Imaging genomics reveals genetic architecture of the globular human braincase

Compared with our fossil ancestors and Neandertal kin, modern humans have evolved a distinctive skull shape, with a rounder braincase and more delicate face. Competing explanations for this rounder skull have either linked it to changes in brain organisation, or seen it as a by-product of gracilization (evolution of thinner and lighter skeletal anatomy). Here, we combined palaeoanthropological data from hominin fossils and imaging genomics data from living humans to gain insight into evolutionary and developmental mechanisms shaping this uniquely modern human phenotype. We analysed endocranial globularity from magnetic resonance imaging (MRI) brain scans and genetic data of more than 33,000 adults. We discovered 28 genomic loci significantly associated with endocranial globularity. There was genetic overlap with the brains ventricular system, white matter microstructure, and sulcal morphology, and with multivariate genetic analyses of reading/language skills, but not with general cognition. The associated genes exhibited enriched expression in the brain during prenatal development and early childhood. The connection to the ventricular system hints at a role for cerebrospinal fluid pressure in shaping the endocranium during development. Genes linked to endocranial globularity also showed enhanced expression in the cardiovascular and female reproductive systems. This finding suggests co-evolutionary pathways whereby changes impacting factors such as energy needs, pregnancy, or fertility concurrently shape the brain and its structure.