(d) 15 and 18 ASD-associated eQTLs affect at least one transcription factor binding sites within the fetal and adult cortical tissues, respectively. 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. Files containing cleaned Hi-C contacts locations (i.e. et al. However, the potential contributions of cortex-specific developmental changes to these networks in ASD development have yet to be investigated. J. M. OSullivan. This is further complicated by tissue averaging across the complex cellular organization and composition which is also different in early development and adulthood. Fetal and adult cortical tissue-specific PPI networks with immune and growth related phenotypes are affected by ASD-associated eQTLs. Am. The proteinprotein interaction (PPIs) network serves as a foundation for cellular signalling circuitry, which mediates cellular responses to environmental and genetic cues. In Handbook of Hormones (eds Takei, Y. et al.) Nott, A. et al. Tidsskr Nor Laegeforen. SNPs and Disease We are all genetically different. Google Scholar. 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. Each SNP represents a difference in a single DNA building block, called a "nucleotide." For example, an SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA. Rev. Circ. eCollection 2022. 370, 12091219 (2014). 86, 885898 (2019). Explaining the disease phenotype of intergenic SNP through - PubMed Within-family IDs were used as sample IDs in the output vcf file (recode vcf-iid bgz). Gaugler, T. et al. Fetal and adult ASD-associated eQTLs were also associated with schizophrenia, unipolar depression, ADHD, bipolar disorder, anorexia nervosa and obsessivecompulsive disorder (Supplementary Fig. enhancer reporter assays); (b) confirm that the Polycomb complexes are responsible for the observed activity (e.g. Nat. Nat. CAS 2, Supplementary Table 5). & Crawford, D. A. Genotype data quality control was performed using PLINK (v2.0). Genet. Clipboard, Search History, and several other advanced features are temporarily unavailable. Szklarczyk, D. et al. 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. T.L. Husson, T. et al. 1). For example, rs35828350: (1) upregulates NMB in fetal cortex. Bauer, D. E. et al. PPI data was retrieved from STRING33 (version 11.0; 24/09/2020). Mechanism of HPSE Gene SNPs Function: From Normal Processes - Springer 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. Robinson, E. B. et al. Finally a number of fetal (n=50) and adult (n=28) cortex-specific eQTLs were observed (Supplementary Table 3). HCG27, TAP2, HLA-F, HLA-DMA and HLA-DMB) are not highly expressed (TPM<3) within fetal cortical tissue. The SNPs located in enhancer elements may affect gene expression and lead to disease. Diagnostic and Statistical Manual of Mental Disorders (DSM-5 (R)) (American Psychiatric Association Publishing, 2013). https://doi.org/10.1038/s41588-022-01087-y, Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity. 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. Understanding the mechanisms underlying the effects of SNPs that . Gandal, M. J. et al. However, this would require randomised control trials in animals prior to testing in humans. Nancy Y. Genet. For example, rs4481150 eQTL is present in both fetal and adult eQTL databases. 45, D139D144 (2017). 4). In the adult cortex, the known functions of the impacted genes were enriched in immune pathways. Previous research has reported shared neurobiological and cellular processes associated with differences in cortical thickness across six psychiatric disorders (i.e. 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. In the meantime, to ensure continued support, we are displaying the site without styles 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. Chang, X. 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. A single nucleotide polymorphism, or SNP (pronounced "snip"), is a variation at a single position in a DNA sequence among individuals. Only SNPs associated with ASD with a p<5108 were included in downstream analyses. 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. Tissue-wide cell-specific proteogenomic modeling reveals novel candidate risk genes in autism spectrum disorders, Integrative analyses indicate an association between ITIH3 polymorphisms with autism spectrum disorder, A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles, Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks, Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism, Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD, Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes, Rare coding variants as risk modifiers of the 22q11.2 deletion implicate postnatal cortical development in syndromic schizophrenia, Convergent and distributed effects of the 3q29 deletion on the human neural transcriptome, http://autism.mindspec.org/autdb/Welcome.do, https://github.com/broadinstitute/gtex-pipeline/tree/master/rnaseq, https://github.com/broadinstitute/gtex-pipeline/tree/master/qtl, https://github.com/broadinstitute/gtex-pipeline/tree/master/genotype, https://www.well.ox.ac.uk/~wrayner/strand/, ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/technical/reference/, https://github.com/broadinstitute/tensorqtl, https://egg2.wustl.edu/roadmap/data/byFileType/chromhmmSegmentations/ChmmModels/coreMarks/jointModel/final/, https://github.com/Genome3d/genetic_regulation_in_ASD, https://doi.org/10.1038/s41380-020-0773-x, http://creativecommons.org/licenses/by/4.0/, Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism, The tRNA regulome in neurodevelopmental and neuropsychiatric disease, Investigation of Genetic Polymorphism in Autism Spectrum Disorder: a Pathogenesis of the Neurodevelopmental Disorder, Cancel A Dockerfile (including the CoDeS3D pipeline and downstream analyses), all findings, scripts and reproducibility report are available on github at https://github.com/Genome3d/genetic_regulation_in_ASD. Integrating datasets across biological levels enables us to predict how genetic variation impacts on biological pathways and their involvement in the etiology of ASD. 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. Neurosci. Karczewski, K. J. et al. by chromatin immunoprecipitation); and (c) identify the Polycomb subunits that differentiate those sites that enhance or repress transcription within the developing cortex. 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. Nature Genetics 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. SNPs are plotted based on the reference duck genome chromosome (x-axis).The horizontal solid line is the threshold for the . Neurosci. In our study eQTL data represent composite datasets across critical periods of development (e.g. 11, 27 (2017). Increasing role of maternal immune activation in neurodevelopmental disorders. 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. Google Scholar. 4). RNA-seq data) were mapped to Ensembl gene identifiers. There are several reasons for this apparent discrepancy. To obtain (b) Thirty ASD-associated SNPs are eQTLs in both fetal and adult cortical tissues. Front. Transl. 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. 3). Backman, J. D. et al. Basically, SNPs are copying errors. Physiol. 1). Neurol. 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. The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). 3, 1 (2011). Nucleic Acids Res. Finally, we tested for enrichment of ASD-associated eQTLs within active regulatory elements and histone modification marks, using ChromHMM28 15-state models for adult dorsolateral prefrontal cortex and fetal brain. Neurosci. The PPI clusters with unknown functions (Fig. 2b). Furthermore, the Hi-C dataset used to inform the adult cortex analysis consisted of one sample (with one replicate), while two samples (each with three replicates) were used for the fetal cortex analysis (Supplementary Table 1). The majority of ASD-associated SNPs are located within the non-coding components of the genome. FOIA The SNP2TFBS27 database was queried to identify eQTLs that are predicted to alter the affinity of transcription factor binding sites (TFBSs). expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. genes, whose expression levels are associated with a SNP). We detail the method, apply it to data from The Cancer Genome Atlas, and provide a tool to explore the findings. Sign up for the Nature Briefing: Translational Research newsletter top stories in biotechnology, drug discovery and pharma. Autism Spectr. McCarthy, S. et al. Identifying comorbid ADHD in autism: Attending to the inattentive presentation. 22, 345361 (2016). How do SNPs occur? Science 342, 253257 (2013). Ann. PRC2-associated chromatin contacts in the developing limb reveal a possible mechanism for the atypical role of PRC2 in HoxA gene expression. PubMedGoogle Scholar. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. & Zhang, Z. PGBD1, ZKSCAN7, MPHOSPH9, TCF19 and VWA7); (b) decreases in transcript levels for VARS2; and (c) two genes (i.e. Genet. However, our study also has several limitations. Solution 5 (1 Ratings ) Solved Biology 3 Years Ago 40 Views This Question has Been Answered! Raudvere, U. et al. Hi-C data) enables the identification of novel local and distal eQTL-gene connections. Sci. Here, we integrated ASD-associated GWAS SNPs with cortex-specific 3D genome structure and eQTL information to identify genes that are spatially regulated in fetal (1421 postconceptional weeks) and adult (2170years of age) cortical tissues. (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). 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. Adult PPIs form three modules that were enriched in immune pathways and two unknown modules. and co-wrote the manuscript. One of main contributions of SNPs in clinical research is genome-wide association study (GWAS). Tam, V. et al. 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. STRING v11: Proteinprotein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. 57, 580594 (2015). & Paro, R. Transcriptional silencing by polycomb-group proteins. Patches of disorganization in the neocortex of children with autism. Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. doi: 10.1136/bmjdrc-2022-003164. 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. Neurosci. Identification of functional single nucleotide polymorphisms in the branchpoint site. 