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

Johnson, M. R. et al. (2016) Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Nature Neuroscience, 19(2), pp. 223-232. (doi: 10.1038/nn.4205) (PMID:26691832)

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.

• Item Type: Articles
• Additional Information: We acknowledge funding from UK Imperial National Institute for Health Research Biomedical Research Centre (M.R.J.), the UK Medical Research Council (M.R.J., E.P. and D.S.), The National Genome Research Network (NGFNplus: EMINet, grant 01GS08122; A.J.B.), EuroEpinomics (A.J.B.), UCB Pharma (M.R.J. and E.P.) and the Singapore Ministry of Health (E.P.). We thank the Lothian Birth Cohort 1936 research team for data collection and collation. The Lothian Birth Cohort 1936 is supported by Age UK (Disconnected Mind project). The work at The University of Edinburgh was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). We acknowledge funding from the Biotechnology and Biological Sciences Research Council and MRC. Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of the GS:SFHS samples was carried out by staff at the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the UK’s Medical Research Council. We thank all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. A.D.-D. was supported by a Marie Curie Intra European Fellowship within the 7th European Community Framework Programme.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Padmanabhan, Professor Sandosh
• Authors: 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., Starr, J. M., Liewald, D. C., Visconti, A., Falchi, M., Bottolo, L., Rossetti, T., Danis, B., Mazzuferi, M., Foerch, P., Grote, A., Helmstaedter, C., Becker, A. J., Kaminski, R. M., Deary, I. J., and Petretto, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature Neuroscience
• Publisher: Nature Publishing Group
• ISSN: 1097-6256
• ISSN (Online): 1546-1726