The molecular genetic landscape of human brain size variation

Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease. [Display omitted] •Transcriptomic analysis of human BW revealed 928 significant genes•BW genes align with predicted developmental and evolutionary changes in brain size•BW genes are cell-type specific and align with structural neuroimaging GWASs and TWASs•BW genes are differentially expressed in psychiatric and neurodegenerative disorders Seidlitz et al. identify genes differentially expressed in individuals with larger or smaller brains that are enriched in growth signaling pathways and are highly expressed in cell types critical for human development and primate evolution. Translational results in a “real world” clinical biobank demonstrate promise for more informed polygenic scoring.