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

• DOI: 10.1038/nn.4205
• Publication Date: 2015-12-21T16:15:29Z
• Authors: Michael R Johnson; Kirill Shkura; Sarah R Langley; Andree Delahaye-D...; 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 Starr; David C Liewald; Alessia Visconti; Mario Falchi; Leonardo Bottolo; Tiziana Rossetti; Bénédicte Danis; Manuela Mazzuferi; Patrik Foerch; Alexander Grote; Christoph Helmsta...; Albert J Becker; Rafal M Kaminski; Ian J Deary; Enrico Petretto
• Keywords: 0301 basic medicine; INTELLECTUAL DISABILITY; Developmental Disabilities; 610; Gene Expression; Hippocampus; Nervous System; Gene regulatory networks; SET ANALYSIS; 618; 03 medical and health sciences; Cognition; /dk/atira/pure/subjectarea/asjc/2800/2800; Animals; Humans; EPILEPTIC ENCEPHALOPATHIES; HUMAN INTELLIGENCE; Gene Regulatory Networks; GENOME-WIDE ASSOCIATION; Brain Chemistry; Epilepsy; Science & Technology; Neurology & Neurosurgery; GENERATION SCOTLAND; Developmental disorders; TEST BATTERIES; Neurosciences; Genetic Variation; 1702 Cognitive Science; name=General Neuroscience; HUMAN BRAIN; Temporal Lobe; SCOTTISH FAMILY HEALTH; Epilepsy, Temporal Lobe; DE-NOVO MUTATIONS; Synapses; Neurosciences & Neurology; Systems biology; 1109 Neurosciences; Life Sciences & Biomedicine; Genome-Wide Association Study

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.