Genome-Wide Genotyping Demonstrates a Polygenic Risk Score Associated With White Matter Hyperintensity Volume in CADASIL
Genome-Wide Genotyping Demonstrates a Polygenic Risk Score Associated With White Matter Hyperintensity Volume in CADASIL
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DOI：
10.1161/strokeaha.113.004461
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发表时间：
2014-04-01
期刊：
影响因子：
8.3
通讯作者：
Dichgans, Martin
中科院分区：
文献类型：
--
作者：
Opherk, Christian;Gonik, Mariya;Dichgans, Martin
背景和目的MRI上的白色高信号（WMH）是散发性脑小血管病的一个定量标志，具有高度遗传性。迄今为止，大规模的遗传研究已经确定只有一个单一的位点影响WMH负担。这可能部分与散发性WMH的生物异质性有关。目前的研究寻找遗传修饰WMH体积常染色体显性脑动脉病与皮质下梗死和白质脑病（CADASIL），单基因小vesseldiseases.Methods我们进行了全基因组关联研究，以确定WMH体积的数量性状位点相结合的数据从517 CADASIL患者收集通过7个中心在欧洲。集中分析WMH体积，并在液体衰减反转恢复图像上定量。基因分型使用Affytechnology 6.0平台进行。个体被分配到2个不同的遗传簇（簇1和簇2）根据他们的遗传background.Results 466例患者进入最终的全基因组关联研究分析。在CADASIL的WMH负荷的表型方差解释的所有单核苷酸多态性在集群1是0.85（SE=0.21），这表明了大量的遗传贡献。使用聚类1作为推导，聚类2作为验证样本，校正年龄、性别和血管危险因素后，多基因评分与WMH负担显著相关（P=0.001）。没有单核苷酸多态性达到全基因组significant.Conclusions，我们发现一个多基因得分与WMH体积CADASIL科目。我们的研究结果表明，多种影响较小的变异影响CADASIL中的WMH负荷。对这些变异体和相关生物学途径的鉴定将为CADASIL中白色物质疾病和可能的一般小血管疾病的病理生理学提供见解。
Background and Purpose White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease.Methods We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background.Results Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance.Conclusions We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general.