Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
PLoS One. 2010 Jun 21;5(6):e11244. doi: 10.1371/journal.pone.0011244.
Recent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden.
METHODS/PRINCIPAL FINDINGS: Thirty-two single nucleotide polymorphisms (SNPs) previously implicated in AD susceptibility were genotyped in 414 subjects with both annual clinical evaluation and completed brain autopsies from the Religious Orders Study and the Rush Memory and Aging Project. Regression analyses evaluated the relation of SNP genotypes to continuous measures of AD neuropathology and cognitive function proximate to death. A SNP in the zinc finger protein 224 gene (ZNF224, rs3746319) was associated with both global AD neuropathology (p = 0.009) and global cognition (p = 0.002); whereas, a SNP at the phosphoenolpyruvate carboxykinase locus (PCK1, rs8192708) was selectively associated with global cognition (p = 3.57 x 10(-4)). The association of ZNF224 with cognitive impairment was mediated by neurofibrillary tangles, whereas PCK1 largely influenced cognition independent of AD pathology, as well as Lewy bodies and infarcts.
CONCLUSIONS/SIGNIFICANCE: The findings support the association of several loci with AD, and suggest how intermediate phenotypes can enhance analysis of susceptibility loci in this complex genetic disorder.
最近的遗传研究已经确定了越来越多的与阿尔茨海默病（AD）易感性具有提示性关联的基因座。然而，对于这些候选基因在影响与 AD 诊断相关的中间表型（包括认知下降或 AD 神经病理负担）方面的作用知之甚少。
方法/主要发现：对来自宗教秩序研究和拉什记忆与衰老项目的 414 名具有年度临床评估和完成脑部尸检的受试者进行了 32 个先前与 AD 易感性相关的单核苷酸多态性（SNP）的基因分型。回归分析评估了 SNP 基因型与死亡时接近的 AD 神经病理学和认知功能的连续测量值之间的关系。锌指蛋白 224 基因（ZNF224，rs3746319）中的 SNP 与全球 AD 神经病理学（p=0.009）和全球认知（p=0.002）均相关；而磷酸烯醇丙酮酸羧激酶基因座（PCK1，rs8192708）中的 SNP 则与全球认知（p=3.57x10(-4)）选择性相关。ZNF224 与认知障碍的关联受神经原纤维缠结的影响，而 PCK1 主要影响认知，而与 AD 病理无关，以及路易体和梗死。
结论/意义：这些发现支持了几个基因座与 AD 的关联，并提出了如何通过中间表型来增强对这种复杂遗传疾病易感性基因座的分析。
