PDF(Pubmed)
Abstract：
Cognitive decline is a major health concern and identification of genes that may serve as drug targets to slow decline is important to adequately support an aging population. Whilst genetic studies of cross-sectional cognition have been carried out, cognitive change is less well-understood. Here, using data from the TOMMORROW trial, we investigate genetic associations with cognitive change in a cognitively normal older cohort. We conducted a genome-wide association study of trajectories of repeated cognitive measures (using generalised estimating equation (GEE) modelling) and tested associations with polygenic risk scores (PRS) of potential risk factors. We identified two genetic variants associated with change in attention domain scores, rs534221751 (p = 1 × 10-8 with slope 1) and rs34743896 (p = 5 × 10-10 with slope 2), implicating NCAM2 and CRIPT/ATP6V1E2 genes, respectively. We also found evidence for the association between an education PRS and baseline cognition (at >65 years of age), particularly in the language domain. We demonstrate the feasibility of conducting GWAS of cognitive change using GEE modelling and our results suggest that there may be novel genetic associations for cognitive change that have not previously been associated with cross-sectional cognition. We also show the importance of the education PRS on cognition much later in life. These findings warrant further investigation and demonstrate the potential value of using trial data and trajectory modelling to identify genetic variants associated with cognitive change.
摘要：
认知衰退是一个主要的健康问题，识别可能作为减缓衰退的药物靶标的基因对于充分支持老龄化人口很重要。虽然已经进行了横断面认知的遗传研究，认知变化不太容易理解。这里,使用TOMMORROW试验的数据，我们在认知正常的老年队列中调查了认知改变与遗传关联.我们对重复认知测量的轨迹进行了全基因组关联研究（使用广义估计方程（GEE）建模），并测试了与潜在风险因素的多基因风险评分（PRS）的关联。我们确定了两种与注意力领域得分变化相关的遗传变异，rs534221751(p=1×10-8,斜率1)和rs34743896(p=5×10-10,斜率2),涉及NCAM2和CRIPT/ATP6V1E2基因，分别。我们还发现了教育PRS与基线认知（>65岁）之间关联的证据，特别是在语言领域。我们证明了使用GEE模型进行认知变化的GWAS的可行性，我们的结果表明，认知变化可能存在新的遗传关联，而这些遗传关联以前与横断面认知无关。我们还显示了教育PRS对以后生活中认知的重要性。这些发现值得进一步研究，并证明了使用试验数据和轨迹建模来识别与认知变化相关的遗传变异的潜在价值。
