Department of Medicine, Boston University School of Medicine, MA, USA.
Ann Neurol. 2012 Jul;72(1):65-75. doi: 10.1002/ana.23644. Epub 2012 Jun 28.
Large genome-wide association studies (GWASs) have identified many novel genes influencing Alzheimer disease (AD) risk, but most of the genetic variance remains unexplained. We conducted a 2-stage GWAS for AD-related quantitative measures of hippocampal volume (HV), total cerebral volume (TCV), and white matter hyperintensities (WMH).
Brain magnetic resonance imaging measures of HV, TCV, and WMH were obtained from 981 Caucasian and 419 African American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer's Genetic Epidemiology) Study, and from 168 AD cases, 336 individuals with mild cognitive impairment, and 188 controls in the Alzheimer's Disease Neuroimaging Initiative Study. A GWAS for each trait was conducted in the 2 Caucasian data sets in stage 1. Results from the 2 data sets were combined by meta-analysis. In stage 2, 1 single nucleotide polymorphism (SNP) from each region that was nominally significant in each data set (p < 0.05) and strongly associated in both data sets (p < 1.0 × 10(-5)) was evaluated in the African American data set.
Twenty-two markers (14 for HV, 3 for TCV, and 5 for WMH) from distinct regions met criteria for evaluation in stage 2. Novel genome-wide significant associations (p < 5.0 × 10(-8)) were attained for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set. Associations with different SNPs in the same gene (p < 1 × 10(-5) in Caucasians and p < 2.2 × 10(-4) in African Americans) were also observed for PICALM with HV, SYNPR with TCV, and TTC27 with WMH.
Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD.
全基因组关联研究（GWAS）已经确定了许多影响阿尔茨海默病（AD）风险的新基因，但大部分遗传变异仍然无法解释。我们对 AD 相关的海马体积（HV）、总脑体积（TCV）和脑白质高信号（WMH）的定量测量进行了 2 阶段 GWAS。
来自 MIRAGE（多机构阿尔茨海默病遗传流行病学研究）研究的 981 名白种人和 419 名非裔美国人 AD 病例及其认知正常的兄弟姐妹的脑磁共振成像 HV、TCV 和 WMH 测量值，以及来自 168 名 AD 病例、336 名轻度认知障碍患者和 188 名对照者的阿尔茨海默病神经影像学倡议研究。在第 1 阶段，在 2 个白种人数据集中对每个特征进行了 GWAS。通过荟萃分析合并这 2 个数据集的结果。在第 2 阶段，在每个数据集中有显著意义的（p < 0.05）和在两个数据集中都强烈相关的（p < 1.0×10(-5)）的每个区域的 1 个单核苷酸多态性（SNP）在非裔美国人数据集中进行了评估。
有 22 个标记物（14 个 HV，3 个 TCV，5 个 WMH）来自不同的区域，符合第 2 阶段的评估标准。HV 与 APOE、F5/SEL、LHFP 和 GCFC2 基因区域中的 SNP 存在新的全基因组显著关联（p < 5.0×10(-8)）。这些关联在每个数据集中都有证据支持。在同一基因中不同 SNP 之间的关联（白种人 p < 1.0×10(-5)，非裔美国人 p < 2.2×10(-4)）也在 PICALM 与 HV、SYNPR 与 TCV 和 TTC27 与 WMH 中观察到。
我们的研究表明，表型对于扩大我们对 AD 遗传基础的理解是有效的。
