Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes

Guillaume  Huguet; Thomas  Renne; Cécile Poulain; Alma  Dubuc; Kuldeep Kumar; Sayeh  Kazem; Worrawat  Engchuan; Omar  Shanta; Elise  Douard; Catherine  Proulx; Martineau Jean-Louis; Zohra  Saci; Josephine Mollon; Laura M  Schultz; Emma E. M. Knowles; Simon R. Cox; David Porteous; Gail Davies; Paul Redmond; Sarah E. Harris; Gunter Schumann; Guillaume  Dumas; Aurélie  Labbe; Zdenka Pausova; Tomas Paus; Stephen W. Scherer; Jonathan  Sebat; Laura  Almasy; David C. Glahn; Sébastien Jacquemont

doi:10.1016/j.xgen.2024.100721

Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes

Guillaume Huguet^*, Thomas Renne, Cécile Poulain, Alma Dubuc, Kuldeep Kumar, Sayeh Kazem, Worrawat Engchuan, Omar Shanta, Elise Douard, Catherine Proulx, Martineau Jean-Louis, Zohra Saci, Josephine Mollon, Laura M Schultz, Emma E. M. Knowles, Simon R. Cox, David Porteous, Gail Davies, Paul Redmond, Sarah E. HarrisGunter Schumann, Guillaume Dumas, Aurélie Labbe, Zdenka Pausova, Tomas Paus, Stephen W. Scherer, Jonathan Sebat, Laura Almasy, David C. Glahn, Sébastien Jacquemont

^*Corresponding author for this work

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

Abstract / Description of output

Genomic Copy Number Variants (CNVs) that increase risk for neurodevelopmental disorders are also associated with lower cognition. Most studies have focused on the most frequently recurrent CNVs. However, it has been difficult to investigate ultra-rare CNVs and as a result, we have a limited understanding of the full range of gene-dosage-sensitive biological processes linked to cognitive ability. We performed GWAS and functional burden analyses across tissues, cell-types, and ontologies to test the association between all rare CNVs and cognitive ability in 258,292 individuals. We identified a novel association of a duplication at 2q12.3 with higher performance in cognitive ability. Functional burden tests performed on 6,502 gene sets identified 864 gene-sets associated with cognition. The effects-sizes of deletion and duplication were negatively correlated, suggesting that functions across all levels of biological observations were either sensitive to deletion (e.g. subcortical and postsynaptic functions.) or duplication (e.g. cerebral cortex and presynaptic functions). Associations between non-brain tissue and cognition were driven in part by genes under constraint with lower tissue specificity. The latter may help investigate medical comorbidities observed in neurodevelopmental and psychiatric disorders.

Original language	English
Article number	100721
Number of pages	21
Journal	Cell Genomics
Volume	4
Issue number	12
Early online date	11 Dec 2024
DOIs	https://doi.org/10.1016/j.xgen.2024.100721
Publication status	Published - Dec 2024

Keywords / Materials (for Non-textual outputs)

Copy Number Variants (CNV)
gene dosage
cognitive ability
CNV-GWAS
burden association
genetic constraint
transcriptomic
gene ontology

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HuguetEtalCG2025EffectsOfGeneDosageFinal published version, 7.02 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

https://doi.org/10.1016/j.xgen.2024.100721Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Cite this

Huguet, G., Renne, T., Poulain, C., Dubuc, A., Kumar, K., Kazem, S., Engchuan, W., Shanta, O., Douard, E., Proulx, C., Jean-Louis, M., Saci, Z., Mollon, J., Schultz, L. M., Knowles, E. E. M., Cox, S. R., Porteous, D., Davies, G., Redmond, P., ... Jacquemont, S. (2024). Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes. Cell Genomics, 4(12), Article 100721. https://doi.org/10.1016/j.xgen.2024.100721

@article{2805fe6e7b934ea4a4dfc91639643d05,

title = "Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes",

abstract = "Genomic Copy Number Variants (CNVs) that increase risk for neurodevelopmental disorders are also associated with lower cognition. Most studies have focused on the most frequently recurrent CNVs. However, it has been difficult to investigate ultra-rare CNVs and as a result, we have a limited understanding of the full range of gene-dosage-sensitive biological processes linked to cognitive ability. We performed GWAS and functional burden analyses across tissues, cell-types, and ontologies to test the association between all rare CNVs and cognitive ability in 258,292 individuals. We identified a novel association of a duplication at 2q12.3 with higher performance in cognitive ability. Functional burden tests performed on 6,502 gene sets identified 864 gene-sets associated with cognition. The effects-sizes of deletion and duplication were negatively correlated, suggesting that functions across all levels of biological observations were either sensitive to deletion (e.g. subcortical and postsynaptic functions.) or duplication (e.g. cerebral cortex and presynaptic functions). Associations between non-brain tissue and cognition were driven in part by genes under constraint with lower tissue specificity. The latter may help investigate medical comorbidities observed in neurodevelopmental and psychiatric disorders.",

