Department of Biology, Brigham Young University, Provo, UT, 84602, USA.
Washington University School of Medicine, St. Louis, MO, 63110, USA.
Genome Med. 2017 Nov 29;9(1):100. doi: 10.1186/s13073-017-0486-1.
While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline.
We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs.
Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aβ42 (p value = 0.0003) and in the Aβ42/Aβ40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04).
Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.
虽然年龄和 APOE ε4 等位基因是阿尔茨海默病（AD）的主要危险因素，但一小部分具有这些危险因素的个体表现出 AD 抗性，他们的寿命超过 75 岁，没有任何认知能力下降的临床症状。
我们使用了 200 多名“AD 抗性”个体和一种创新的基于谱系的方法来识别与 AD 抗性分离的遗传变异。首先，我们在具有抗性个体和 AD 死亡统计过剩的谱系中进行连锁分析。其次，我们使用全基因组序列在显著连锁区域中识别候选 SNP。第三，我们在独立数据集和基于基因的测试中复制了降低 AD 风险的连锁峰中的 SNP。最后，我们对复制的 SNP 进行了实验表征。
RAB10 中的 rs142787485 赋予了对 AD 的显著保护作用（p 值=0.0184，优势比=0.5853）。此外，我们在一组独立的无关个体中复制了这种关联（p 值=0.028，优势比=0.69），并使用基于基因的测试来确认 RAB10 变异在修饰 AD 风险方面的作用（p 值=0.002）。实验表明，RAB10 的敲低导致神经母细胞瘤细胞中 Aβ42 显著减少（p 值=0.0003）和 Aβ42/Aβ40 比值降低（p 值=0.0001）。我们还发现 RAB10 的表达在人类 AD 脑中显著升高（p 值=0.04）。
我们的结果表明，RAB10 可能是 AD 预防的一个有前途的治疗靶点。此外，我们的基因发现方法可以扩展和适应其他表型，从而成为识别 AD 和其他复杂人类疾病罕见变异的未来努力的模型。
