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Psychiatric gene discoveries shape evidence on ADHD's biology

Thapar, Anita, Martin, Joanna, Mick, E., Arias Vasquez, A., Langley, Kate, Scherer, S.W., Schacher, R., Crosbie, J., Williams, Nigel Melville, Franke, B., Elia, J., Glessner, J., Hakonarson, H., Owen, Michael John, Faraone, S.V., O'Donovan, Michael Conlon and Holmans, Peter Alan 2016. Psychiatric gene discoveries shape evidence on ADHD's biology. Molecular Psychiatry 21 (9) , pp. 1202-1207. 10.1038/mp.2015.163

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Abstract

A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10-4) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.Molecular Psychiatry advance online publication, 17 November 2015

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Psychology
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: Nature Publishing Group
ISSN: 1359-4184
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 8 September 2015
Last Modified: 17 Oct 2019 15:54
URI: http://orca.cf.ac.uk/id/eprint/83629

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