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Journal Article

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

MPS-Authors
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Devanna,  Paolo
Neurogenetics of Vocal Communication Group, MPI for Psycholinguistics, Max Planck Society;

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Chen,  Xiaowei Sylvia
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;

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Ho,  Joses
Neurogenetics of Vocal Communication Group, MPI for Psycholinguistics, Max Planck Society;
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
International Max Planck Research School for Language Sciences, MPI for Psycholinguistics, Max Planck Society, Nijmegen, NL;

Gajewski,  Dario
Neurogenetics of Vocal Communication Group, MPI for Psycholinguistics, Max Planck Society;

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Gialluisi,  Alessandro
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Francks,  Clyde
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;
Imaging Genomics, MPI for Psycholinguistics, Max Planck Society;

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Fisher,  Simon E.
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;

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Vernes,  Sonja C.
Neurogenetics of Vocal Communication Group, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;

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Fulltext (public)

Devanna_etal_2018.pdf
(Publisher version), 469KB

Supplementary Material (public)

mp201730x1.docx
(Supplementary material), 601KB

Citation

Devanna, P., Chen, X. S., Ho, J., Gajewski, D., Smith, S. D., Gialluisi, A., et al. (2018). Next-gen sequencing identifies non-coding variation disrupting miRNA binding sites in neurological disorders. Molecular Psychiatry, 23(5), 1375-1384. doi:10.1038/mp.2017.30.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002C-9367-D
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