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

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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
Volume19
Issue number2
Early online date21 Dec 2015
DOIs
Publication statusPublished - Feb 2016

Keywords

  • Animals
  • Brain Chemistry
  • Cognition
  • Developmental Disabilities
  • Epilepsy, Temporal Lobe
  • Gene Expression
  • Gene Regulatory Networks
  • Genetic Variation
  • Genome-Wide Association Study
  • Hippocampus
  • Humans
  • Nervous System
  • Synapses
  • Journal Article
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Johnson, M. R., Shkura, K., Langley, S. R., Delahaye-Duriez, A., Srivastava, P., Hill, W. D., Rackham, O. J. L., Davies, G., Harris, S. E., Moreno-Moral, A., Rotival, M., Speed, D., Petrovski, S., Katz, A., Hayward, C., Porteous, D. J., Smith, B. H., Padmanabhan, S., Hocking, L. J., ... Petretto, E. (2016). Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Nature Neuroscience, 19(2), 223-232. https://doi.org/10.1038/nn.4205