Thirty novel sequence variants impacting human intracranial volume

Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume (n= 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder.

Automated summary

Intracranial volume is heritable and associated with cognitive traits and neurological disorders. This study identified genetic variants and genes that mediate the effect of these variants on intracranial volume. Additionally, intracranial volume is genetically correlated with volumes of different brain regions, cognitive abilities, and neurological traits. Importantly, differences in intracranial volume were observed in Parkinson's disease and attention deficit hyperactivity disorder cases.