T Cuenco Karen, Lunetta Kathryn L, Baldwin Clinton T, McKee Ann C, Guo Jianping, Cupples L Adrienne, Green Robert C, St George-Hyslop Peter H, Chui Helena, DeCarli Charles, Farrer Lindsay A
Genetics Program, Department of Medicine, Room L320, Boston University School of Medicine, 715 Albany St, Boston, MA 02118, USA.
Arch Neurol. 2008 Dec;65(12):1640-8. doi: 10.1001/archneur.65.12.1640.
Single-nucleotide polymorphisms (SNPs) in 2 distinct regions of the gene for the sortilin-related receptor (SORL1) (bounded by consecutively numbered SNPs 8-10 and 22-25) were shown to be associated with Alzheimer disease (AD) in multiple ethnically diverse samples.
To test the hypothesis that SORL1 is associated with brain magnetic resonance imaging (MRI) measurements of atrophy and/or vascular disease.
DESIGN, SETTING, AND PATIENTS: We evaluated the association of 30 SNPs spanning SORL1 with MRI measures of general cerebral atrophy, hippocampal atrophy, white matter hyperintensities, and overall cerebrovascular disease in 44 African American and 182 white sibships from the MIRAGE Study. We performed single- and 3-SNP haplotype association analyses using family-based tests. Haplotypes found to be significantly associated with at least 1 MRI trait were tested for association with 6 pathological traits in a separate sample of 69 white patients with autopsy-confirmed AD.
In white patients, white matter hyperintensities were associated with multiple markers in the region encompassing SNPs 6 to 10, whereas cerebral and hippocampal atrophy were associated with markers from the region including SNPs 21 to 26. Examination of specific 3-SNP haplotypes from these 2 regions in the autopsy-confirmed cases of AD revealed association of white matter disease with SNPs 8 to 10 and association of hippocampal atrophy with SNPs 22 to 26. The haplotype CGC at SNPs 8 to 10 was associated with fewer white matter changes in the clinical (P<.001) and autopsy (P=.02) samples.
Variants of SORL1 previously associated with AD are also associated with MRI and neuropathological measures of neurodegenerative and cerebrovascular disease. These findings not only support the hypothesis that multiple areas in SORL1 are of functional importance but also raise the possibility that multiple SORL1 variants influence amyloid precursor protein or endothelial lipoprotein processing or both in different regions of the brain.
分拣蛋白相关受体（SORL1）基因两个不同区域的单核苷酸多态性（SNP）（由连续编号的SNP 8 - 10和22 - 25界定）在多个不同种族样本中显示与阿尔茨海默病（AD）相关。
检验SORL1与脑磁共振成像（MRI）测量的萎缩和/或血管疾病相关的假设。
设计、设置和患者：我们在MIRAGE研究的44个非裔美国人和182个白人同胞家庭中，评估了跨越SORL1的30个SNP与一般脑萎缩、海马萎缩、白质高信号和总体脑血管疾病的MRI测量值之间的关联。我们使用基于家系的检验进行单SNP和3 - SNP单倍型关联分析。在69例经尸检确诊为AD的白人患者的单独样本中，对发现与至少1种MRI特征显著相关的单倍型进行与6种病理特征的关联测试。
在白人患者中，白质高信号与包含SNP 6至10区域的多个标记相关，而脑萎缩和海马萎缩与包括SNP 21至26区域的标记相关。在经尸检确诊的AD病例中，对这两个区域的特定3 - SNP单倍型进行检查发现，白质疾病与SNP 8至10相关，海马萎缩与SNP 22至26相关。SNP 8至10处的单倍型CGC与临床样本（P <.001）和尸检样本（P =.02）中较少的白质变化相关。
先前与AD相关的SORL1变体也与神经退行性和脑血管疾病的MRI及神经病理学测量相关。这些发现不仅支持SORL1中多个区域具有功能重要性的假设，还增加了多种SORL1变体在大脑不同区域影响淀粉样前体蛋白或内皮脂蛋白加工或两者的可能性。