keywords = "Copy Number Variants (CNV), gene dosage, cognitive ability, CNV-GWAS, burden association, genetic constraint, transcriptomic, gene ontology",

author = "Guillaume Huguet and Thomas Renne and C{\'e}cile Poulain and Alma Dubuc and Kuldeep Kumar and Sayeh Kazem and Worrawat Engchuan and Omar Shanta and Elise Douard and Catherine Proulx and Martineau Jean-Louis and Zohra Saci and Josephine Mollon and Schultz, {Laura M} and Knowles, {Emma E. M.} and Cox, {Simon R.} and David Porteous and Gail Davies and Paul Redmond and Harris, {Sarah E.} and Gunter Schumann and Guillaume Dumas and Aur{\'e}lie Labbe and Zdenka Pausova and Tomas Paus and Scherer, {Stephen W.} and Jonathan Sebat and Laura Almasy and Glahn, {David C.} and S{\'e}bastien Jacquemont",

note = "Conceptualization: G.H., T.R., S.J. Data curation: G.H., M.J.-L., Z.S., E.D. Formal Analysis: G.H., T.R., C.P., A.D. Funding acquisition: L.A., D.C.G., S.J. Investigation: G.H., T.R., C.P., A.D. Methodology: G.H., M.J.-L., Z.S., E.D., T.R., C.P., A.D. Project administration: G.H., S.J. Resources: G.H., M.J.-L., Z.S., T.R., C.P. Software: G.H., M.J.-L., Z.S., E.D., T.R., C.P. Supervision: G.H., S.J. Validation: G.H., T.R., S.J. Visualization: G.H., T.R., S.J. Writing – original draft: G.H., T.R., S.J. Writing – review & editing: G.H., T.R., C.P., A.D., K.K., S.K., W.E., O.S., E.D., C.P., M.J.- L., Z.S., J.M., L.M.S., E.E.M.K., S.R.C., D.P., G.D., P.R., S.E.H., G.S., G.D., A.L., Z.P., T.P., S.W.S., J.S., L.A., D.C.G., S.J.",

year = "2024",

month = dec,

doi = "10.1016/j.xgen.2024.100721",

language = "English",

volume = "4",

journal = "Cell Genomics",

issn = "2666-979X",

publisher = "Cell Press",

number = "12",

}

Huguet, G, Renne, T, Poulain, C, Dubuc, A, Kumar, K, Kazem, S, Engchuan, W, Shanta, O, Douard, E, Proulx, C, Jean-Louis, M, Saci, Z, Mollon, J, Schultz, LM, Knowles, EEM, Cox, SR, Porteous, D, Davies, G, Redmond, P, Harris, SE, Schumann, G, Dumas, G, Labbe, A, Pausova, Z, Paus, T, Scherer, SW, Sebat, J, Almasy, L, Glahn, DC & Jacquemont, S 2024, 'Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes', Cell Genomics, vol. 4, no. 12, 100721. https://doi.org/10.1016/j.xgen.2024.100721

TY - JOUR

T1 - Effects of gene dosage on cognitive ability

T2 - A function-based association study across brain and non-brain processes

AU - Huguet, Guillaume

AU - Renne, Thomas

AU - Poulain, Cécile

AU - Dubuc, Alma

AU - Kumar, Kuldeep

AU - Kazem, Sayeh

AU - Engchuan, Worrawat

AU - Shanta, Omar

AU - Douard, Elise

AU - Proulx, Catherine

AU - Jean-Louis, Martineau

AU - Saci, Zohra

AU - Mollon, Josephine

AU - Schultz, Laura M

AU - Knowles, Emma E. M.

AU - Cox, Simon R.

AU - Porteous, David

AU - Davies, Gail

AU - Redmond, Paul

AU - Harris, Sarah E.

AU - Schumann, Gunter

AU - Dumas, Guillaume

AU - Labbe, Aurélie

AU - Pausova, Zdenka

AU - Paus, Tomas

AU - Scherer, Stephen W.

AU - Sebat, Jonathan

AU - Almasy, Laura

AU - Glahn, David C.

