Contextualizing the polygenic basis of human brain shape

Authors

Casas i Riu, J., Boeckx, C.

Abstract

As the most recently evolved neuroanatomical trait of our species, our globular head shape ('globularity') constitutes a promising point of entry to probe possible associations between brain morphology and cognitive traits that may be distinctive of Homo sapiens. To shed additional light on the underlying biology of globularity and its cognitive consequences, we capitalize on data pairing genetic variation to brain shape differences from magnetic resonance imaging (MRI) scans of 34,595 adults of European ancestry, and embed genome-wide associations of globularity within genetic variation underpinning up to 75 brain-related traits. Through extensive hypergeometric tests, we observe significant associations between globularity and white matter traits at the gene level, but stronger associations with cerebellar volume, ventricular size, and the fornix at the genomic variant level. Combining conjunctional false discovery rate (FDR) with genetic correlations, we notice homogeneously concordant relations between globularity and the volume of the brain ventricles, and homogeneously discordant relations with glymphatic function. We also unravel more selective, spatially organized relations between globularity and cerebellar volume, white matter connectivity and sulcal width. Spatial permutation tests reveal that sulcal width associations are systematically distributed along a sensorimotor-association gradient of cortical organization. Additionally, correlations of brain- and lifespan-wise gene expression patterns linked to globularity and the brain ventricles highlight recurrent associations with the pentose phosphate metabolic pathway. Finally, deploying an open repository of genetic variant age estimations and an extensive catalog of single nucleotide changes distinguishing hominins, we uncover a coincidence between the establishment of globularity and the time of emergence of modifications in the cerebrospinal fluid proteome. Overall, we provide a finer-grained genetic architecture for globularity, with novel biological associations to traits across evolutionary and developmental timescales, leading us to draw implications for the early development of cognitive networks but also for liabilities to neurodegeneration late in life.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 10 Oct 2026.

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