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Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability

Abstract

Genomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs > 50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.

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Fig. 1: Effect of intolerant score on general intelligence measured for deletions and duplications.
Fig. 2: Effect size of intellectual disability (ID) genes on general intelligence.
Fig. 3: Concordance between model predictions and published observations for CNV effects on general intelligence and for de novo frequency.
Fig. 4: Effect size on general intelligence of individual genes encompassed in CNVs and their GOterms enrichment.

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Acknowledgements

The authors wish to acknowledge the resources of MSSNG (www.mss.ng), Autism Speaks, and The Centre for Applied Genomics at The Hospital for Sick Children, Toronto, Canada. The authors also thank the participating families for their time and contributions to this database, as well as the generosity of the donors who supported this program. The authors are grateful to all the families who participated in the Simons Variation in Individuals Project (VIP) and the Simons VIP Consortium (data from Simons VIP are available through SFARI Base). The authors thank the coordinators and staff at the Simons VIP and SCC sites. The authors are grateful to all of the families at the participating SSC sites and the principal investigators (A. Beaudet, MD, R. Bernier, PhD, J. Constantino, MD, E. Cook, MD, E. Fombonne, MD, D. Geschwind, MD, PhD, R. Goin-Kochel, PhD, E. Hanson, PhD, D. Grice, MD, A. Klin, PhD, D. Ledbetter, PhD, C. Lord, PhD, C. Martin, PhD, D. Martin, MD, PhD, R. Maxim, MD, J. Miles, MD, PhD, O. Ousley, PhD, K. Pelphrey, PhD, B. Peterson, MD, J. Piggot, MD, C. Saulnier, PhD, M. State, MD, PhD, W. Stone, PhD, J. Sutcliffe, PhD, C. Walsh, MD, PhD, Z. Warren, PhD, and E. Wijsman, PhD). The authors appreciate obtaining access to phenotypic data on SFARI base.

Funding

This research was enabled by support provided by Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca). SJ is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. CS is supported by an Institute for Data Valorization (IVADO) fellowship. PT is supported by a Canadian Institute of Health Research (CIHR) Scholarship Program. GH is supported by the Sainte-Justine Foundation, the Merit Scholarship Program for foreign students, and the Network of Applied Genetic Medicine fellowships. TB is a recipient of a chair of the Bettencourt-Schueler foundation. This work is supported by a grant from the Brain Canada Multi-Investigator initiative and CIHR grant 159734 (SJ, CMTG, TP). The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada fund the Saguenay Youth Study (SYS). SYS was funded by the Canadian Institutes of Health Research (TP, ZP) and the Heart and Stroke Foundation of Canada (ZP). Funding for the project was provided by the Wellcome Trust. This work was also supported by an NIH award U01 MH119690 granted to LA, SJ, and DG and U01 MH119739.

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Julien Buratti (Institute Pasteur) and Vincent Frouin, PhD (Neurospin) acquired data for IMAGEN. Manon Bernard, BSc (Database Architect, The Hospital for Sick Children) and Helene Simard, MA, and her team of research assistants (Cégep de Jonquière) acquired data for the Saguenay Youth Study. Antoine Main, MSc (UHC Sainte-Justine Research Center, HEC Montreal), Lionel Lemogo, MSc (UHC Sainte-Justine Research Center), and Claudine Passo, PhD (UHC Sainte-Justine Research Center) provided bioinformatical support. Maude Auger, PhD, and Kristian Agbogba, BSc (UHC Sainte-Justine Research Center) provided website development. Dr. Paus is the Tanenbaum Chair in Population Neuroscience at the Rotman Research Institute, University of Toronto, and the Dr. John and Consuela Phelan Scholar at Child Mind Institute, New York.

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Correspondence to Guillaume Huguet or Sébastien Jacquemont.

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Huguet, G., Schramm, C., Douard, E. et al. Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability. Mol Psychiatry 26, 2663–2676 (2021). https://doi.org/10.1038/s41380-020-00985-z

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