AU - Jacquemont, Sébastien

N1 - Conceptualization: G.H., T.R., S.J. Data curation: G.H., M.J.-L., Z.S., E.D. Formal Analysis: G.H., T.R., C.P., A.D. Funding acquisition: L.A., D.C.G., S.J. Investigation: G.H., T.R., C.P., A.D. Methodology: G.H., M.J.-L., Z.S., E.D., T.R., C.P., A.D. Project administration: G.H., S.J. Resources: G.H., M.J.-L., Z.S., T.R., C.P. Software: G.H., M.J.-L., Z.S., E.D., T.R., C.P. Supervision: G.H., S.J. Validation: G.H., T.R., S.J. Visualization: G.H., T.R., S.J. Writing – original draft: G.H., T.R., S.J. Writing – review & editing: G.H., T.R., C.P., A.D., K.K., S.K., W.E., O.S., E.D., C.P., M.J.- L., Z.S., J.M., L.M.S., E.E.M.K., S.R.C., D.P., G.D., P.R., S.E.H., G.S., G.D., A.L., Z.P., T.P., S.W.S., J.S., L.A., D.C.G., S.J.

PY - 2024/12

Y1 - 2024/12

N2 - Genomic Copy Number Variants (CNVs) that increase risk for neurodevelopmental disorders are also associated with lower cognition. Most studies have focused on the most frequently recurrent CNVs. However, it has been difficult to investigate ultra-rare CNVs and as a result, we have a limited understanding of the full range of gene-dosage-sensitive biological processes linked to cognitive ability. We performed GWAS and functional burden analyses across tissues, cell-types, and ontologies to test the association between all rare CNVs and cognitive ability in 258,292 individuals. We identified a novel association of a duplication at 2q12.3 with higher performance in cognitive ability. Functional burden tests performed on 6,502 gene sets identified 864 gene-sets associated with cognition. The effects-sizes of deletion and duplication were negatively correlated, suggesting that functions across all levels of biological observations were either sensitive to deletion (e.g. subcortical and postsynaptic functions.) or duplication (e.g. cerebral cortex and presynaptic functions). Associations between non-brain tissue and cognition were driven in part by genes under constraint with lower tissue specificity. The latter may help investigate medical comorbidities observed in neurodevelopmental and psychiatric disorders.

AB - Genomic Copy Number Variants (CNVs) that increase risk for neurodevelopmental disorders are also associated with lower cognition. Most studies have focused on the most frequently recurrent CNVs. However, it has been difficult to investigate ultra-rare CNVs and as a result, we have a limited understanding of the full range of gene-dosage-sensitive biological processes linked to cognitive ability. We performed GWAS and functional burden analyses across tissues, cell-types, and ontologies to test the association between all rare CNVs and cognitive ability in 258,292 individuals. We identified a novel association of a duplication at 2q12.3 with higher performance in cognitive ability. Functional burden tests performed on 6,502 gene sets identified 864 gene-sets associated with cognition. The effects-sizes of deletion and duplication were negatively correlated, suggesting that functions across all levels of biological observations were either sensitive to deletion (e.g. subcortical and postsynaptic functions.) or duplication (e.g. cerebral cortex and presynaptic functions). Associations between non-brain tissue and cognition were driven in part by genes under constraint with lower tissue specificity. The latter may help investigate medical comorbidities observed in neurodevelopmental and psychiatric disorders.

KW - Copy Number Variants (CNV)

KW - gene dosage

KW - cognitive ability

KW - CNV-GWAS

KW - burden association

KW - genetic constraint

KW - transcriptomic

KW - gene ontology

UR - https://github.com/labjacquemont/CNV_cognitive_ability

UR - https://figshare.com/s/219dd9437e72782fafa0

UR - https://martineaujeanlouis.github.io/MIND-GENESPARALLELCNV/

UR - https://github.com/labjacquemont/DigCNV

U2 - 10.1016/j.xgen.2024.100721

DO - 10.1016/j.xgen.2024.100721

M3 - Article

SN - 2666-979X

VL - 4

JO - Cell Genomics

JF - Cell Genomics

IS - 12

M1 - 100721

ER -

Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

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The Lothian Birth Cohort 1936 Waves 6 and 7

Factors of biological ageing: does it all go together when it goes?

Generation Scotland: NextGenScot

Genetics Core, Edinburgh Clinical Research Facility

Cite this

Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

Other files and links

Fingerprint

Projects

The Lothian Birth Cohort 1936 Waves 6 and 7

Factors of biological ageing: does it all go together when it goes?

Generation Scotland: NextGenScot

Equipment

Genetics Core, Edinburgh Clinical Research Facility

Cite this