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. Starr; David 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

doi:10.1038/nn.4205

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

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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 language	English
Pages (from-to)	223-232
Number of pages	10
Journal	Nature Neuroscience
Volume	19
Issue number	2
Early online date	21 Dec 2015
DOIs	https://doi.org/10.1038/nn.4205
Publication status	Published - 1 Feb 2016

Keywords

Developmental disorders
Gene regulatory networks
Systems biology

ASJC Scopus subject areas

General Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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

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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.",

keywords = "Developmental disorders, Gene regulatory networks, Systems biology",

author = "Johnson, {Michael R.} and Kirill Shkura and Langley, {Sarah R.} and Andree Delahaye-Duriez and Prashant Srivastava and Hill, {W. David} and Rackham, {Owen J L} and Gail Davies and Harris, {Sarah E.} and Aida Moreno-Moral and Maxime Rotival and Doug Speed and Slav{\'e} Petrovski and Ana{\"i}s Katz and Caroline Hayward and Porteous, {David J.} and Smith, {Blair H.} and Sandosh Padmanabhan and Hocking, {Lynne J.} and Starr, {John M.} and Liewald, {David C.} and Alessia Visconti and Mario Falchi and Leonardo Bottolo and Tiziana Rossetti and B{\'e}n{\'e}dicte Danis and Manuela Mazzuferi and Patrik Foerch and Alexander Grote and Christoph Helmstaedter and Becker, {Albert J.} and Kaminski, {Rafal M.} and Deary, {Ian J.} and Enrico Petretto",

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Johnson, MR, Shkura, K, Langley, SR, Delahaye-Duriez, A, Srivastava, P, Hill, WD, Rackham, OJL, Davies, G, Harris, SE, Moreno-Moral, A, Rotival, M, Speed, D, Petrovski, S, Katz, A, Hayward, C, Porteous, DJ, Smith, BH, Padmanabhan, S, Hocking, LJ, Starr, JM, Liewald, DC, Visconti, A, Falchi, M, Bottolo, L, Rossetti, T, Danis, B, Mazzuferi, M, Foerch, P, Grote, A, Helmstaedter, C, Becker, AJ, Kaminski, RM, Deary, IJ & Petretto, E 2016, 'Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease', Nature Neuroscience, vol. 19, no. 2, pp. 223-232. https://doi.org/10.1038/nn.4205

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AU - Johnson, Michael R.

AU - Shkura, Kirill

AU - Langley, Sarah R.

AU - Delahaye-Duriez, Andree

AU - Srivastava, Prashant

AU - Hill, W. David

AU - Rackham, Owen J L

AU - Davies, Gail

AU - Harris, Sarah E.

AU - Moreno-Moral, Aida

AU - Rotival, Maxime

AU - Speed, Doug

AU - Petrovski, Slavé

AU - Katz, Anaïs

AU - Hayward, Caroline

AU - Porteous, David J.

AU - Smith, Blair H.

AU - Padmanabhan, Sandosh

AU - Hocking, Lynne J.

AU - Starr, John M.

AU - Liewald, David C.

AU - Visconti, Alessia

AU - Falchi, Mario

AU - Bottolo, Leonardo

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AU - Danis, Bénédicte

AU - Mazzuferi, Manuela

AU - Foerch, Patrik

AU - Grote, Alexander

AU - Helmstaedter, Christoph

AU - Becker, Albert J.

AU - Kaminski, Rafal M.

AU - Deary, Ian J.

AU - Petretto, Enrico

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N2 - 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.

AB - 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.

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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