In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. & Chen, Y.-T. de la Torre-Ubieta, L., Won, H., Stein, J. L. & Geschwind, D. H. Advancing the understanding of autism disease mechanisms through genetics. Google Scholar. 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. 4, Supplementary Table 9). Solved 1. In which ways can the individual steps of this - Chegg Applications of computational tools to predict functional SNPs effects in human ErbB genes. Disord. However, rs4481150 is only associated with increased transcript levels for ITIH4 in adult cortex. 42, 399403 (2017). 45, 984994 (2013). Functional gene ontology enrichment analysis identified immune-related processes (e.g. The CoDeS3D algorithm then identified the restriction fragments containing the SNPs within fetal (i.e. Our results support a dual role for Polycombas both a repressor and enhancer of transcriptionin the development of ASD risk. PGBD1, ZKSCAN7, MPHOSPH9, TCF19 and VWA7); (b) decreases in transcript levels for VARS2; and (c) two genes (i.e. 44, 60466054 (2016). (f) The majority of the fetal ASD-associated eQTLs that are located within weakly repressed PolyComb (ReprPCWk) and repressed PolyComb (ReprPC) regions were not identified as being eQTLs within the adult cortex. 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. 52, 13551363 (2020). Genetic and molecular features of seizure-freedom following surgical resections for focal epilepsy: A pilot study. ASD-associated SNPs are enriched within non-coding putative regulatory regions. We found 80 and 58 SNPs that mark regulatory regions (i.e. High-throughput identification of human SNPs affecting regulatory element activity. government site. The mutational constraint spectrum quantified from variation in 141,456 humans. Google Scholar. Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. HLA-DRB1, HLA-DMB and HLA-DMA; associated with exogenous peptide processing) genes. Cardiovasc. CAS J Hum Genet. These differences can underlie susceptibility to common diseases, human traits, and differential responses to drugs. Identification of positional candidate genes for the skin fat phenotype in ducks. Blondel, V. D., Guillaume, J.-L., Lambiotte, R. & Lefebvre, E. Fast unfolding of communities in large networks. Notably, eQTLs involving rs13218591 and rs2237234 regulate different butyrophilin alleles (i.e. Fifteen of these shared eQTLs control the same eGenes in fetal and adult cortex (e.g. Science 360, 327331 (2018). We contend that changing the transcription levels of these genes, alters biological pathways that modify an individuals predisposition to develop ASD. 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. Single Nucleotide Polymorphisms (SNPs) - Genome.gov Thereby, SNPs contribute to disease susceptibility, various responses to medication treatment and differences in outcomes within a disease population [8, 9]. Adult PPIs form three modules that were enriched in immune pathways and two unknown modules. 45, D139D144 (2017). A novel candidate gene CLN8 regulates fat deposition in avian Our finding that a subset of the identified ASD-associated eQTLs were linked to psychiatric phenotypes highlights the existence of potential shared regulatory mechanisms contributing to the risk of developing these multimorbid conditions. SNPs: impact on gene function and phenotype - PubMed Genes whose transcript levels are associated with a trans-acting ASD-associated eQTL. (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). the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in J. Psychiatry 175, 359369 (2018). Single nucleotide polymorphism (SNP) is the simplest form of DNA variation among individuals. 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. The SNPs located in enhancer elements may affect gene expression and lead to disease. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). Rev. By contrast, in the adult cortex they largely affect immune pathways. Estes, M. L. & McAllister, A. K. Maternal immune activation: Implications for neuropsychiatric disorders. Genome-wide association study of traits in sacred lotus uncovers MITE-associated variants underlying stamen petaloid and petal number variations. PDF GENETIC ASSOCIATION STUDIES OF COMPLEX DISEASES ByYen - arXiv Synaptic Neurosci. Guillaume Lettre. Trials 18, 131 (2017). Chapter SNPs may change the encoded amino acids (nonsynonymous) or can be silent (synonymous) or simply occur in the noncoding regions. Google Scholar. 