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Human Cerebral Cortex Surface Area, Thickness Shaped By Different Genes

NEW YORK – Different genes are likely involved in the development of various parts of the human cerebral cortex, according to a new analysis. 


The cerebral cortex, the outer grey matter layer of the brain, is involved in human higher cognitive function, but little is known about the genetic loci that influence its structure.

An international team of researchers performed genome-wide association meta-analyses using brain MRI data to uncover genomic loci associated with the surface area and average thickness of the entire cerebral cortex and of nearly three dozen cortical regions. Both cortical surface area and cortical thickness have been implicated in neuropsychiatric disorders and are associated with psychological traits 


As they reported in Science on Thursday, the researchers found common genetic variants account for about a third and a quarter, respectively, of the variation observed in surface area and thickness of the cerebral cortex. Different variants affect the two traits, and the researchers' findings appear to support the radial unit hypothesis, which says cortical surface area is driven by the proliferation of neural progenitor cells, while cortical thickness is governed by the number of neurogenic divisions. 


"The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas," QIMR Berghofer Medical Research Institute's Katrina Grasby and her colleagues wrote in their paper. "Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function." 


The researchers used brain MRI data collected from 51,665 individuals, largely of European ancestry, from 60 different cohorts for genome-wide association meta-analyses of cortical surface area and cortical thickness, both globally and at 34 specific cortical regions in each hemisphere. They examined these 70 distinct phenotypes in an initial cohort of 33,992 individuals and replicated their analysis in an additional 17,673 participants. 


Overall, they identified 199 loci associated with cortical structure following multiple testing corrections. Of these, 187 loci influenced cortical surface area and 12 affected cortical thickness. They estimated that common variants explained 34 percent of the variation in cortical surface area, but a slightly lower percentage, 26 percent, of the variation in cortical thickness.  


Among the loci they uncovered was the surface area-linked loci rs1117173, which is an expression quantitative trait loci that affects RPS26 in the fetal and adult cortex, while another surface area-linked loci, rs12630663, is located within about 200 kilobases of EOMES, which is expressed by intermediate progenitor cells in the developing fetal cortex. 


At the same time, the cortical thickness-linked loci rs533577 is a fetal cortex eQTL for RPSA, which encodes a potential laminin receptor. Laminins, the researchers noted, have key roles in neurogenesis, neuronal differentiation, and migration. 


They also noted a negative genetic correlation between cortical surface area and thickness. 


Many of the genetic variants that influence cortical surface area also affect the regulation of genes expressed by neural progenitor cells during fetal development. However, genetic variants that influence cortical thickness affect regulatory elements that are active in adult brain samples. Partitioned heritability analysis likewise supported those findings. 


These findings, the researchers noted, are also consistent with the radial unit hypothesis that says different developmental mechanisms affect surface area and thickness.  


At the regional level, a number of surface area-linked loci clustered around genes involved in the Wnt signaling pathway, which is involved in cell fate determination and areal identity. 


"[T]his work identifies genome-wide significant loci associated with cortical [surface area] and [thickness] and enables a deeper understanding of the genetic architecture of the human cerebral cortex and its patterning," Grasby and her colleagues wrote.