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

Guillaume Huguet (1, 2) , Catherine Schramm (1, 2, 3) , Elise Douard (1, 2) , Petra Tamer (1, 2) , Antoine Main (2, 4) , Pauline Monin (2, 5) , Jade England (1, 2) , Khadije Jizi (1, 2) , Thomas Renne (2, 6) , Myriam Poirier (1, 2) , Sabrina Nowak (1, 2) , Charles-Olivier Martin (1, 2) , Nadine Younis (1, 2) , Inga Sophia Knoth (1, 2) , Martineau Jean-Louis (1, 2) , Zohra Saci (1, 2) , Maude Auger (1, 2) , Frédérique Tihy (1, 2) , Géraldine Mathonnet (1, 2) , Catalina Maftei (1, 2) , France Léveillé (1, 2) , David Porteous (7) , Gail Davies (7) , Paul Redmond (7) , Sarah E. Harris (7) , W. David Hill (7) , Emmanuelle Lemyre (1, 2) , Gunter Schumann (8) , Thomas Bourgeron (5, 9) , Zdenka Pausova (10) , Tomas Paus (11) , Sherif Karama (12, 13) , Sarah Lippe (2, 1) , Ian J. Deary (7) , Laura Almasy (14) , Aurélie Labbe (5) , David Glahn (15, 16, 17) , Celia M. T. Greenwood (3, 12) , Sébastien Jacquemont (1, 2)

1 UdeM - Université de Montréal
2 CHU Sainte Justine [Montréal]
3 Jewish General Hospital
4 HEC Montréal - HEC Montréal
5 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
6 UNIROUEN - Université de Rouen Normandie
7 University of Edinburgh
8 King‘s College London
9 CNRS - UMR3571 - Gènes, Synapses et Cognition
10 SickKids - The Hospital for sick children [Toronto]
11 University of Toronto
12 McGill University = Université McGill [Montréal, Canada]
13 Douglas Mental Health University Institute [Montréal]
14 CHOP - Children’s Hospital of Philadelphia
15 Boston Children's Hospital
16 HMS - Harvard Medical School [Boston]
17 Hartford Hospital

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.

Domains: Cognitive science; Neuroscience

Guillaume Huguet, Catherine Schramm, Elise Douard, Petra Tamer, Antoine Main, et al.. Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability. Molecular Psychiatry, 2021, ⟨10.1038/s41380-020-00985-z⟩. ⟨pasteur-03325369⟩