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Wednesday, January 29 2025

Mapping the impacts of DNA modifications to better understand neurodevelopment and cognitive abilities

 

Montreal, January 29, 2025—A significant advancement on the link between cognition and genetics was found thanks to a study led by Guillaume Huguet and Thomas Renne, under the direction of Dr. Sébastien Jacquemont. This research explored how the copy number variation, or CNV, of certain DNA segments can influence cognitive abilities. CNV analysis of nearly 260,000 individuals in the general population has allowed the researchers to compare each individual’s CNV and cognition to define a reference model—a “map” of sorts of the effects of CNV on cognition, such as the intelligence quotient and memory—and to establish links between these CNVs and achievements within the brain, as well as in other organs and tissues. This research clears the way for new diagnostic strategies, care practices and continuing care for neurodevelopmental disorders.

What we can learn from CNV

Usually, each individual has two copies of every gene, one inherited from each parent. However, frequently there will be variation in the number of copies of certain segments in each individual. These variations can be losses (deletions) or gains (duplications), in which an individual will have fewer than two copies or more than two copies of a given segment, respectively. Most of these variations do not have a significant impact on one’s health, but some of them may contribute to the occurrence of illness or genetic syndromes. Interpretation of CNV impact relies on the genetic information contained within the genes present in the given DNA sequence. These CNVs can modify gene expression, whether by increasing in the case of duplication or reducing in the case of deletion.

Some changes in genetic expression are linked to impacts on cognitive abilities. For example, deletions in the subcortical structures in the brain where gene expression is especially strong showed marked negative effects on cognitive function, contrary to duplications, which seem to have a more significant effect when it comes to genes in the cortex. Furthermore, the results from this study show that certain duplications have a protective effect against neurodegenerative disorders. “We have observed the first genetic duplication that could prevent cognitive decline,” explains Guillaume Huguet, research associate in Dr. Jacquemont’s laboratory. In fact, elderly participants in the study who had these duplications showed less cognitive decline than other participants of the same age.

New links to non-brain organs

One of the innovative facets of this study is the analysis of organs other than the brain. Huguet and Renne thus observed that CNVs of genes expressed in other organs, theoretically independent from the brain, also influence cognitive functions. This study offers an especially convincing demonstration of the effect of CNVs across multiple organs, thereby helping to explain the (non-cerebral) comorbidities observed in patients with an intellectual disability.

Thanks to existing DNA mapping, these discoveries pave the way for a broader understanding of the ways in which genetic alterations affecting various organs interact with brain function, and they illustrate the importance of adopting a holistic approach to the study of cognitive or neurodevelopmental disorders in the general population.

New perspectives in cognitive and neurodevelopmental medicine

This study marks a turning point in our understanding of the genetic foundations of cognitive abilities and neurodevelopmental disorders. Specialized teams can now use these “maps” in future research projects. The results of this research reveals new opportunities for early diagnosis, personalized treatment and risk management. By linking genetics and the understanding of complex biological interactions between the brain and other organs, this research could transform the way in which we approach cognitive disorders, offering new paths for prevention and innovative treatment all while improving patients’ quality of life. This research also offers a new perspective on cognition, suggesting that it is not solely influenced by brain function, but by the entire body, just like an ecosystem.

Regarding care, one major goal of this research was to allow clinicians to better understand the risks of CNVs and to personalize medical management according to a person’s genetic profile. For example, a prediction tool developed by the team allows for the evaluation of the impact of duplications and deletions on IQ and on neurodevelopmental disorders such as autism. “This allows clinicians to better adapt their diagnostics using genetic data as a starting point,” explains Huguet. By identifying “risky” CNVs, doctors may be able to anticipate potential negative effects and offer better follow-up care and targeted interventions.

For example, in the case of a genetic deletion thought to have a strong impact on cognition in a young child referred to a clinic for motor skill delays, the child could receive appropriate support well before the onset of cognitive symptoms. This proactive approach could mitigate long-term effects of neurodevelopmental disorders.

While much still remains to be done to confirm these discoveries and to apply them clinically, the advancements made by this team open up many inspiring avenues for the future of personalized neurological medicine. Thanks to the detailed maps the various effects of variations in DNA segments, the study shows the way forward for other researchers.

 

Dr_S_Jacquemont_et_G_Huguet

Dr. Sébastien Jacquemont (left) and Guillaume Huguet (right) (Thomas Renne not appearing) © CHU Sainte-Justine (Véronique Lavoie)

About this study

« Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes » was published by Guillaume Huguet, Thomas Renne, ... Sébastien Jacquemont in Cell Genomics.

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Updated on 1/29/2025
Created on 1/29/2025
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