Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

W. D. Hill; G. Davies; L. N. Van De Lagemaat; A. Christoforou; R. E. Marioni; C. P D Fernandes; D. C. Liewald; M. D R Croning; A. Payton; L. C A Craig; L. J. Whalley; M. Horan; W. Ollier; N. K. Hansell; M. J. Wright; N. G. Martin; G. W. Montgomery; V. M. Steen; S. Le Hellard; T. Espeseth; A. J. Lundervold; I. Reinvang; J. M. Starr; N. Pendleton; S. G N Grant; T. C. Bates; I. J. Deary

doi:10.1038/tp.2013.114

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

W. D. Hill, G. Davies, L. N. Van De Lagemaat, A. Christoforou, R. E. Marioni, C. P D Fernandes, D. C. Liewald, M. D R Croning, A. Payton, L. C A Craig, L. J. Whalley, M. Horan, W. Ollier, N. K. Hansell, M. J. Wright, N. G. Martin, G. W. Montgomery, V. M. Steen, S. Le Hellard, T. EspesethA. J. Lundervold, I. Reinvang, J. M. Starr, N. Pendleton, S. G N Grant, T. C. Bates, I. J. Deary^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P = 0.002. Replication was sought in two additional cohorts (N = 670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

Original language	English
Article number	e341
Pages (from-to)	1-8
Number of pages	8
Journal	Translational Psychiatry
Volume	4
Early online date	7 Jan 2014
DOIs	https://doi.org/10.1038/tp.2013.114
Publication status	Published - 7 Jan 2014

Bibliographical note

Acknowledgements
We thank the cohort participants who contributed to these studies and the research staff who collected phenotypic data. Genotyping of the CAGES cohorts and the analyses conducted here were supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK’s The Disconnected Mind project). Phenotype collection in the Aberdeen Birth Cohort 1936 was supported by BBSRC, the Wellcome Trust and Alzheimer’s Research UK. Phenotype collection in the Manchester and Newcastle Longitudinal Studies of Cognitive Ageing cohorts was supported by Social Science Research Council, Medical Research Council, Economic and Social Research Council, Research Into Ageing, Wellcome Trust and Unilever plc. The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. Australian BATS sample: we especially thank the twins and their families for participation. The research was supported by the Australian Research Council (A7960034, A79906588, A79801419, DP0212016 and DP0343921), with genotyping funded by the National Health and Medical Research Council (Medical Bioinformatics Genomics Proteomics Program, 389891). The Norwegian study was supported by the Bergen Research Foundation (BFS), the University of Bergen, the Research Council of Norway (including FUGE grant nos. 151904 and 183327, Psykisk Helse grant no. 175345, 154313/V50 to IR and 177458/V50 to TE), Helse Vest RHF (Grant 911397 and 911687 to AJL) and Dr Einar Martens Fund. We thank the Centre for Advanced Study (CAS) at the Norwegian Academy of Science and Letters in Oslo for hosting collaborative projects and workshops between Norway and Scotland in 2011–2012. SGNG and LV van de L were supported by the MRC, Wellcome Trust and European Union Seventh Framework Programme under grant agreements number 241498 ‘EUROSPIN’ project, 242167 ‘SynSys project’ and 241995 ‘GENCODYS’ project.

Keywords

GWAS
Intelligence
NMDA-RC
Pathway analysis
Synapse

UN SDGs

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

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10.1038/tp.2013.114Licence: CC BY

Cite this

Hill, W. D., Davies, G., Van De Lagemaat, L. N., Christoforou, A., Marioni, R. E., Fernandes, C. P. D., Liewald, D. C., Croning, M. D. R., Payton, A., Craig, L. C. A., Whalley, L. J., Horan, M., Ollier, W., Hansell, N. K., Wright, M. J., Martin, N. G., Montgomery, G. W., Steen, V. M., Le Hellard, S., ... Deary, I. J. (2014). Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins. Translational Psychiatry, 4, 1-8. Article e341. https://doi.org/10.1038/tp.2013.114

Hill, WD, Davies, G, Van De Lagemaat, LN, Christoforou, A, Marioni, RE, Fernandes, CPD, Liewald, DC, Croning, MDR, Payton, A, Craig, LCA, Whalley, LJ, Horan, M, Ollier, W, Hansell, NK, Wright, MJ, Martin, NG, Montgomery, GW, Steen, VM, Le Hellard, S, Espeseth, T, Lundervold, AJ, Reinvang, I, Starr, JM, Pendleton, N, Grant, SGN, Bates, TC & Deary, IJ 2014, 'Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins', Translational Psychiatry, vol. 4, e341, pp. 1-8. https://doi.org/10.1038/tp.2013.114

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abstract = "Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P = 0.002. Replication was sought in two additional cohorts (N = 670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.",

