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Nat Neurosci. 2016 Feb;19(2):223-32. doi: 10.1038/nn.4205. Epub 2015 Dec 21.

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

Author information

1
Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.
2
Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, London, UK.
3
Duke-NUS Medical School, Singapore, Republic of Singapore.
4
Université Paris 13, Sorbonne Paris Cité, UFR de Santé, Médecine et Biologie Humaine, Paris, France.
5
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
6
Department of Psychology, University of Edinburgh, Edinburgh, UK.
7
Medical Genetics Section, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
8
University College London Genetics Institute, London, UK.
9
Department of Medicine, Austin Hospital and Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
10
Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
11
Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
12
Division of Population Health Sciences, University of Dundee, Dundee, UK.
13
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
14
Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
15
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
16
Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
17
Department of Mathematics, Imperial College, London, UK.
18
Department of Medical Genetics, University of Cambridge, Cambridge, UK.
19
Neuroscience TA, UCB Pharma, Braine-l'Alleud, Belgium.
20
Department of Neurosurgery, University of Bonn, Bonn, Germany.
21
Department of Neuropsychology, University of Bonn, Bonn, Germany.
22
Department of Neuropathology, University of Bonn, Bonn, Germany.

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.

Comment in

PMID:
26691832
DOI:
10.1038/nn.4205
[Indexed for MEDLINE]
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