General and specific patterns of cortical gene expression as substrates of complex cognitive functioning

Moodie, J. E.; Harris, S. E.; Harris, M. A.; Buchanan, C. R.; Davies, G.; Taylor, A.; Redmond, P.; Liewald, D.; Valdes Hernandez, M. D.; Shenkin, S. D.; Russ, T. C.; Munoz Maniega, S. C.; Luciano, M.; Corley, J.; Stolicyn, A.; Shen, X.; Steele, D.; Waiter, G.; Sandu-Giuraniuc, A.; Bastin, M.; Wardlaw, J.; McIntosh, A. M.; Whalley, H. C.; Tucker-Drob, E. M.; Deary, I.; Cox, S. R.

doi:10.1101/2023.03.16.532915

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bioRxiv · 10.1101/2023.03.16.532915

General and specific patterns of cortical gene expression as substrates of complex cognitive functioning

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Abstract

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given genes expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components : gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 41 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|{beta}| range = 0.15 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

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Moodie, J. E., Harris, S. E., Harris, M. A., Buchanan, C. R., Davies, G., Taylor, A., Redmond, P., Liewald, D., Valdes Hernandez, M. D., Shenkin, S. D., Russ, T. C., Munoz Maniega, S. C., Luciano, M., Corley, J., Stolicyn, A., Shen, X., Steele, D., Waiter, G., Sandu-Giuraniuc, A., Bastin, M., Wardlaw, J., McIntosh, A. M., Whalley, H. C., Tucker-Drob, E. M., Deary, I., Cox, S. R.. 2023-03-17. General and specific patterns of cortical gene expression as substrates of complex cognitive functioning. https://doi.org/10.1101/2023.03.16.532915

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