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note = "Acknowledgements We thank the cohort participants who contributed to these studies and the research staff who collected phenotypic data. Genotyping of the CAGES cohorts and the analyses conducted here were supported by the UK{\textquoteright}s Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK{\textquoteright}s The Disconnected Mind project). Phenotype collection in the Aberdeen Birth Cohort 1936 was supported by BBSRC, the Wellcome Trust and Alzheimer{\textquoteright}s Research UK. Phenotype collection in the Manchester and Newcastle Longitudinal Studies of Cognitive Ageing cohorts was supported by Social Science Research Council, Medical Research Council, Economic and Social Research Council, Research Into Ageing, Wellcome Trust and Unilever plc. The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. Australian BATS sample: we especially thank the twins and their families for participation. The research was supported by the Australian Research Council (A7960034, A79906588, A79801419, DP0212016 and DP0343921), with genotyping funded by the National Health and Medical Research Council (Medical Bioinformatics Genomics Proteomics Program, 389891). The Norwegian study was supported by the Bergen Research Foundation (BFS), the University of Bergen, the Research Council of Norway (including FUGE grant nos. 151904 and 183327, Psykisk Helse grant no. 175345, 154313/V50 to IR and 177458/V50 to TE), Helse Vest RHF (Grant 911397 and 911687 to AJL) and Dr Einar Martens Fund. We thank the Centre for Advanced Study (CAS) at the Norwegian Academy of Science and Letters in Oslo for hosting collaborative projects and workshops between Norway and Scotland in 2011–2012. SGNG and LV van de L were supported by the MRC, Wellcome Trust and European Union Seventh Framework Programme under grant agreements number 241498 {\textquoteleft}EUROSPIN{\textquoteright} project, 242167 {\textquoteleft}SynSys project{\textquoteright} and 241995 {\textquoteleft}GENCODYS{\textquoteright} project.",

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T1 - Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

AU - Hill, W. D.

AU - Davies, G.

AU - Van De Lagemaat, L. N.

AU - Christoforou, A.

AU - Marioni, R. E.

AU - Fernandes, C. P D

AU - Liewald, D. C.

AU - Croning, M. D R

AU - Payton, A.

AU - Craig, L. C A

AU - Whalley, L. J.

AU - Horan, M.

AU - Ollier, W.

AU - Hansell, N. K.

AU - Wright, M. J.

AU - Martin, N. G.

AU - Montgomery, G. W.

AU - Steen, V. M.

AU - Le Hellard, S.

AU - Espeseth, T.

AU - Lundervold, A. J.

AU - Reinvang, I.

AU - Starr, J. M.

AU - Pendleton, N.

AU - Grant, S. G N

AU - Bates, T. C.

AU - Deary, I. J.

N1 - Acknowledgements We thank the cohort participants who contributed to these studies and the research staff who collected phenotypic data. Genotyping of the CAGES cohorts and the analyses conducted here were supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK’s The Disconnected Mind project). Phenotype collection in the Aberdeen Birth Cohort 1936 was supported by BBSRC, the Wellcome Trust and Alzheimer’s Research UK. Phenotype collection in the Manchester and Newcastle Longitudinal Studies of Cognitive Ageing cohorts was supported by Social Science Research Council, Medical Research Council, Economic and Social Research Council, Research Into Ageing, Wellcome Trust and Unilever plc. The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. Australian BATS sample: we especially thank the twins and their families for participation. The research was supported by the Australian Research Council (A7960034, A79906588, A79801419, DP0212016 and DP0343921), with genotyping funded by the National Health and Medical Research Council (Medical Bioinformatics Genomics Proteomics Program, 389891). The Norwegian study was supported by the Bergen Research Foundation (BFS), the University of Bergen, the Research Council of Norway (including FUGE grant nos. 151904 and 183327, Psykisk Helse grant no. 175345, 154313/V50 to IR and 177458/V50 to TE), Helse Vest RHF (Grant 911397 and 911687 to AJL) and Dr Einar Martens Fund. We thank the Centre for Advanced Study (CAS) at the Norwegian Academy of Science and Letters in Oslo for hosting collaborative projects and workshops between Norway and Scotland in 2011–2012. SGNG and LV van de L were supported by the MRC, Wellcome Trust and European Union Seventh Framework Programme under grant agreements number 241498 ‘EUROSPIN’ project, 242167 ‘SynSys project’ and 241995 ‘GENCODYS’ project.

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N2 - Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P = 0.002. Replication was sought in two additional cohorts (N = 670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

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Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

Abstract

Bibliographical note

Keywords

UN SDGs

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Aberdeen Birth Cohort Study 1936 (ABC 1936)

Leone Craig

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Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Datasets

Aberdeen Birth Cohort Study 1936 (ABC 1936)

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Leone Craig

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