Background Cysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL, have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remains unclear. Methods Cysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200,632). Frequency of stroke, dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls. Results Of 200,632 participants with exome sequencing data available, 443 (~1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjusting for age, sex, and ancestry principal components, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0003), and vascular dementia (OR: 5.03, p=0.007), and increased WMH volume (standardised difference: 0.52, p<0.001), and white matter ultrastructural damage on DTI-PSMD (standardised difference: 0.71, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 4.83, p<0.001) and cerebral microbleeds (OR: 3.61, p<0.001). WMH prevalence was most increased in the anterior temporal lobes (OR: 6.92, p<0.001) and external capsule (OR: 12.44, p<0.001). Conclusions Cysteine-changing NOTCH3 variants are common in the general population and are risk factors for apparently "sporadic" stroke and vascular dementia. They are associated with MRI changes of SVD, in a distribution similar to that seen in CADASIL.

中文翻译：

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NOTCH3变异体在普通人群中很常见，并与中风和血管性痴呆有关：对200,000名参与者的分析

背景技术据报道，与半胱氨酸改变的NOTCH3变体与导致罕见的单基因形式的中风的CADASIL相同，在普通人群中比预期的更为普遍，但尚不清楚它们的临床意义以及对社区中风和痴呆症风险的贡献。方法改变半胱氨酸的NOTCH3在UK Biobank全外显子组测序数据中鉴定了变体（N = 200,632）。比较变异型携带者和非携带者的卒中频率，痴呆症和CADASIL的其他临床特征以及MRI白质高信号量。对具有变体的患者的MRI进行视觉评分，每一个都与三个对照匹配。结果200,632名具有外显子组测序数据的参与者中，有443名（约450名中的1名）携带67个不同的改变半胱氨酸的NOTCH3变体。在调整了年龄，性别和血统主要成分后，NOTCH3变异携带者的中风风险（OR：2.33，p = 0.0003）和血管性痴呆（OR：5.03，p = 0.007）和WMH量增加（标准差） ：0.52，p <0.001），以及对DTI-PSMD的白质超微结构损害（标准差：0.71，p <0.001）。在对来自47个携带者和148个匹配对照的MRI的视觉分析中，变体与存在腔（OR：4.83，p <0.001）和脑微出血（OR：3.61，p <0.001）相关。在前颞叶（OR：6.92，p <0.001）和外囊（OR：12.44，p <0.001）中，WMH患病率最高。结论半胱氨酸改变NOTCH3变异体在普通人群中很常见，并且是明显的“散发性”中风和血管性痴呆的危险因素。它们与SVD的MRI改变相关，其分布类似于CADASIL中的分布。