Warstadt Nicholus M, Dennis Emily L, Jahanshad Neda, Kohannim Omid, Nir Talia M, McMahon Katie L, de Zubicaray Greig I, Montgomery Grant W, Henders Anjali K, Martin Nicholas G, Whitfield John B, Jack Clifford R, Bernstein Matt A, Weiner Michael W, Toga Arthur W, Wright Margaret J, Thompson Paul M
Imaging Genetics Center, Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA.
Neurobiol Aging. 2014 Nov;35(11):2504-2513. doi: 10.1016/j.neurobiolaging.2014.05.024. Epub 2014 Jun 2.
Several common genetic variants influence cholesterol levels, which play a key role in overall health. Myelin synthesis and maintenance are highly sensitive to cholesterol concentrations, and abnormal cholesterol levels increase the risk for various brain diseases, including Alzheimer's disease. We report significant associations between higher serum cholesterol (CHOL) and high-density lipoprotein levels and higher fractional anisotropy in 403 young adults (23.8 ± 2.4 years) scanned with diffusion imaging and anatomic magnetic resonance imaging at 4 Tesla. By fitting a multi-locus genetic model within white matter areas associated with CHOL, we found that a set of 18 cholesterol-related, single-nucleotide polymorphisms implicated in Alzheimer's disease risk predicted fractional anisotropy. We focused on the single-nucleotide polymorphism with the largest individual effects, CETP (rs5882), and found that increased G-allele dosage was associated with higher fractional anisotropy and lower radial and mean diffusivities in voxel-wise analyses of the whole brain. A follow-up analysis detected white matter associations with rs5882 in the opposite direction in 78 older individuals (74.3 ± 7.3 years). Cholesterol levels may influence white matter integrity, and cholesterol-related genes may exert age-dependent effects on the brain.
几种常见的基因变异会影响胆固醇水平，而胆固醇水平在整体健康中起着关键作用。髓鞘的合成与维持对胆固醇浓度高度敏感，胆固醇水平异常会增加包括阿尔茨海默病在内的各种脑部疾病的风险。我们报告了在403名年龄在23.8±2.4岁的年轻人中，较高的血清胆固醇（CHOL）和高密度脂蛋白水平与较高的各向异性分数之间存在显著关联，这些年轻人接受了4特斯拉的扩散成像和解剖磁共振成像扫描。通过在与CHOL相关的白质区域内拟合多基因座遗传模型，我们发现一组与阿尔茨海默病风险相关的18个胆固醇相关单核苷酸多态性预测了各向异性分数。我们聚焦于个体效应最大的单核苷酸多态性CETP（rs5882），发现在全脑的体素分析中，G等位基因剂量增加与较高的各向异性分数以及较低的径向和平均扩散率相关。一项后续分析在78名年龄较大的个体（74.3±7.3岁）中检测到rs5882与白质的关联方向相反。胆固醇水平可能会影响白质完整性，与胆固醇相关的基因可能会对大脑产生年龄依赖性影响。
