Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex

Abstract 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...

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Autores principales:	E. Golovina, T. Fadason, T. J. Lints, C. Walker, M. H. Vickers, J. M. O’Sullivan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/425d5ed5bfc445a0925f6ffce0d4ddc0
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spelling	oai:doaj.org-article:425d5ed5bfc445a0925f6ffce0d4ddc02021-12-02T17:06:09ZUnderstanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex10.1038/s41598-021-95447-z2045-2322https://doaj.org/article/425d5ed5bfc445a0925f6ffce0d4ddc02021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95447-zhttps://doaj.org/toc/2045-2322Abstract 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 < 5 × 10–8) 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.E. GolovinaT. FadasonT. J. LintsC. WalkerM. H. VickersJ. M. O’SullivanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q E. Golovina T. Fadason T. J. Lints C. Walker M. H. Vickers J. M. O’Sullivan Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex
description	Abstract 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 < 5 × 10–8) 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.
format	article
author	E. Golovina T. Fadason T. J. Lints C. Walker M. H. Vickers J. M. O’Sullivan
author_facet	E. Golovina T. Fadason T. J. Lints C. Walker M. H. Vickers J. M. O’Sullivan
author_sort	E. Golovina
title	Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex
title_short	Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex
title_full	Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex
title_fullStr	Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex
title_full_unstemmed	Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex
title_sort	understanding the impact of snps associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/425d5ed5bfc445a0925f6ffce0d4ddc0
work_keys_str_mv	AT egolovina understandingtheimpactofsnpsassociatedwithautismspectrumdisorderonbiologicalpathwaysinthehumanfetalandadultcortex AT tfadason understandingtheimpactofsnpsassociatedwithautismspectrumdisorderonbiologicalpathwaysinthehumanfetalandadultcortex AT tjlints understandingtheimpactofsnpsassociatedwithautismspectrumdisorderonbiologicalpathwaysinthehumanfetalandadultcortex AT cwalker understandingtheimpactofsnpsassociatedwithautismspectrumdisorderonbiologicalpathwaysinthehumanfetalandadultcortex AT mhvickers understandingtheimpactofsnpsassociatedwithautismspectrumdisorderonbiologicalpathwaysinthehumanfetalandadultcortex AT jmosullivan understandingtheimpactofsnpsassociatedwithautismspectrumdisorderonbiologicalpathwaysinthehumanfetalandadultcortex
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Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex

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