An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder

Sarah M. Williams, Joon Yong An, Janette Edson, Michelle Watts, Valentine Murigneux, Andrew J.O. Whitehouse, Colin J. Jackson, Mark A. Bellgrove, Alexandre S. Cristino, Charles Claudianos

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

A 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.

Original languageEnglish
Pages (from-to)1707-1719
Number of pages13
JournalMolecular Psychiatry
Volume24
DOIs
Publication statusPublished - Nov 2019

Cite this

Williams, S. M., An, J. Y., Edson, J., Watts, M., Murigneux, V., Whitehouse, A. J. O., ... Claudianos, C. (2019). An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder. Molecular Psychiatry, 24, 1707-1719. https://doi.org/10.1038/s41380-018-0049-x
Williams, Sarah M. ; An, Joon Yong ; Edson, Janette ; Watts, Michelle ; Murigneux, Valentine ; Whitehouse, Andrew J.O. ; Jackson, Colin J. ; Bellgrove, Mark A. ; Cristino, Alexandre S. ; Claudianos, Charles. / An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder. In: Molecular Psychiatry. 2019 ; Vol. 24. pp. 1707-1719.
@article{57677678e4964b648bf13c1c287f203c,
title = "An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder",
abstract = "A 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.",
author = "Williams, {Sarah M.} and An, {Joon Yong} and Janette Edson and Michelle Watts and Valentine Murigneux and Whitehouse, {Andrew J.O.} and Jackson, {Colin J.} and Bellgrove, {Mark A.} and Cristino, {Alexandre S.} and Charles Claudianos",
year = "2019",
month = "11",
doi = "10.1038/s41380-018-0049-x",
language = "English",
volume = "24",
pages = "1707--1719",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",

}

Williams, SM, An, JY, Edson, J, Watts, M, Murigneux, V, Whitehouse, AJO, Jackson, CJ, Bellgrove, MA, Cristino, AS & Claudianos, C 2019, 'An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder', Molecular Psychiatry, vol. 24, pp. 1707-1719. https://doi.org/10.1038/s41380-018-0049-x

An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder. / Williams, Sarah M.; An, Joon Yong; Edson, Janette; Watts, Michelle; Murigneux, Valentine; Whitehouse, Andrew J.O.; Jackson, Colin J.; Bellgrove, Mark A.; Cristino, Alexandre S.; Claudianos, Charles.

In: Molecular Psychiatry, Vol. 24, 11.2019, p. 1707-1719.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder

AU - Williams, Sarah M.

AU - An, Joon Yong

AU - Edson, Janette

AU - Watts, Michelle

AU - Murigneux, Valentine

AU - Whitehouse, Andrew J.O.

AU - Jackson, Colin J.

AU - Bellgrove, Mark A.

AU - Cristino, Alexandre S.

AU - Claudianos, Charles

PY - 2019/11

Y1 - 2019/11

N2 - A 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.

AB - A 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.

UR - http://www.scopus.com/inward/record.url?scp=85046026074&partnerID=8YFLogxK

U2 - 10.1038/s41380-018-0049-x

DO - 10.1038/s41380-018-0049-x

M3 - Article

VL - 24

SP - 1707

EP - 1719

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

ER -