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

Cell Genom. 2024 Dec 11;4(12):100721. doi: 10.1016/j.xgen.2024.100721.

Authors

Guillaume Huguet¹, Thomas Renne², Cécile Poulain², Alma Dubuc³, Kuldeep Kumar⁴, Sayeh Kazem², Worrawat Engchuan⁵, Omar Shanta⁶, Elise Douard⁴, Catherine Proulx⁴, Martineau Jean-Louis⁴, Zohra Saci⁴, Josephine Mollon⁷, Laura M Schultz⁸, Emma E M Knowles⁷, Simon R Cox⁹, David Porteous¹⁰, Gail Davies⁹, Paul Redmond⁹, Sarah E Harris⁹, Gunter Schumann¹¹, Guillaume Dumas¹², Aurélie Labbe¹³, Zdenka Pausova¹⁴, Tomas Paus¹⁵, Stephen W Scherer¹⁶, Jonathan Sebat¹⁷, Laura Almasy¹⁸, David C Glahn¹⁹, Sébastien Jacquemont²⁰

Affiliations

¹ Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada. Electronic address: [email protected].
² Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada.
³ École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
⁴ Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada.
⁵ The Hospital for Sick Children, Genetics and Genome Biology, Toronto, ON, Canada; The Hospital for Sick Children, The Centre for Applied Genomics, Toronto, ON, Canada.
⁶ Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA.
⁷ Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁹ Lothian Birth Cohorts, Department of Psychology, School of Philosophy, Psychology and Language Sciences, The University of Edinburgh, Edinburgh EH8 9JZ, UK.
¹⁰ Lothian Birth Cohorts, Department of Psychology, School of Philosophy, Psychology and Language Sciences, The University of Edinburgh, Edinburgh EH8 9JZ, UK; Medical Genetics Section, Centre for Genomic & Experimental Medicine, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
¹¹ Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
¹² Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada; Mila - Quebec Artificial Intelligence Institute, Montréal, QC, Canada.
¹³ Département de Sciences de la Décision, HEC Montreal, Montreal, QC, Canada.
¹⁴ Research Institute of the Hospital for Sick Children, Toronto, ON, Canada; Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON, Canada; ECOGENE-21, Chicoutimi, QC, Canada.
¹⁵ Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada; Department of Psychiatry and Addictology, Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
¹⁶ The Hospital for Sick Children, Genetics and Genome Biology, Toronto, ON, Canada; The Hospital for Sick Children, The Centre for Applied Genomics, Toronto, ON, Canada; McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁷ University of California, San Diego, Department of Psychiatry, Department of Cellular & Molecular Medicine, Beyster Center of Psychiatric Genomics, San Diego, CA, USA.
¹⁸ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁹ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.
²⁰ Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC, Canada. Electronic address: [email protected].

PMID: 39667348
DOI: 10.1016/j.xgen.2024.100721

Abstract

Copy-number variants (CNVs) that increase the risk for neurodevelopmental disorders also affect cognitive ability. However, such CNVs remain challenging to study due to their scarcity, limiting our understanding of gene-dosage-sensitive biological processes linked to cognitive ability. We performed a genome-wide association study (GWAS) in 258,292 individuals, which identified-for the first time-a duplication at 2q12.3 associated with higher cognitive performance. We developed a functional-burden analysis, which tested the association between cognition and CNVs disrupting 6,502 gene sets biologically defined across tissues, cell types, and ontologies. Among those, 864 gene sets were associated with cognition, and effect sizes of deletion and duplication were negatively correlated. The latter suggested that functions across all biological processes were sensitive to either deletions (e.g., subcortical regions, postsynaptic) or duplications (e.g., cerebral cortex, presynaptic). Associations between non-brain tissues and cognition were driven partly by constrained genes, which may shed light on medical comorbidities in neurodevelopmental disorders.

Keywords: CNV-GWAS; Gene Ontology; burden association; cognitive ability; copy-number variants; gene dosage; genetic constraint; transcriptomic.

MeSH terms

Adult
Brain* / metabolism
Cognition* / physiology
DNA Copy Number Variations* / genetics
Female
Gene Dosage*
Genome-Wide Association Study*
Humans
Male