Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex
| Autor: | Caroline G. Walker, Evgeniia Golovina, Justin M. O’Sullivan, Thierry Lints, Tayaza Fadason, Mark H. Vickers |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Autism Spectrum Disorder Science Quantitative Trait Loci Single-nucleotide polymorphism Genome-wide association study Biology behavioral disciplines and activities Polymorphism Single Nucleotide Article Gene regulatory networks Fetus Neurodevelopmental disorder Cortex (anatomy) Databases Genetic Protein Interaction Mapping mental disorders medicine Humans Genetic Predisposition to Disease Bipolar disorder Cerebral Cortex Genetics Multidisciplinary Genetic interaction Neurodevelopmental disorders Brain Genomics medicine.disease Gene regulation medicine.anatomical_structure Schizophrenia Autism spectrum disorder Expression quantitative trait loci Medicine Data integration Genome-Wide Association Study |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) |
| ISSN: | 2045-2322 |
| Popis: | Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. Here, we integrated four distinct levels of biological information (GWAS, eQTL, spatial genome organization and protein–protein interactions) to identify potential regulatory impacts of ASD-associated SNPs (p –8) on biological pathways within fetal and adult cortical tissues. We found 80 and 58 SNPs that mark regulatory regions (i.e. expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. These eQTLs were also linked to other psychiatric disorders (e.g. schizophrenia, ADHD, bipolar disorder). Functional annotation of ASD-associated eQTLs revealed that they are involved in diverse regulatory processes. In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. Furthermore, we constructed fetal and adult cortex-specific protein–protein 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. By contrast, in the adult cortex they largely affect immune pathways. Overall, our findings highlight potential regulatory mechanisms and pathways important for the etiology of ASD in early brain development and adulthood. This approach, in combination with clinical studies on ASD, will contribute to individualized mechanistic understanding of ASD development. |
| Databáze: | OpenAIRE |
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