Meta-analyses of genome-wide association studies identify novel loci influencing Japanese white matter hyperintensities

White matter hyperintensities (WMH) are common findings on brain magnetic resonance imaging (MRI) in older adults and are associated with an increased risk of dementia and stroke. Although large-scale European genome-wide association studies (GWAS) have identified more than 20 loci associated with WMH, the genetic architecture of WMH in Asian populations has not been fully elucidated. Here, we conducted a GWAS comprising 1001 Japanese individuals from the National Center for Geriatrics and Gerontology (NCGG) Biobank, followed by a meta-analysis with GWAS data from 9479 individuals in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD), identifying three novel loci significantly associated with WMH volume (P < 5 × 10^-8). A subsequent trans-ethnic meta-analysis with UK Biobank data revealed twelve genome-wide significance loci, including one novel locus. Cis-expression quantitative trait locus (cis-eQTL) analyses using blood RNA-Seq data implicated 39 genes, especially showing downregulation of ACOX1 at a chromosome 17 locus. Protein QTL (pQTL) analyses using plasma proteomics data further demonstrated associations between these loci and increased levels of immune and inflammatory proteins. These findings provide new insights into the genetic architecture of WHH in the Japanese population and highlight immune and inflammatory pathways in the pathogenesis of age-related neurological diseases.