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

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Devanna_2018_MolPsych_Next_gen_sequencing_CC.pdf (2.471Mb)
Date
05/2018
Author
Devanna, P
Chen, X S
Ho, J
Gajewski, D
Smith, S D
Gialluisi, A
Francks, C
Fisher, S E
Newbury, D F
Vernes, S C
Keywords
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
QH301 Biology
QH426 Genetics
RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
DAS
SDG 3 - Good Health and Well-being
Metadata
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Abstract
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.
Citation
Devanna , P , Chen , X S , Ho , J , Gajewski , D , Smith , S D , Gialluisi , A , Francks , C , Fisher , S E , Newbury , D F & Vernes , S C 2018 , ' Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders ' , Molecular Psychiatry , vol. 23 , no. 5 , pp. 1375-1384 . https://doi.org/10.1038/mp.2017.30
Publication
Molecular Psychiatry
Status
Peer reviewed
DOI
https://doi.org/10.1038/mp.2017.30
ISSN
1359-4184
Type
Journal article
Rights
Copyright © The Author(s) 2018. This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/
Description
Funding: This work was funded by a Marie Curie Career Integration Grant and by a Max Planck Research Group Grant both awarded to SCV. The work of the Newbury lab is funded by the Medical Research Council (G1000569/1 and MR/J003719/1). XSC, AG, CF and SEF were supported by the Max Planck Society. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provided core support for ALSPAC. The work of the Wellcome Trust Centre in Oxford is supported by the Wellcome Trust (090532/Z/09/Z). JH was supported by a scholarship from the Agency for Science, Technology, and Research, Singapore. The work of SDS is supported by the grant HD027802 from NIH.
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/21699

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