Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Neurology. 2011 Apr 12;76(15):1302-9. doi: 10.1212/WNL.0b013e3182166df5.
Copy number variants (CNVs) have been recognized as a source of genetic variation that contributes to disease phenotypes. Alzheimer disease (AD) has high heritability for occurrence and age at onset (AAO). We performed a cases-only genome-wide CNV association study for age at onset of AD.
The discovery case series (n = 40 subjects with AD) was evaluated using array comparative genome hybridization (aCGH). A replication case series (n = 507 subjects with AD) was evaluated using Affymetrix array (n = 243) and multiplex ligation-dependent probe amplification (n = 264). Hazard models related onset age to CNV.
The discovery sample identified a chromosomal segment on 14q11.2 (19.3-19.5 Mb, NCBI build 36, UCSC hg18 March 2006) as a region of interest (genome-wide adjusted p = 0.032) for association with AAO of AD. This region encompasses a cluster of olfactory receptors. The replication sample confirmed the association (p = 0.035). The association was found for each APOE4 gene dosage (0, 1, and 2).
High copy number in the olfactory receptor region on 14q11.2 is associated with younger age at onset of AD.
拷贝数变异（CNVs）已被认为是遗传变异的来源，可导致疾病表型。阿尔茨海默病（AD）的发病和发病年龄（AAO）具有很高的遗传性。我们对 AD 的发病年龄进行了仅病例全基因组 CNV 关联研究。
使用阵列比较基因组杂交（aCGH）评估发现病例系列（n=40 例 AD 患者）。使用 Affymetrix 阵列（n=243 例）和多重连接依赖性探针扩增（n=264 例）评估复制病例系列（n=507 例 AD 患者）。危险模型将发病年龄与 CNV 相关联。
发现样本确定 14q11.2 上的染色体片段（19.3-19.5 Mb，NCBI 构建 36，UCSC hg18 2006 年 3 月）为 AD 的 AAO 关联的感兴趣区域（全基因组调整后的 p=0.032）。该区域包含一组嗅觉受体。复制样本证实了这种关联（p=0.035）。在每个 APOE4 基因剂量（0、1 和 2）中均发现了这种关联。
14q11.2 上嗅觉受体区域的高拷贝数与 AD 的发病年龄较小有关。
