Brown Foundation Institute of Molecular Medicine, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
Ann Neurol. 2011 Jun;69(6):928-39. doi: 10.1002/ana.22403.
White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).
This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
磁共振成像（MRI）可检测到的脑白质高信号（WMHs）是与大脑衰老相关的血管损伤谱的一部分，被认为反映了小深部脑血管的缺血性损伤。WMHs 与认知和运动功能障碍、痴呆、抑郁和中风的风险增加有关。尽管遗传率很高，但影响 WMH 负担的遗传基因座很少被发现。
我们对 7 个基于社区的队列中 9361 名无中风的欧洲血统个体的 WMH 负担进行了全基因组关联研究（GWAS）的荟萃分析。在另外 2 个队列的 3024 名个体中对显著发现进行了复制测试。
我们在 17q25 染色体上的 1 个包含 6 个已知基因（包括 WBP2、TRIM65、TRIM47、MRPL38、FBF1 和 ACOX1）的基因座中发现了 6 个新的风险相关单核苷酸多态性（SNPs）。最显著的关联是 rs3744028（发现 p 值=4.0×10(-9)；复制 p 值=1.3×10(-7)；合并 p 值=4.0×10(-15)）。该区域中达到全基因组显著水平的其他 SNPs 还有 rs9894383（p=5.3×10(-9)）、rs11869977（p=5.7×10(-9)）、rs936393（p=6.8×10(-9)）、rs3744017（p=7.3×10(-9)）和 rs1055129（p=4.1×10(-8)）。这些基因座上的变异等位基因使 WMH 负担略有增加（样本中总 WMH 负担的 4-8%）。
这项针对欧洲血统个体的基于社区队列的 WMH 负担的大型 GWAS 确定了 17 号染色体上的一个新基因座。对该基因座的进一步特征分析可能为大脑 WMH 的发病机制提供新的见解。
