Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Neurobiol Aging. 2012 May;33(5):1017.e1-15. doi: 10.1016/j.neurobiolaging.2011.09.033. Epub 2011 Nov 4.
Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (P(DISC) = 5.6 × 10(-9); P(JOINT)= 3.7 × 10(-27)). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (P(DISC) = 6.7 × 10(-5); P(REP) = 9.4 × 10(-3); P(JOINT) = 2.3 × 10(-5)). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.
年龄相关性认知衰退可能是由于衰老的慢性疾病引起的累积性脑损伤所致，包括神经退行性和血管疾病。由于常见的神经元机制可能介导对不同大脑损伤的适应，我们假设与年龄相关的认知衰退的易感性部分可能是由于共同的遗传网络。因此，我们使用基于 749 名受试者的 17 项认知测试的重复测量的全球认知衰退斜率的定量测量值，进行了全基因组关联研究。顶级结果在 3 个独立的复制队列中进行了评估，该队列由 2279 名具有重复认知测试的额外受试者组成。正如预期的那样，我们发现阿尔茨海默病（AD）易感性基因座 APOE 与认知衰退速度密切相关（P(DISC)=5.6×10(-9); P(JOINT)=3.7×10(-27)）。我们还发现了一个变体 rs10808746，它在复制队列中表现出一致的效果，并且在联合分析中适度提高了关联证据（P(DISC)=6.7×10(-5); P(REP)=9.4×10(-3); P(JOINT)=2.3×10(-5)）。该变体影响了 2 个相邻基因 PDE7A 和 MTFR1 的表达，它们分别是炎症和氧化损伤的潜在调节剂。使用遗传风险的综合指标，我们发现心血管疾病、2 型糖尿病和炎症性疾病的已知易感性基因座与我们队列中的认知衰退没有显著相关性。我们的研究结果表明，中间表型与更大的样本量相结合，可能是剖析与年龄相关的认知衰退的易感性基因座并发现具有神经元损伤作用的共同分子途径的有用工具。
