Bordeaux Population Health Research Center, UMR 1219, University of Bordeaux, Inserm, Bordeaux, France.
Department of Neurology, Institute of Neurodegenerative Diseases, Bordeaux University Hospital, Bordeaux, France.
Nat Med. 2023 Apr;29(4):950-962. doi: 10.1038/s41591-023-02268-w. Epub 2023 Apr 17.
Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.
血管周围间隙（PVS）负担是一种新兴的、尚未被充分了解的磁共振成像脑小血管疾病标志物，是中风和痴呆的主要原因。多达 40095 名参与者（18 个基于人群的队列，66.3±8.6 岁，96.9%欧洲血统）的全基因组关联研究显示了 24 个与 PVS 风险相关的全基因组显著位点，主要位于白质中。这些与年轻成年人（N=1748；22.1±2.3 岁）的白质 PVS 有关，并且在早发性脑白质营养不良基因和在胎儿脑内皮细胞中表达的基因中富集，表明存在生命早期的机制。总的来说，53%的白质 PVS 风险位点在基于日本人群的队列中具有名义上显著的相关性（27%经过多重测试校正）（N=2862；68.3±5.3 岁）。孟德尔随机化支持高血压与基底节和海马 PVS 之间的因果关系，以及基底节 PVS 和海马 PVS 与中风之间的因果关系，这些都与血压有关。我们的研究结果为 PVS 和脑小血管疾病的生物学提供了深入的了解，指出了涉及细胞外基质、膜转运和发育过程的途径，以及基于遗传信息优先考虑药物靶点的潜力。