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. Transcriptome-wide fetal and adult cortex-specific PPIs (CSPPIs) were constructed by combining the STRING PPI network with cortex-specific expression data from GTEx v8 or fetal brain datasets (Fig. Nasser, J. et al. By contrast, the adult cortical gene set was largely related to immune pathways. Future studies of the roles of these genes in ASD will be important for understanding the full impact of ASD-associated genetic variation in the cortex. Estes, M. L. & McAllister, A. K. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Karczewski, K. J. et al. Genet. The resulting vcf file was converted to plink format and information on sample sex included. Universit de Montral, Montreal, Quebec, Canada, Institut de Cardiologie de Montral, Montreal, Quebec, Canada, You can also search for this author in Systematic identification of trans eQTLs as putative drivers of known disease associations. Nucleic Acids Res. Transcript levels for four genes: (a) increased (i.e. 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. Tolerance to loss-of-function (LoF) variants was measured using the probability-of-being-LoF-intolerant (pLI) method and gene LoF metrics were obtained from gnomAD (v2.1.1, https://gnomad.broadinstitute.org/)32. Scientific Reports (Sci Rep) Similar approaches, in combination with existing and future clinical studies of ASD will contribute to individualized mechanistic understanding of ASD etiology in early brain development and adulthood. 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 . Google Scholar. 2022 Sep 16;13:942643. doi: 10.3389/fneur.2022.942643. 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. BTN2A2 and BTN3A1 in the adult and fetal cortex, respectively). If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. To illustrate the effect of SNPs on gene function and phenotype, this minireview focuses on evidences revealing the impact of SNPs on the development and progression of three human eye disorders (Norrie disease, familial exudative vitreoretinopathy, and retinopathy of prematurity) that have overlapping clinical manifestations. The transcript levels of the genes within the two unknown adult cortex PPI clusters increased (i.e. Transl. As such, our results only represent snap-shots within the plastic neurodevelopmental trajectory69,70. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Cell Syst. Therefore, the aims of the present study were to determine the TCOF1 gene's core promoter and to identify mutations in this region that could contribute to the phenotypic variation observed in this syndrome. The regulatory effects can occur in trans (e.g. This network illustrates potential evidence for gene regulation related to RA-associated SNPs, and may provide comprehensive information for subsequent functional analyses and experiments. McCarthy, S. 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). 12, 24782492 (2017). Gaugler, T. et al. Genet. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. 22, 2126 (2014). Silbereis, J. C., Pochareddy, S., Zhu, Y., Li, M. & Sestan, N. The cellular and molecular landscapes of the developing human central nervous system. 20, 327348 (2010). 2009 May;37(5):977-91. doi: 10.1124/dmd.108.026047. 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). A large number of genes associated with various cancer types contain single nucleotide polymorphisms (SNPs). 19, 13211330 (2016). Article 16, 551563 (2015). In the adult cortex, the known functions of the impacted genes were enriched in immune pathways. 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. Psychiatry 8, 233 (2018). Google Scholar. Systematic localization of common disease-associate variation in regulatorty DNA. 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). Res. Genet. SNPs represent an important class of genetic variant, defined as a single-base change in the DNA sequence. Fourthly, the human brain takes over two decades to build via precisely regulated cell type-specific molecular processes governed by both genetic blueprint and environmental factors. Recall that the DNA sequence is formed from a chain of . The proteinprotein interaction (PPIs) network serves as a foundation for cellular signalling circuitry, which mediates cellular responses to environmental and genetic cues. Here, we focused on roles for changes within cortical tissue. performed the analyses and wrote the manuscript. 