The surface area (SA) of the human cerebral cortex, which plays an integral role in cognitive function and susceptibility to mental disorders, has long captivated researchers. A recent study has illuminated the genetic underpinnings of this expansion, particularly focusing on the impact of rare copy number variants (CNVs) during the pivotal stages of cortical development, primarily during fetal growth.
The research, conducted across community-based cohorts—most prominently the IMAGEN study, the Saguenay Youth Study, and the UK Biobank—investigated how these rare genetic variations associate with surface area reductions of the cerebral cortex. By analyzing data from 39,015 individuals, the study provides invaluable insights about the neurodevelopmental mechanisms influenced by genetic factors.
Importantly, the study established clear links between both genome-wide CNV deletions and duplications, finding these genetic alterations were associated with diminished cortical SA. "Our findings suggest CNVs influence SA by interrupting the expression of genes involved in neural proliferation during the fetal period," the authors state, outlining how these CNVs disrupt key cellular pathways during the irreplaceable fetal period of brain development.
Prior to this inquiry, most research concentrated on the broad heritability of SA without delving deeply enough to assess the role of CNVs comprehensively. With estimates indicating around 90% heritability of SA, scientists have relied heavily on genome-wide association studies (GWAS) to identify common genetic variants linked to cortical size and growth. Yet, rare CNVs—which are defined as structural variations of the genome involving segments of DNA longer than 50 kilobases—have remained less explored. The majority of these CNVs, being very infrequent, disrupt protein-coding regions and have substantial consequences for gene expression.
The study utilized mega-analyses to correlate CNV presence with cortical surface areas, adopting cutting-edge techniques such as virtual ontogeny to unravel cellular-level mechanisms—essentially allowing researchers to draw links between molecular profiles and observable anatomical traits within the cortex.
Deletions of specific genes—primarily identified as the proximal genes—were found to be particularly detrimental, showing larger effects on reducing SA compared to distal genes. Particularly, the analysis identified how the expression of genes co-expressed with progenitor cells dictated the overall impact on SA across vastly diverse regions of the cortex. "The association of deletions of proximal genes showed stronger influence on cortical expansion compared to distal genes," the authors pointed out.
This tangential expansion of the cortex, occurring mainly during prenatal development and early childhood, showcases the importance of the radial unit hypothesis, which posits the role of neural progenitor cell proliferation as central to cortical size. By evaluating gene expression during fetal development, the analysis corroborated hypotheses positing genetic elements as integral contributors to the shaping of the cerebral cortex's architecture.
To elaborate on the broader impact of these findings, the researchers highlighted specific CNVs, such as those found on chromosomes 1q21.1, 16p11.2, and 22q11.2. These CNVs have been linked with increased risks for neurodevelopmental disorders, particularly autism spectrum disorders and schizophrenia. Therefore, by establishing clearer connections between genetic variations and observable traits such as SA, the current study paves the way for future explorations of therapies aimed at mitigating or counteracting these genetic influences.
The researchers also call for more extensive population-based genetic investigations to capture the wide array of rare CNVs affecting the cerebral cortex, as their potential impacts on cognitive functions hold significant ramifications for developing treatment strategies for mental illnesses. "This genome-wide association study of rare CNVs revealed genes influencing cortical expansion, providing mechanistic insights on the human cerebral cortex development," they conclude, emphasizing the importance of continuing to unravel the complexity within the genetic architecture guiding brain development.