Rare-variant aggregation highlights disease-linked genes associated with brain volume variation.

Rare brain disorders often present with changes in brain volume, and variation in brain volume is known to be highly heritable. Recent work studying brain volume variation has largely focused on common variants and structural variants. Rare variants often have large effect sizes and clearer connections to biological mechanisms, but the role of rare variants has not been extensively studied. We performed rare-variant gene aggregation analysis for total brain volume and 43 regional brain volume phenotypes (n = 50,061) to identify genes associated with brain volume variation through loss-of-function and missense variants. We identified and replicated mutations in DISP1 and SCUBE2 that were associated with reduced cerebellar volume and suggest that this was mediated by modifying sonic hedgehog signaling. Additionally, we found an association between mutations in PTEN and macrocephaly that are likely mediated through the PI3K/mTOR pathway and hypothesize that mutations in FA2H influence cerebral white matter volume. Further, we identified 7 genes associated with volume variation in the population and rare brain diseases in ClinVar, supporting the role of mutations in these genes causing diseases and related subclinical phenotypes. Overall, we showed that rare-variant analysis can provide clarity on the biological processes connecting brain volume and disease.