Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes

Area of Science:

• Genetics
• Neuroscience
• Cognitive Science

Background:

• Copy-number variants (CNVs) are associated with neurodevelopmental disorders and cognitive ability.
• Studying CNVs is difficult due to their rarity, limiting understanding of gene-dosage effects on cognition.

Purpose of the Study:

• To identify genetic variants associated with cognitive performance.
• To investigate the impact of gene-dosage sensitivity on cognitive ability across biological processes.

Main Methods:

• Genome-wide association study (GWAS) in 258,292 individuals.
• Functional-burden analysis of CNVs disrupting 6,502 gene sets.
• Analysis of gene set associations with cognition, considering deletion and duplication effects.

Main Results:

• A novel duplication at 2q12.3 was identified as the first GWAS hit associated with higher cognitive performance.
• 864 gene sets were significantly associated with cognition.
• Negative correlation between deletion and duplication effect sizes suggested sensitivity across biological processes, with specific patterns for deletions (subcortical, postsynaptic) and duplications (cerebral cortex, presynaptic).
• Associations between non-brain tissues and cognition were partly driven by constrained genes.

Conclusions:

• CNVs significantly impact cognitive ability through gene-dosage effects.
• The identified 2q12.3 duplication provides a new target for understanding cognitive performance.
• Gene-dosage sensitivity affects diverse biological processes, offering insights into neurodevelopmental disorder comorbidities.