Genetic variation shapes modes of population covariation linking brain and behavior
Presented During:
Monday, June 24, 2024: 5:45 PM - 7:00 PM
COEX
Room:
Grand Ballroom 101-102
Poster No:
1963
Submission Type:
Abstract Submission
Authors:
Jakub Kopal1, Anny Maza Pino2, Justin Marotta1, Nicole Osayande1, Shambhavi Aggarwal1, Guillaume Huguet3, Kuldeep Kumar3, Zohra Saci3, Martineau Jean-Louis3, Ole Andreassen4, Sébastien Jacquemont3, Danilo Bzdok1
Institutions:
1McGill University, Montreal, Canada, 2Politècnica de València, Valencia, Spain, 3CHU Saint-Justine, Montreal, Canada, 4NORMENT, Oslo, Norway
First Author:
Co-Author(s):
Introduction:
Adolescence is a pivotal phase in human development marked by significant transformations in brain and behavior. As individuals transition from childhood to adulthood, the brain undergoes dynamic changes in its structure and function, influencing cognitive, emotional, and social behaviors. The development of the adolescent brain and behavior is intricately shaped by a complex interplay of genetic factors and environmental influences1,2. Yet, how genetic variation influences the multifaceted relationship between the brain and behavior remains understudied.
Copy number variations (CNVs) represent a notable source of genetic variation. This class of genetic mutations is defined as either a deletion or duplication of sequences of nucleotides more than 1000 base pairs long3,4. It is increasingly recognized that many CNVs exert far-reaching consequences throughout the body, making them a sharp imaging-genetics tool for interrogating the effects of genetic modifications on brain physicality and behavioral differentiation5,6. We thus hypothesize that CNVs shape the complex brain-behavior relationship.
Copy number variations (CNVs) represent a notable source of genetic variation. This class of genetic mutations is defined as either a deletion or duplication of sequences of nucleotides more than 1000 base pairs long3,4. It is increasingly recognized that many CNVs exert far-reaching consequences throughout the body, making them a sharp imaging-genetics tool for interrogating the effects of genetic modifications on brain physicality and behavioral differentiation5,6. We thus hypothesize that CNVs shape the complex brain-behavior relationship.
Methods:
We leveraged data from 8,549 children aged 9 to 11 years from the ABCD study (Fig. 1A). Based on our CNV calling pipeline7, 616 children carried a deletion, 1,628 carried a duplication, and 6,305 did not carry any CNV >=50Kb. In the next step, using canonical partial least squares deployed in the children without any CNV, we estimated modes of population covariation linking brain architecture represented by 148 regional volumes according to the Destrieux atlas with 962 behavioral variables spanning 20 categories (Fig. 1B). The robustness of derived modes was assessed by cross-validation and permutation testing2,8. Finally, using a cross-validation scheme, we quantified the effects of deletions and duplications on the identified brain-behavior modes (Fig. 1C).
·Figure 1
Results:
Our analysis uncovered three significant modes of brain-behavior covariation. The first mode connected a vast network of brain regions with measures of cognition and demographics (Fig. 2). The second mode linked dorsal attention, somatomotor, and frontoparietal networks with measures of mental health. Finally, the third mode highlighted associations between the default mode network and environmental assessments. Importantly, carrying a CNV influences the latent brain and behavior variables (scores) across these three identified modes. We observed opposite effects of duplications on the brain second mode scores compared to deletions, which points to the previously reported mirroring effects of deletions and duplications on brain architecture9 (Fig. 2A). Conversely, both deletions and duplications led to similarly-oriented effects on behavioral scores. Specifically, both CNV classes were associated with decreased cognitive functioning (Fig. 2C), mental health, and socioeconomic measures. The effects of deletions were more pronounced compared to duplications, confirming the stronger effects of deletions compared to duplications on cognitive measures observed in pediatric clinics. Our results also highlight the similar ramifications for cognition and behavior associated with deletions and duplication despite their distinct effects on brain anatomy.
·Figure 2
Conclusions:
Our study provides valuable insights into the complex interplay between genetic factors, brain architecture, and a diverse array of cognitive, behavioral, psychosocial, and socioeconomic measures during adolescence. The identified modes of population-level covariation shed light on the intricate relationships between specific brain networks and real-life functioning, underscoring the multidimensional nature of human development. Notably, our findings highlight the impact of CNVs extending beyond their known influence on cognitive abilities and language, potentially affecting various dimensions of individuals' lives.
Genetics:
Genetic Modeling and Analysis Methods 2
Higher Cognitive Functions:
Higher Cognitive Functions Other
Lifespan Development:
Normal Brain Development: Fetus to Adolescence
Modeling and Analysis Methods:
Multivariate Approaches 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Anatomy and Functional Systems
Keywords:
Cognition
Development
Multivariate
STRUCTURAL MRI
Other - population imaging
1|2Indicates the priority used for review
Provide references using author date format
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3. Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).
4. Freeman, J. L. et al. Copy number variation: New insights in genome diversity. Genome Res. 16, 949–961 (2006).
5. Auwerx, C. et al. The individual and global impact of copy-number variants on complex human traits. Am. J. Hum. Genet. S0002-9297(22)00061–1 (2022)
6. Kopal, J. et al. Rare CNVs and phenome-wide profiling highlight brain structural divergence and phenotypical convergence. Nat. Hum. Behav. 1–17 (2023)
7. Huguet G., et al. Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability. Mol Psychiatry. 26, 2663-2676 (2021)
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