Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes
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.
Authors
- Laura Almasy
- Aurélie Labbe (ORCID: https://orcid.org/0000-0002-4207-8143)
- Zohra Saci (ORCID: https://orcid.org/0000-0003-2788-1306)
- Élise Douard (ORCID: https://orcid.org/0000-0003-4205-8828)
- Gail Davies (ORCID: https://orcid.org/0000-0003-1120-7026)
- Guillaume Dumas (ORCID: https://orcid.org/0000-0002-2253-1844)
- Zdenka Pausová (ORCID: https://orcid.org/0000-0002-7784-1380)
- Sayeh Kazem (ORCID: https://orcid.org/0009-0003-2772-5538)
- Catherine Proulx (ORCID: https://orcid.org/0000-0002-9341-2076)
- Guillaume Huguet (ORCID: https://orcid.org/0000-0002-4746-6030)
- Thomas Renné (ORCID: https://orcid.org/0000-0003-4594-5975)
- Stephen W. Scherer (ORCID: https://orcid.org/0000-0002-8326-1999)
- Kuldeep Kumar (ORCID: https://orcid.org/0000-0003-3313-135X)
- Martineau Jean‐Louis (ORCID: https://orcid.org/0000-0002-3305-3307)
- Omar Shanta (ORCID: https://orcid.org/0000-0003-2387-2787)
- Worrawat Engchuan (ORCID: https://orcid.org/0000-0001-6138-1925)
- Josephine Mollon (ORCID: https://orcid.org/0000-0003-4557-1838)
- Paul H. Redmond (ORCID: https://orcid.org/0000-0001-8272-8596)
- Emma E. M. Knowles (ORCID: https://orcid.org/0000-0003-0642-267X)
- Simon R. Cox (ORCID: https://orcid.org/0000-0003-4036-3642)
- Sébastien Jacquemont (ORCID: https://orcid.org/0000-0001-6838-8767)
- Laura M. Schultz (ORCID: https://orcid.org/0000-0001-7506-8235)
- David J. Porteous (ORCID: https://orcid.org/0000-0003-1249-6106)
- Jonathan Sebat (ORCID: https://orcid.org/0000-0002-9087-526X)
- Alma Dubuc (ORCID: https://orcid.org/0009-0008-8396-9189)
- Cécile Poulain (ORCID: https://orcid.org/0000-0002-5371-1581)
- Günter Schumann (ORCID: https://orcid.org/0000-0002-7740-6469)
- Sarah E. Harris
- Tomaš Paus
- David C. Glahn
Institutions
- Université Claude Bernard Lyon 1 (FR)
- HEC Montréal (CA)
- École Normale Supérieure de Lyon (FR)
- Boston Children's Hospital (US)
- Hartford Hospital (US)
- NHS Lothian (GB)
- Children's Hospital of Philadelphia (US)
- Harvard University (US)
- University of San Diego (US)
- King's College London (GB)
- University of Toronto (CA)
- Western General Hospital (GB)
- Hospital for Sick Children (CA)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Edinburgh Cancer Research (GB)
- University of California San Diego (US)
- Language Science (South Korea) (KR)
- Mila - Quebec Artificial Intelligence Institute (CA)
- University of Edinburgh (GB)
Publication Details
- Journal
- Cell Genomics
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.xgen.2024.100721
- Citations
- 4
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.20
Funders
- Heart and Stroke Foundation of Canada
- South London and Maudsley NHS Foundation Trust
- Fondation Brain Canada
- Wellcome Trust
- Health and Care Research Wales
- Scottish Government
- Compute Canada
- National Institute for Health and Care Research
- Scottish Funding Council
- Age UK
- King's College London
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- National Institutes of Health
- Directorate for Biological Sciences
- Chief Scientist Office, Scottish Government Health and Social Care Directorate
- Canadian Institutes of Health Research
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Economic and Social Research Council
- National Center for Mental Health