The genetic architecture of human cerebellar morphology supports a key role for the cerebellum in recent human evolution and psychopathology

Abstract The functional domain of the cerebellum has expanded beyond motor control to also include cognitive and affective functions. In line with this notion, cerebellar volume has increased over recent primate evolution, and cerebellar alterations have been linked to heritable mental disorders. To map the genetic architecture of human cerebellar morphology, we here studied a large imaging genetics sample from the UK Biobank (n discovery = 27,302; n replication: 11,264) with state-of-the art neuroimaging and biostatistics tools. Multivariate GWAS (MOSTest) on empirically derived regional cerebellar MRI features yielded 351 significant genetic loci (228 novel, 94% replicated). Candidate SNPs showed significant positive enrichment for relatively recent genetic mutations over the last 300k years (i.e., coinciding with the emergence of Homo sapiens), while gene level analyses revealed enrichment for genes associated with human-specific evolution over the last ∼6-8 million years. Finally, we observed genetic overlap with major mental disorders, reinforcing the notion of cerebellar involvement in psychopathology. Teaser Genome-wide analysis of cerebellar morphology reveals links to recent human evolution and psychopathology