Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease

Michael R. Johnson, Kirill Shkura, Sarah R. Langley, Andree Delahaye-Duriez, Prashant Srivastava, W. David Hill, Owen J L Rackham, Gail Davies, Sarah E. Harris, Aida Moreno-Moral, Maxime Rotival, Doug Speed, Slavé Petrovski, Anaïs Katz, Caroline Hayward, David J. Porteous, Blair H. Smith, Sandosh Padmanabhan, Lynne J. Hocking, John M. StarrDavid C. Liewald, Alessia Visconti, Mario Falchi, Leonardo Bottolo, Tiziana Rossetti, Bénédicte Danis, Manuela Mazzuferi, Patrik Foerch, Alexander Grote, Christoph Helmstaedter, Albert J. Becker, Rafal M. Kaminski, Ian J. Deary, Enrico Petretto

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    Genetic determinants of cognition are poorly characterized, and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here we performed a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities, including memory. Using exome sequence data from 6,871 trios, we found that M3 genes were also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease-associated genes in the developed human brain, and provide empirical support for a convergent gene-regulatory network influencing cognition and neurodevelopmental disease.

    Original languageEnglish
    Pages (from-to)223-232
    Number of pages10
    JournalNature Neuroscience
    Issue number2
    Early online date21 Dec 2015
    Publication statusPublished - 1 Feb 2016


    • Developmental disorders
    • Gene regulatory networks
    • Systems biology

    ASJC Scopus subject areas

    • Neuroscience(all)


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