific to fetal cortex, and 29 eGenes were specific to the adult cortex. The proportions of eQTL and non-eQTL SNPs are significantly different in fetal and adult cortical tissues (Fishers exact test, p=0.04531). This problem has been solved! Genotype data quality control was performed using PLINK (v2.0). By contrast, incorporating data on spatial chromatin organization (i.e. 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. VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction. These spatial interactions are dynamic, developmentally and temporally dependent13. MeSH D'Esposito D, Guadagno A, Amoroso CG, Cascone P, Cencetti G, Michelozzi M, Guerrieri E, Ercolano MR. Planta. Westra, H.-J. Article Lai, M.-C., Lombardo, M. V. & Baron-Cohen, S. Autism. miRNA) or by spatial associations of the regulatory element and target gene. Notably, Polycomb repressive complexes have distinct regulatory roles in identity, proliferation and differentiation of neuronal progenitor cells during development29,30. b, Epigenomic sequencing reads (ChIP-seq and ATAC-seq) are merged on a per-individual basis and used to impute. Maternal immune activation and abnormal brain development across CNS disorders. 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. & Jernigan, T. L. The basics of brain development. We find that sex-het SNPs influence a large set of diseases and health-related . dorsolateral prefrontal cortex cells)12 Hi-C chromatin interaction libraries (Supplementary Table 1). Science 376, eabf3041 (2022). In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. WDR73 encodes the WD Repeat-containing protein 73 that is linked to microtubule organization and dynamics.