Genome-wide Association Study of Subcortical Brain Structures in Japanese Ancestry: The Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study

Subcortical brain volumes have been extensively mapped by genome-wide association studies (GWASs) in Europeans, but their genetic architecture in East Asians remains unclear. We conducted GWASs on magnetic resonance imaging derived volumes of eight subcortical structures in 9,225 Japanese participants aged 21.6–88.0 years (mean 54.0 ± 15.5 years) from the Tohoku Medical Megabank Brain MRI Study. Genotyping used Japonica Array and volumes were estimated with FreeSurfer. GWASs were performed separately in the discovery ( n  = 7,328) and replication ( n  = 1,897) studies, followed by a meta-analysis. We identified nine significant genome-wide loci in the discovery study, three of which were replicated. Meta-analysis revealed four additional significant loci. We identified three novel variants associated with the volumes of subcortical structures. Previously reported loci in European ancestry studies, including ALPL , SMIM19 , CHRNB3 , DSCAML1 , KTN1 , RPL13AP3 , and DCC , were replicated, leading to the identification of ancestry-specific signals. Functional mapping and expression analyses revealed brain-specific enrichment of genes associated with the caudate and putamen. This first GWAS of subcortical volumes in a Japanese population refines the genetic architecture of these structures and provides insight into mechanisms of brain aging and neuropsychiatric disease.