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. Nat. Hum. The significance of these associations in the developing cortex and how they contribute to the etiology of ASD remains to be empirically determined. ISSN 2045-2322 (online). Cell 50, 184-196.e4 (2019). 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. 4). 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. Single nucleotide polymorphisms (SNPs) are one of the most common types of genetic variations in the human genome. CAS 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. Notably, the significant difference (p=0.04531) in numbers of fetal cortical eQTLs, when compared to adult cortical eQTLs is consistent with a developmental origin for ASD risk. The .gov means its official. Overview of the analysis pipeline used in this study. *The same eQTL is associated with transcription levels for the gene in both the fetal and adult cortical tissues. Single nucleotide polymorphism (SNP) is the simplest form of DNA variation among individuals. All genomic positions and SNP annotations were obtained for human genome reference build hg38 (GRCh38) release 75. Since the output is an easily manipulated spreadsheet, the user can sort the SNPs to highlight different SNP features. This data-driven approach enables the discovery of SNPs whose alleles impact gene regulation by miRNAs, with functional consequences for tumor biology. 2c). 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). 12, 405 (2018). Usui, N. et al. Google Scholar. Genes that have been curated as being involved in ASD (AutDB31; http://autism.mindspec.org/autdb/Welcome.do, assessed on 16/11/2020). & Kellis, M. Chromatin-state discovery and genome annotation with ChromHMM. Nucleic Acids Res. The authors would like to thank the Genomics and Systems Biology Group (Liggins Institute) for useful discussions. PubMed Transl. Genet. Virtual histology of cortical thickness and shared neurobiology in 6 psychiatric disorders. doi: 10.1093/hmg/ddp003. 2022 Sep 23;13:973347. doi: 10.3389/fpls.2022.973347. non-coding RNAs); (2) ASD is a spectrum . 3, 9598 (2016). 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. Schmitt, A. D. et al. TYW5, FTCDNL1, and RTN1) whose transcript levels decrease with the ASD-eQTL and NDRG4, whose transcript levels increase or decrease dependent upon the ASD-eQTL. Firstly, SNPs can mark regulatory regions that affect distant genes (i.e. The remaining read pairs we refer to as contacts. Next, the CoDeS3D algorithm identified the restriction fragments interacting with the SNP-containing restriction fragments. de la Torre-Ubieta, L., Won, H., Stein, J. L. & Geschwind, D. H. Advancing the understanding of autism disease mechanisms through genetics. These mechanisms are not limited to impacts on gene regulation and can affect the splicing activity (so called sQTL SNPs35), or trans-acting factors (e.g. Roles for immune dysfunction in ASD etiology are increasingly being identified57,58,59. g:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update). Maurano, M. T. et al. J. Psychiatry 175, 359369 (2018). Nucleic Acids Res. Common genetic variants, acting additively, are a major source of risk for autism. 3). VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. 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. How far from the SNP may the causative genes be?. GWAS has been commonly used in identifying SNPs associated with diseases or clinical phenotypes or traits. Dynamics and stage-specificity of between-population gene expression How could SNPs contribute to gene regulation? Chromosome conformation elucidates regulatory relationships in developing human brain. 52, 13551363 (2020). von Schimmelmann, M. et al. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. Google Scholar. To create a lookup table, genetic variants were annotated with rsIDs from dbSNP build 151 database. 69, 101468 (2020). Most genetic risk for autism resides with common variation. Genome Res. We extracted 2,000,451 proteinprotein interactions (with a combined score 400) between a total of 19,258 unique human proteins (Fig. 2, Supplementary Table 5). Article Furthermore, we constructed fetal and adult cortex-specific proteinprotein interaction networks and identified that ASD-associated regulatory SNPs impact on immune pathways, fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome in the fetal cortex. 46, 881885 (2014). Nat. Walker, R. L. et al. 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. 48, 552555 (2016). Mottron, L. & Bzdok, D. Autism spectrum heterogeneity: Fact or artifact?. 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. SNPs: impact on gene function and phenotype - PubMed 3). T.F. Changes to genes within the immune-related processes within adult cortex mostly affect the processing of exogenous antigen. Rau, S. et al. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. 6, a019331 (2014). Article Scientific Reports (Sci Rep) 2 How could SNPs contribute to gene regulation? Sunwoo, M. et al. Here, we focused on roles for changes within cortical tissue. performed the analyses and wrote the manuscript. The mapping is shown for A the 1D linear genome and B the 3D genome structure constructed at the Hi-C resolution of 10 kbp. Single-nucleotide polymorphism - Wikipedia View Solution Related Answers how could SNP's contribute to gene regulation?. Gentile, C. et al. Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation. Benefits and limitations of genome-wide association studies. Google Scholar. Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: A systematic review. spliceosome and splicing, aminoacyl-tRNA biosynthesis, and ribosome biogenesis) in the fetal cortex. Science 376, eabf3041 (2022). Nat. dorsolateral prefrontal cortex cells) cortex-specific Hi-C libraries. Nat. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 3). 20, 467484 (2019). Article 2008, P10008 (2008). TAP1 and TAP2); (b) decreased (HLA-DQB1); or (c) both increased and decreased depending on specific ASD-eQTLs (HLA-DMA; Fig. Google Scholar. Article Nat. Cell Tissue Res. MeSH 3, Supplementary Table 4). Psychiatry 10, 77 (2020). A functional SNP in the promoter region of TCOF1 is associated - PubMed The mutational constraint spectrum quantified from variation in 141,456 humans. The Gene module within AutDB is a manually curated reference set of ASD-linked genes that was first released in 2007. Cell Rep. 17, 20422059 (2016). datasets) to construct tissue-specific transcriptome-wide PPI networks. Google Scholar. ADS MacArthur, J. et al. For example, identical samples were not used in the ChromHMM, eQTL and Hi-C analyses of the fetal and adult cortical tissues. Systematic identification of trans eQTLs as putative drivers of known disease associations. 12, 230 (2018). In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. Child Psychol. KLC1, ZSCAN31 and TRIM26), or decreased (i.e. We identified 42 PPIs in the fetal and 10 PPIs in the adult cortical tissues. ASD-eQTLs within the fetal cortex PPI aminoacyl-tRNA biosynthesis cluster are associated with: (a) increases in transcript levels for five genes (i.e. This method prioritizes genes for functional characterization and helps address questions about the architecture of human phenotypes. J. Immunol. Moreover, we identified development stage-specific eQTLs that were associated with gene transcript levels in either fetal, or adult cortical tissue (Supplementary Fig. Of the 66 fetal cortex genes, transcript levels for 36 are upregulated in association with a change of the eQTL SNP to the minor allele, while 24 are reduced (Fig. The butyrophilin genes encode proteins that belong to the immunoglobulin superfamily and help modulate the immune system23. PubMed PPI network analyses have been used to discover essential proteins, clusters of proteins with similar, overlapping or combinatorial functions, and associated pathways involved in tissue-specific contributions to ASD etiology17,18. ISSN 1546-1718 (online) 84% of the genes we identified were not present in AutDB. ADS rs10791097-SNX19, rs11191419-AS3MT, rs7085104-AS3MT, rs174592-FADS1; Supplementary Table 4). However, it is likely that additional regions of the brain (e.g. Google Scholar. Commun. Single nucleotide polymorphism, or SNP. 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. Synaptic Neurosci. Cell 155, 9971007 (2013). Single Nucleotide Polymorphism (SNP) SNPs are variations that involve a change in just one nucleotide. https://doi.org/10.1038/s41588-022-01093-0, DOI: https://doi.org/10.1038/s41588-022-01093-0. What are some common examples of known SNPs used in Nat. 1). This will revolutionize the medical field in the future. Both HLA-DQB1 and HLA-DMA are examples of the MHC class II genes that are associated with processing of exogenous antigen. Rev. b, Epigenomic sequencing reads (ChIP-seq and ATAC-seq) are merged on a per-individual basis and used to impute. 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. 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). volume54,pages 748749 (2022)Cite this article. Boyle, E. A., Li, Y. I. SNPs in genes that regulate DNA mismatch repair, cell cycle regulation, metabolism and immunity are associated with genetic susceptibility to cancer [ 1 - 12 ]. Thirdly, the brain regions that are involved in the etiology of ASD remain difficult to determine. Cells 8, 788 (2019). Paternally inherited cis-regulatory structural variants are associated with autism. Nucleic Acids Res. 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. Grossniklaus, U. PMC Google Scholar. (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. HLA-DMA and BAG6 gene transcript levels are associated with distinct sets of eQTLs in both fetal and adult cortical tissues (Supplementary Fig. & Chen, Y.-T. 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. By contrast, in the adult cortex they largely affect immune pathways. 2008 Sep 11;128(17):1951-5. 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. government site. Van Rooij, D. et al. Fifthly, we are aware that the tools and datasets used in this study are potentially biased. E.G. SNPs) among conditions was counted for each bootstrap iteration. High-throughput identification of human SNPs affecting regulatory element activity.
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