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 journalArticle

6 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)1-13
Number of pages13
JournalMolecular Psychiatry
DOIs
Publication statusE-pub ahead of print - 27 Apr 2018

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DNA
Nucleotides
Genes
Nucleic Acid Regulatory Sequences
MicroRNAs
Genome
Genetic Heterogeneity
Transcription Factors
Binding Sites
Autism Spectrum Disorder
Mutation
Proteins
Paternal Inheritance
Datasets
Maternal Inheritance
Neurodevelopmental Disorders

Cite this

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. 2018 ; pp. 1-13.
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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.",
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Williams, SM, An, JY, Edson, J, Watts, M, Murigneux, V, Whitehouse, AJO, Jackson, CJ, Bellgrove, MA, Cristino, AS & Claudianos, C 2018, 'An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder' Molecular Psychiatry, pp. 1-13. 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, 27.04.2018, p. 1-13.

Research output: Contribution to journalArticle

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AU - Whitehouse, Andrew J.O.

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