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. The results of these experiments would be valuable in identifying novel therapeutic approaches to reduce the risk of full-blown ASD development, particularly given the strength of the evidence for Polycomb roles transcription control46 and increasing evidence for links to neuronal development (e.g. Dynamics and stage-specificity of between-population gene expression Furthermore, despite not having discussed them in detail, there are number of genes whose transcript levels are affected by ASD-eQTLs whose functions were not enriched within known pathways. 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. Randomised controlled trials involving pre- and post-conception interventions with different lipids are currently being undertaken or followed up (e.g.51)opening the possibility of post-hoc analyses for ASD risk. Nucleic Acids Res. VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction. Pedapati, E. V. et al. Basically, SNPs are copying errors. Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Weissbrod, O. et al. Bourgeron, T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nineteen eGenes are regulated by Polycomb-repressed eQTL SNPs, and seven eGenesby trans-acting eQTL SNPs in fetal cortex (Fig. single nucleotide polymorphism / SNP | Learn Science at Scitable - Nature Frontiers | Exploring the Impact of Single-Nucleotide Polymorphisms on Slider with three articles shown per slide. Bootstrapping analysis (n=10,000 iterations) was performed to test if observed overlaps were non-random. Files containing cleaned Hi-C contacts locations (i.e. Rev. The pipeline included BWA (v0.7.15) alignment of paired-end reads onto the hg38 reference genome, merging paired-end read alignments and removing chimeric, unmapped and duplicated reads. SNPs can also be used to track the inheritance of disease genes within families. Understanding how ASD-eQTLs affect fetal and adult cortex PPIs could lead to the identification of the pathways that affect cortical development and ASD susceptibility. Trlungeanu, D. C. et al. Nancy Y. Unauthorized use of these marks is strictly prohibited. PubMed Neuropsychol. The remaining read pairs we refer to as contacts. Genes were inverse normal transformed across samples. In the meantime, to ensure continued support, we are displaying the site without styles Single nucleotide polymorphisms, frequently called SNPs (pronounced "snips"), are the most common type of genetic variation. Identification of non-coding silencer elements and their regulation of To build ASD-specific fetal and adult CSPPIs, only interactions between ASD-associated genes we extracted from fetal and adult CSPPIs. 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. Commun. Rev. Malinowska, M., Tokarz-Deptua, B. From these CSPPI networks we identified 42 ASD-associated PPIs within the fetal gene set, and 10 ASD-associated PPIs from the adult cortical tissue gene set (Fig. 9, 5198 (2018). Maternal immune activation and abnormal brain development across CNS disorders. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Single-nucleotide polymorphisms (SNPs) associated with ASD (n=454) were downloaded from the GWAS Catalog (www.ebi.ac.uk/gwas/; 05/04/2020; Supplementary Table 2). https://doi.org/10.1038/s41588-022-01093-0, DOI: https://doi.org/10.1038/s41588-022-01093-0. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. This problem has been solved! Cent. Motor cortex facilitation: A marker of attention deficit hyperactivity disorder co-occurrence in autism spectrum disorder. Neuron 89, 248268 (2016). N. Engl. Writing Committee for the Attention-Deficit/Hyperactivity Disorder et al. Yazar, S. et al. Prevalence and outcomes of young people with concurrent autism spectrum disorder and first episode of psychosis. Abell, N. S. et al. Front. 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. Grossniklaus, U. Golovina, E., Fadason, T., Lints, T.J. et al. PubMed Central Walker, R. L. et al. It is estimated that the human genome contains more than 10 million different SNPs. 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. The same reference genome and annotation files were used to calculate expression for fetal brain RNA-seq data. Formulate hypotheses Expert Answer 100% (1 rating) Answer : 1 : In an indivisual the protein expression is regulated by higher and lower methods . 2002;47(11):561-6. doi: 10.1007/s100380200086. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). Stoner, R. et al. We find that sex-het SNPs influence a large set of diseases and health-related . Perez, R. K. et al. Buniello, A. et al. Changes to genes within the immune-related processes within adult cortex mostly affect the processing of exogenous antigen. 