Department of Medicine, University of Washington, Box 359780, 325 Ninth Avenue, Seattle, WA 98104, USA.
Brain Imaging Behav. 2012 Dec;6(4):621-33. doi: 10.1007/s11682-012-9184-1.
The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (±100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD diseases. Complete data were available for 750 ADNI participants of European descent. Executive functioning resilience was highly heritable (H² = 0.76; S.E. = 0.44). rs3748348 on chromosome 14 in the region of RNASE13 was associated with executive functioning resilience (p-value = 4.31 × 10⁻⁷). rs3748348 is in strong linkage disequilibrium (D' of 1.00 and 0.96) with SNPs that map to TPPP2, a member of the α-synuclein family of proteins. We identified nominally significant associations between rs3748348 and expression levels of three genes (FLJ10357, RNASE2, and NDRG2). The strongest association was for FLJ10357 in cortex, which also had the most significant difference in expression between AD and non-AD brains, with greater expression in cortex of decedents with AD (p-value = 7 × 10⁻⁷). Further research is warranted to determine whether this signal can be replicated and whether other loci may be associated with cognitive resilience.
韧性的遗传基础，定义为认知功能优于基于神经影像学或神经病理学的预测，目前还不太清楚。我们的目标是确定与执行功能韧性相关的遗传变异。我们通过回归模型计算了执行功能的残差，调整了年龄、性别、教育、哈钦斯基评分和 MRI 发现（腔隙、皮质厚度、白质高信号体积和海马体）。我们估计了遗传率，并在每个 SNP 的模型中分析了这些残差。我们通过评估附近（±100 kb）基因的顺式关联来进一步评估我们最有希望的 SNP 结果，来自一个配套数据集中，比较了 AD 患者皮质和小脑中的表达水平与其他非 AD 疾病的表达水平。欧洲血统的 750 名 ADNI 参与者提供了完整的数据。执行功能的韧性具有很高的遗传性（H²=0.76；S.E.=0.44）。14 号染色体上的 rs3748348 与执行功能的韧性有关（p 值=4.31×10⁻⁷）。rs3748348 与映射到 TPPP2 的 SNPs 紧密连锁不平衡（D'为 1.00 和 0.96），TPPP2 是α-突触核蛋白家族蛋白的成员。我们发现 rs3748348 与三个基因（FLJ10357、RNASE2 和 NDRG2）的表达水平之间存在显著的关联。在皮质中，FLJ10357 的相关性最强，AD 和非 AD 大脑之间的表达差异也最大，AD 患者皮质中的表达更高（p 值=7×10⁻⁷）。需要进一步的研究来确定这个信号是否可以复制，以及其他基因座是否与认知弹性相关。
