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BackgroundBrain arterial diameters are novel imaging biomarkers of cerebrovascular disease, cognitive decline and dementia. Traditional vascular risk factors have been associated with brain arterial diameters but whether there may be genetic determinants of brain arterial diameters is unknown.ResultsWe studied 4150 participants from six geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). We measured brain arterial diameters for 13 segments and averaged them to obtain a global measure of brain arterial diameters as well as the posterior and anterior circulations. A genome-wide association study (GWAS) revealed 14 variants at one locus associated with global brain arterial diameter at genome-wide significance (P−8) (top SNP, rs7921574; β =0.06, P=1.54×10−8). This locus mapped to an intron ofCNNM2. A trans-ancestry GWAS meta-analysis identified two more loci atNT5C2(rs10748839; P=2.54×10−8) and atAS3MT(rs10786721; P=4.97×10−8), associated with global brain arterial diameter. In addition, two SNPs co-localized with expression ofCNNM2(rs7897654, β=0.12, P=6.17×10−7) andAL356608.1(rs10786719, β =-0.17, P=6.60×10−6) in brain tissue. For the posterior brain arterial diameter, two variants at one locus mapped to an intron ofTCF25were identified (top SNP, rs35994878; β =0.11, P=2.94×10−8). For the anterior brain arterial diameter, one locus atADAP1was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10−8).ConclusionOur study reveals three novel risk loci (CNNM2, NT5C2 and AS3MT) associated with brain arterial diameters. Our finding may elucidate the mechanisms by which brain arterial diameters influence the risk of stroke and dementia.