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dc.contributor.authorWilliams, Sarah M
dc.contributor.authorAn, Joon Yong
dc.contributor.authorEdson, Janette
dc.contributor.authorWatts, Michelle
dc.contributor.authorMurigneux, Valentine
dc.contributor.authorWhitehouse, Andrew JO
dc.contributor.authorJackson, Colin J
dc.contributor.authorBellgrove, Mark A
dc.contributor.authorCristino, Alexandre S
dc.contributor.authorClaudianos, Charles
dc.date.accessioned2020-02-14T01:41:42Z
dc.date.available2020-02-14T01:41:42Z
dc.date.issued2019
dc.identifier.issn1476-5578
dc.identifier.doi10.1038/s41380-018-0049-x
dc.identifier.urihttp://hdl.handle.net/10072/391459
dc.description.abstractA number of genetic studies have identified rare protein-coding DNA variations associated with autism spectrum disorder (ASD), a neurodevelopmental disorder with significant genetic etiology and heterogeneity. In contrast, the contributions of functional, regulatory genetic variations that occur in the extensive non-protein-coding regions of the genome remain poorly understood. Here we developed a genome-wide analysis to identify the rare single nucleotide variants (SNVs) that occur in non-coding regions and determined the regulatory function and evolutionary conservation of these variants. Using publicly available datasets and computational predictions, we identified SNVs within putative regulatory regions in promoters, transcription factor binding sites, and microRNA genes and their target sites. Overall, we found that the regulatory variants in ASD cases were enriched in ASD-risk genes and genes involved in fetal neurodevelopment. As with previously reported coding mutations, we found an enrichment of the regulatory variants associated with dysregulation of neurodevelopmental and synaptic signaling pathways. Among these were several rare inherited SNVs found in the mature sequence of microRNAs predicted to affect the regulation of ASD-risk genes. We show a paternally inherited miR-873-5p variant with altered binding affinity for several risk-genes including NRXN2 and CNTNAP2 putatively overlay maternally inherited loss-of-function coding variations in NRXN1 and CNTNAP2 to likely increase the genetic liability in an idiopathic ASD case. Our analysis pipeline provides a new resource for identifying loss-of-function regulatory DNA variations that may contribute to the genetic etiology of complex disorders.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherSpringer
dc.relation.ispartofpagefrom1707
dc.relation.ispartofpageto1719
dc.relation.ispartofissue11
dc.relation.ispartofjournalMolecular Psychiatry
dc.relation.ispartofvolume24
dc.subject.fieldofresearchBiological Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchPsychology and Cognitive Sciences
dc.subject.fieldofresearchcode06
dc.subject.fieldofresearchcode11
dc.subject.fieldofresearchcode17
dc.titleAn integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationWilliams, SM; An, JY; Edson, J; Watts, M; Murigneux, V; Whitehouse, AJO; Jackson, CJ; Bellgrove, MA; Cristino, AS; Claudianos, C, An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder, Molecular Psychiatry, 2019, 24 (11), pp. 1707-1719
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.date.updated2020-02-14T01:37:16Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© The Author(s) 2018. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
gro.hasfulltextFull Text
gro.griffith.authorCristino, Alex


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