Sébastien Jacquemont
Credit: Amélie Philibert, Université de Montréal
A significant advancement in knowledge of the link between cognition and genetics has been made thanks to a study led by Université de Montréal graduate students Guillaume Huguet and Thomas Renne, working under the supervision of medical geneticist Sébastien Jacquemont, an associate professor of pediatrics and a researcher at the UdeM-affiliated CHU Saint-Justine.
Published last month in Cell Genomics, the research explored how the copy number variation, or CNV, of certain DNA segments can influence cognitive abilities. Analyzing the CNV of nearly 260,000 people in the general population, the scientists were able to compare each individual's CNV and cognition to define a reference model-a kind of "map" 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, according to the co-authors.
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 a person'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, in the study, 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," said Huguet, a research associate in Jacquemont's laboratory. In fact, he added, 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 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, the researchers say.
New perspectives in cognitive and neurodevelopmental medicine
The study marks a turning point in understanding the genetic foundations of cognitive abilities and neurodevelopmental disorders, they believe, as specialized teams can now use these "maps" in future research projects and new opportunities are opened up for early diagnosis, personalized treatment and risk management.
By linking genetics and the understanding of complex biological interactions between the brain and other organs, the researchers think their work 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. In sum, a new perspective is gained 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," said 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 the UdeM and CHU Sainte-Justine team open up many inspiring avenues for the future of personalized neurological medicine, the co-authors believe. Thanks to the detailed maps of the various effects of variations in DNA segments, the study shows the way forward for other researchers, they say.
About this study
"Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes," by Guillaume Huguet et al., was published Dec. 11, 2024 in Cell Genomics.
