title: Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.
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.
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.|Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, London, UK.
authors.forename: Kirill
authors.initials: K
authors.lastname: Shkura
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.|Duke-NUS Medical School, Singapore, Republic of Singapore.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Langley
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.|Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, London, UK.|Université Paris 13, Sorbonne Paris Cité, UFR de Santé, Médecine et Biologie Humaine, Paris, France.
authors.forename: Andree
authors.initials: A
authors.lastname: Delahaye-Duriez
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.
authors.forename: Prashant
authors.initials: P
authors.lastname: Srivastava
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: W David
authors.initials: WD
authors.lastname: Hill
authors.affiliation: Duke-NUS Medical School, Singapore, Republic of Singapore.
authors.forename: Owen J L
authors.initials: OJ
authors.lastname: Rackham
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: Gail
authors.initials: G
authors.lastname: Davies
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Medical Genetics Section, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, London, UK.
authors.forename: Aida
authors.initials: A
authors.lastname: Moreno-Moral
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, London, UK.
authors.forename: Maxime
authors.initials: M
authors.lastname: Rotival
authors.affiliation: University College London Genetics Institute, London, UK.
authors.forename: Doug
authors.identifier: http://orcid.org/0000-0002-0096-9765
authors.initials: D
authors.lastname: Speed
authors.affiliation: Department of Medicine, Austin Hospital and Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Slavé
authors.initials: S
authors.lastname: Petrovski
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.|Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, London, UK.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Katz
authors.affiliation: Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Medical Genetics Section, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Division of Population Health Sciences, University of Dundee, Dundee, UK.
authors.forename: Blair H
authors.identifier: http://orcid.org/0000-0002-5362-9430
authors.initials: BH
authors.lastname: Smith
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Hocking
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: David C
authors.identifier: http://orcid.org/0000-0002-0544-7368
authors.initials: DC
authors.lastname: Liewald
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
authors.forename: Alessia
authors.identifier: http://orcid.org/0000-0003-4144-2019
authors.initials: A
authors.lastname: Visconti
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.affiliation: Department of Mathematics, Imperial College, London, UK.|Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bottolo
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, London, UK.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rossetti
authors.affiliation: Neuroscience TA, UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Danis
authors.affiliation: Neuroscience TA, UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mazzuferi
authors.affiliation: Neuroscience TA, UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Foerch
authors.affiliation: Department of Neurosurgery, University of Bonn, Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grote
authors.affiliation: Department of Neuropsychology, University of Bonn, Bonn, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Helmstaedter
authors.affiliation: Department of Neuropathology, University of Bonn, Bonn, Germany.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
authors.affiliation: Neuroscience TA, UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, London, UK.|Duke-NUS Medical School, Singapore, Republic of Singapore.
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000235:genetics; D003071:Cognition; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D004833:Epilepsy, Temporal Lobe / Q000235:genetics / Q000601:surgery; D015870:Gene Expression; D053263:Gene Regulatory Networks / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000601:surgery; D006801:Humans; D009420:Nervous System / Q000254:growth & development* / Q000503:physiopathology; D013569:Synapses / Q000235:genetics