Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders

P Devanna, X S Chen, J Ho, D Gajewski, S D Smith, A Gialluisi, C Francks, S E Fisher, D F Newbury, S C Vernes

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38 Citations (Scopus)
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Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3'UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease.

Original languageEnglish
Pages (from-to)1375-1384
Number of pages10
JournalMolecular Psychiatry
Issue number5
Early online date14 Mar 2017
Publication statusPublished - May 2018


  • 3' Untranslated Regions/genetics
  • Adult
  • Autistic disorder/genetics
  • Binding sites/genetics
  • Bipolar disorder/genetics
  • Child
  • Cohort studies
  • DNA, intergenic/genetics
  • Female
  • Gene expression regulation/genetics
  • Genetic predisposition to Disease
  • Genetic variation/genetics
  • Genomics
  • High-throughput nucleotide sequencing/methods
  • Humans
  • Language development disorders/genetics
  • Male
  • Mental disorders/genetics
  • microRNAs/genetics
  • Nervous system diseases/genetics
  • Neurodevelopmental disorders/genetics
  • Schizophrenia/genetics
  • Sequence analysis/methods


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