Liu Minghua, Khasiyev Farid, Sariya Sanjeev, Spagnolo-Allende Antonio, Sanchez Danurys L, Andrews Howard, Yang Qiong, Beiser Alexa, Qiao Ye, Thomas Emy A, Romero Jose Rafael, Rundek Tatjana, Brickman Adam M, Manly Jennifer J, Elkind Mitchell Sv, Seshadri Sudha, Chen Christopher, Sacco Ralph L, Hilal Saima, Wasserman Bruce A, Tosto Giuseppe, Fornage Myriam, Gutierrez Jose
Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Department of Neurology, Saint Louis University School of Medicine, St. Louis, MO, USA.
medRxiv. 2023 Feb 15:2023.01.31.23285251. doi: 10.1101/2023.01.31.23285251.
Brain 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.
We 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<5×10) (top SNP, rs7921574; β =0.06, P=1.54×10). This locus mapped to an intron of . A trans-ancestry GWAS meta-analysis identified two more loci at (rs10748839; P=2.54×10) and at (rs10786721; P=4.97×10), associated with global brain arterial diameter. In addition, two SNPs co-localized with expression of (rs7897654, β=0.12, P=6.17×10) and (rs10786719, β =-0.17, P=6.60×10) in brain tissue. For the posterior brain arterial diameter, two variants at one locus mapped to an intron of were identified (top SNP, rs35994878; β =0.11, P=2.94×10). For the anterior brain arterial diameter, one locus at was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10).
Our 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.
脑动脉直径是脑血管疾病、认知衰退和痴呆的新型影像生物标志物。传统血管危险因素已被证明与脑动脉直径有关，但脑动脉直径是否存在遗传决定因素尚不清楚。
我们研究了来自六个不同地理区域的基于人群的队列中的4150名参与者（欧洲血统占40%，非洲血统占14%，西班牙裔占22%，亚洲血统占24%）。我们测量了13个节段的脑动脉直径，并对其进行平均，以获得脑动脉直径的整体测量值以及后循环和前循环的测量值。一项全基因组关联研究（GWAS）在一个位点发现了14个与全脑动脉直径相关的变异，达到全基因组显著性水平（P<5×10）（顶级单核苷酸多态性，rs7921574；β =0.06，P=1.54×10）。该位点定位于……的一个内含子。一项跨血统GWAS荟萃分析在……（rs10748839；P=2.54×10）和……（rs10786721；P=4.97×10）发现了另外两个与全脑动脉直径相关的位点。此外，两个单核苷酸多态性与脑组织中……（rs7897654，β=0.12，P=6.17×10）和……（rs10786719，β =-0.17，P=6.60×10）的表达共定位。对于后脑动脉直径，在一个位点发现了两个变异，定位于……的一个内含子（顶级单核苷酸多态性，rs35994878；β =0.11，P=2.94×10）。对于前脑动脉直径，在跨血统全基因组关联分析中在……发现了一个位点（rs34217249；P=3.11×10）。
我们的研究揭示了三个与脑动脉直径相关的新风险位点（CNNM2、NT5C2和AS3MT）。我们的发现可能阐明脑动脉直径影响中风和痴呆风险的机制。