2022 Sep 23;13:973347. doi: 10.3389/fpls.2022.973347. 1). 2 How could SNPs contribute to gene regulation? 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. Nat. Of the 80 fetal and 58 adult eQTLs, 30 were observed in both fetal and adult cortical tissues (Fig. 3). They may influence promoter activity (gene expression), messenger RNA (mRNA) conformation (stability), and subcellular localization of mRNAs and/or proteins and hence may produce disease. To evaluate possible commonalities among ASD and other phenotypes at the eQTL level in the fetal and adult cortex, we intersected the identified ASD-associated eQTLs with SNPs associated with other traits in the GWAS catalog (p<5108, assessed on 26/08/2020). 2023 Jan 28;257(3):47. doi: 10.1007/s00425-023-04073-8. 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. FOIA MATH 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. D'Esposito D, Guadagno A, Amoroso CG, Cascone P, Cencetti G, Michelozzi M, Guerrieri E, Ercolano MR. Planta. PPI data was retrieved from STRING33 (version 11.0; 24/09/2020). cortical plate and germinal zone neurons)19 and one adult cortex-specific (i.e. PDE10A, PBX1, SF3B1, BAG6 and RERE) were LoF intolerant (Supplementary Table 6). You are using a browser version with limited support for CSS. Notably, Polycomb repressive complexes have distinct regulatory roles in identity, proliferation and differentiation of neuronal progenitor cells during development29,30. 49, 433436 (2012). J.O.S. The results of our study should be interpreted in view of its strengths and limitations. Genetic variants were filtered based on HardyWeinberg equilibrium p<1106, minor allele frequency 0.01 and variant missing genotype rate 0.05. SNP selection and data report Raudvere, U. et al. Hum. Patches of disorganization in the neocortex of children with autism. Cells 8, 788 (2019). Knuesel, I. et al. Imputed genotypes were filtered for HardyWeinberg equilibrium p<1106, variant missing genotype rate 0.05 and minor allele frequency 0.01. Dysregulation of fatty acid metabolism in early brain development may be a risk factor or marker for early-onset of ASD48. An official website of the United States government. & Vasan, R. S. Next-generation genome-wide association studies: Time to focus on phenotype?. Nat. After 10,000 iterations we counted those instances where the number of shared items in the bootstrapped overlap is greater than or equal to the number of shared items in the observed overlap. Epidemiological studies estimate that approximately 1% of people worldwide have ASD2. regioneR: An R/Bioconductor package for the association analysis of genomic regions based on permutation tests. SNPs in genes that regulate DNA mismatch repair, cell cycle regulation, metabolism and immunity are associated with genetic susceptibility to cancer [ 1 - 12 ]. In this study, we integrated four distinct levels of biological information (GWAS, eQTL, genome organization [Hi-C] and proteinprotein interactions [PPI] networks) to translate genetic variation associated with ASD to the biological pathways that are affectedthrough alterations to the transcription levels of their component proteins in fetal and adult cortical tissues. ADS Sample-level gene read and TPM (Transcripts Per kilobase Million) counts were concatenated using combine_GCTs.py. Sign up for the Nature Briefing: Translational Research newsletter top stories in biotechnology, drug discovery and pharma. & Wang, K. wANNOVAR: Annotating genetic variants for personal genomes via the web. Am. 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. 2e). Normalized vcf files were further validated using VCFtools (v0.1.15). cerebellum68) or other organs are important in the pathophysiology of ASD. Genet. 78, 4763 (2021). PubMed Brown, C. M., Austin, D. W. & Busija, L. Observable essential fatty acid deficiency markers and autism spectrum disorder. 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. von Schimmelmann, M. et al. and co-wrote the manuscript. 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). Psychiatry 9, 298 (2019). In the meantime, to ensure continued support, we are displaying the site without styles ZSCAN23 and LY6G5C) whose transcript levels increase or decrease, dependent upon specific eQTL. To obtain SNPs) among conditions was counted for each bootstrap iteration. 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. Porokhovnik, L. Individual copy number of ribosomal genes as a factor of mental retardation and autism risk and severity. Before (e) Most of the fetal ASD-associated eQTLs are located within quiescent/low transcribed, week repressed PolyComb, repressed PolyComb and weak transcription regions. Phenotypes were defined as the mapped traits associated with the SNP in the GWAS Catalog. 