The molecular genetic landscape of human brain size variation

Seidlitz, J.; Mallard, T. T.; Vogel, J. W.; Lee, Y. H.; Warrier, V.; Ball, G.; Hansson, O.; Hernandez, L. M.; Mandal, A. S.; Wagstyl, K.; Lombardo, M. V.; Courchesne, E.; Glessner, J. T.; Satterthwaite, T. D.; Bethlehem, R. A. I.; Lifespan Brain Chart Consortium,; Tasaki, S.; Ng, B.; Gaiteri, C.; Smoller, J. W.; Ge, T.; Gandal, M. J.; Alexander-Bloch, A. F.

doi:10.1101/2022.11.03.514996

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bioRxiv · 10.1101/2022.11.03.514996

The molecular genetic landscape of human brain size variation

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Abstract

Human brain size increases dynamically through early development, peaks in adolescence, and varies up to two-fold among adults. Although previous studies have elucidated changes in brain size across evolution, development, traits, and diseases, the molecular underpinnings of interindividual variation in brain size remain unknown. Here, we leverage postmortem brain RNA sequencing and estimates of brain weight (BW) in 2,531 individuals across three independent datasets, to identify 928 genes that show genome-wide significant associations with either higher or lower BW (BW+, BW-, respectively). These BW gene sets showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto developmental, functional and cellular axes of brain organization. Expression differences among evolutionarily conserved BW genes were predictive of interspecies differences in brain size, and functional annotation of BW genes revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses of in vivo neuroimaging phenotypes confirmed that the genetic regulation of BW-transcripts influences cortical surface area and volume, as well as behavioral traits related to brain function and disease. Cumulatively, our study represents a major step towards the goal of delineating the causal mechanisms of human brain size variation in health and disease.

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Seidlitz, J., Mallard, T. T., Vogel, J. W., Lee, Y. H., Warrier, V., Ball, G., Hansson, O., Hernandez, L. M., Mandal, A. S., Wagstyl, K., Lombardo, M. V., Courchesne, E., Glessner, J. T., Satterthwaite, T. D., Bethlehem, R. A. I., Lifespan Brain Chart Consortium,, Tasaki, S., Ng, B., Gaiteri, C., Smoller, J. W., Ge, T., Gandal, M. J., Alexander-Bloch, A. F.. 2022-11-03. The molecular genetic landscape of human brain size variation. https://doi.org/10.1101/2022.11.03.514996

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