Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability
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Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability. / Huguet, Guillaume; Schramm, Catherine; Douard, Elise; Tamer, Petra; Main, Antoine; Monin, Pauline; England, Jade; Jizi, Khadije; Renne, Thomas; Poirier, Myriam; Nowak, Sabrina; Martin, Charles-Olivier; Younis, Nadine; Knoth, Inga Sophia; Jean-Louis, Martineau; Saci, Zohra; Auger, Maude; Tihy, Frédérique; Mathonnet, Géraldine; Maftei, Catalina; Léveillé, France; Porteous, David; Davies, Gail; Redmond, Paul; Harris, Sarah E; Hill, W David; Lemyre, Emmanuelle; Schumann, Gunter; Bourgeron, Thomas; Pausova, Zdenka; Paus, Tomas; Karama, Sherif; Lippe, Sarah; Deary, Ian J; Almasy, Laura; Labbe, Aurélie; Glahn, David; Greenwood, Celia M T; Jacquemont, Sébastien.
In: MOL PSYCHIATR, Vol. 26, No. 6, 06.2021, p. 2663-2676.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability
AU - Huguet, Guillaume
AU - Schramm, Catherine
AU - Douard, Elise
AU - Tamer, Petra
AU - Main, Antoine
AU - Monin, Pauline
AU - England, Jade
AU - Jizi, Khadije
AU - Renne, Thomas
AU - Poirier, Myriam
AU - Nowak, Sabrina
AU - Martin, Charles-Olivier
AU - Younis, Nadine
AU - Knoth, Inga Sophia
AU - Jean-Louis, Martineau
AU - Saci, Zohra
AU - Auger, Maude
AU - Tihy, Frédérique
AU - Mathonnet, Géraldine
AU - Maftei, Catalina
AU - Léveillé, France
AU - Porteous, David
AU - Davies, Gail
AU - Redmond, Paul
AU - Harris, Sarah E
AU - Hill, W David
AU - Lemyre, Emmanuelle
AU - Schumann, Gunter
AU - Bourgeron, Thomas
AU - Pausova, Zdenka
AU - Paus, Tomas
AU - Karama, Sherif
AU - Lippe, Sarah
AU - Deary, Ian J
AU - Almasy, Laura
AU - Labbe, Aurélie
AU - Glahn, David
AU - Greenwood, Celia M T
AU - Jacquemont, Sébastien
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
U2 - 10.1038/s41380-020-00985-z
DO - 10.1038/s41380-020-00985-z
M3 - SCORING: Journal article
C2 - 33414497
VL - 26
SP - 2663
EP - 2676
JO - MOL PSYCHIATR
JF - MOL PSYCHIATR
SN - 1359-4184
IS - 6
ER -