37, D832D836 (2009). Hum Mol Genet. Louvain clustering identified seven PPI modules within the fetal cortex that were enriched for immune pathways, fatty acid metabolism, aminoacyl-tRNA biosynthesis, spliceosome, ribosome biogenesis in eukaryotes and two unknown modules. Lancet 383, 896910 (2014). 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. Transl. Notably, the transcript levels for 6 genes in the fetal immune cluster (HCG27, TAP2, HLA-F, HLA-DMA, HLA-C and HLA-DMB) are associated with regulation by Polycomb-repressed ASD-eQTLs. & Jernigan, T. L. The basics of brain development. J. PubMed J. Stat. contracts here, Sign up for Nature Briefing: Translational Research. PubMed The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. 2008 Sep 11;128(17):1951-5. 3). https://doi.org/10.1038/s41588-022-01093-0. Nat. WDR73 encodes the WD Repeat-containing protein 73 that is linked to microtubule organization and dynamics. However, the remaining 15 eQTLs are associated with different eGenes in adult and fetal cortical tissues (Supplementary Table 4). Transl. FastQC reports were visually inspected and there were no samples that did not pass the quality check (no failures for Per base sequence quality, Per sequence quality scores, Per base N content and Sequence Length Distribution metrics). Article Fadason, T., Schierding, W., Lumley, T. & OSullivan, J. M. Chromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities. HHS Vulnerability Disclosure, Help 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). Article Rev. How could so-called altruistic behaviors arise through natural selection? Nature Genetics cortical plate and germinal zone neurons), or adult (i.e. 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. 12, 405 (2018). Nature 581, 434443 (2020). 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. By contrast, 9 fetal cortex-specific genes (i.e. Correspondence to 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. 28, 2730 (2000). However, more than 84% of the identified spatially regulated genes were novel and have not previously been linked to autism or curated in AutDB. Integrative analysis of 111 reference human epigenomes. Nature 538, 523527 (2016). Neurosci. Here, we integrated four distinct levels of biological information (GWAS, eQTL, spatial genome organization and proteinprotein interactions) to identify potential regulatory impacts of ASD-associated SNPs (p<5108) on biological pathways within fetal and adult cortical tissues. Studies of non-coding disease-associated SNPs have demonstrated that they can mark regulatory elements that alter gene expression9,10. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. 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. Proteins that were not annotated in the expression datasets were also removed from the CSPPI network. M.V. Removal of all HLA genes from the analysis, identified enrichments for genes involved in fatty acid metabolism and processes related to the endoplasmic-reticulum-associated protein degradation (ERAD) pathway within fetal cortex. 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. The GWAS Catalog is a publicly available database of all published GWAS studies76. 235, 40314045 (2020). However, it is likely that additional regions of the brain (e.g. Article SNPs are plotted based on the reference duck genome chromosome (x-axis).The horizontal solid line is the threshold for the . Thirdly, the brain regions that are involved in the etiology of ASD remain difficult to determine. The fetal immune PPI cluster contains both MHC class I (i.e. ASD-associated SNPs (p<5108, n=454) were downloaded from the GWAS Catalog (Supplementary Tables 1 and 2). Finally, we evaluated identified eQTL SNP associations with other phenotypes in the GWAS Catalog (downloaded on 26/08/2020) (Supplementary Table 4). Notably, 6 genes are associated with multiple eQTLs which exhibit opposing effects on transcript levels (Fig. 3). Transcript levels for these genes are associated with 65 eQTLs in fetal cortex and 39 eQTLs in adult cortex (Supplementary Table 3). g:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update). By contrast, the ASD-eQTL associations within the fetal cortex PPI fatty acid metabolism and spliceosome clusters are less complex (decreases: FADS1, TBL1X, SF3B1, or increases: FADS2, DHX38 and THOC7; Fig. Eur. Front Neurol.