Table_1_A Comprehensive Analysis of the CaMK2A Gene and Susceptibility to Alzheimer’s Disease in the Han Chinese Population.docx

There is ample evidence suggesting that calcium/calmodulin-dependent protein kinase II alpha (CaMK2A) may play an important role in the pathophysiology of Alzheimer’s disease (AD). This genetic study aimed to investigate whether CaMK2A confers susceptibility to the development of AD in the Han Chinese population. A total of seven single nucleotide polymorphisms (SNPs) within CaMK2A were screened in two independent cohorts from southwestern China (333 AD patients and 334 controls) and eastern China (382 AD patients and 426 controls) to discern the potential association between this gene and AD. In addition, a cross-platform normalized expression resource was used to investigate whether CaMK2A is differentially expressed in the brain between individuals with AD and the controls. In addition, expression quantitative trait loci (eQTL) analysis was used to explore the differences in CaMK2A expression in the brain among different genotypes. The cross-platform normalized data showed significant differences in CaMK2A expression in the hippocampus, entorhinal cortex and temporal cortex between the AD patients and the control subjects (|log FC| > 0.1, P < 0.05); however, only the differences in the hippocampus and temporal cortex remained after the multiple comparisons correction [false discovery rate (FDR)-corrected, P < 0.05]. The frequency of the rs4958445 genotype was significantly different between the AD subjects and the controls from southwestern China (P = 0.013, P = 0.034 after FDR correction). When the two samples were combined, rs4958445 still showed a significant association with AD (P = 0.044). Haplotype analysis indicated that the T-A-C-A-T-C-C and T-G-C-A-T-C-C haplotypes in the southwestern cohort and the T-G-C-G-C-T-C haplotype in the eastern cohort, consisting of rs10051644, rs6869634, rs3797617, rs3756577, rs4958445, rs10515639 and rs6881743, showed a significant association with AD (P = 0.037, P = 0.026 and P = 0.045, respectively). Furthermore, the brain eQTL analysis revealed a significant association between the rs4958445 polymorphism and CaMK2A expression in the inferior olivary nucleus (P = 0.029). Our results suggest an important role for CaMK2A in the pathophysiology of AD in the Han Chinese population, especially the southwestern population.

已有充分证据表明，钙/钙调蛋白依赖性蛋白激酶IIα（calcium/calmodulin-dependent protein kinase II alpha, CaMK2A）可能在阿尔茨海默病（Alzheimer’s disease, AD）的病理生理过程中发挥重要作用。本遗传学研究旨在探究在中国汉族人群中，CaMK2A是否会增加阿尔茨海默病的发病易感性。研究共筛选了CaMK2A基因内的7个单核苷酸多态性（single nucleotide polymorphisms, SNPs），并在两个独立队列中开展分型：中国西南队列（333例阿尔茨海默病患者与334例健康对照）以及中国东部队列（382例阿尔茨海默病患者与426例健康对照），以明确该基因与阿尔茨海默病之间的潜在关联。此外，本研究采用跨平台标准化表达数据集，探究阿尔茨海默病患者与健康对照者的脑组织中CaMK2A的表达差异；同时通过表达数量性状基因座（expression quantitative trait loci, eQTL）分析，探索不同基因型个体脑组织中CaMK2A表达的差异。跨平台标准化数据分析显示，阿尔茨海默病患者与健康对照者的海马体、内嗅皮层及颞叶皮层中CaMK2A的表达存在显著差异（|log FC| > 0.1，P < 0.05）；但经多重比较校正后，仅海马体与颞叶皮层的差异仍具有统计学意义[错误发现率（false discovery rate, FDR）校正后，P < 0.05]。中国西南队列中，rs4958445基因型的频率在阿尔茨海默病患者与健康对照间存在显著差异（P = 0.013，FDR校正后P = 0.034）。将两个队列合并分析后，rs4958445仍与阿尔茨海默病显著相关（P = 0.044）。单倍型分析结果显示，西南队列中由rs10051644、rs6869634、rs3797617、rs3756577、rs4958445、rs10515639及rs6881743构成的T-A-C-A-T-C-C与T-G-C-A-T-C-C单倍型，以及东部队列中的T-G-C-G-C-T-C单倍型，均与阿尔茨海默病存在显著关联（对应P值分别为0.037、0.026及0.045）。此外，脑组织eQTL分析显示，rs4958445多态性与下橄榄核中的CaMK2A表达存在显著关联（P = 0.029）。本研究结果表明，CaMK2A在中国汉族人群，尤其是西南汉族人群的阿尔茨海默病病理生理过程中发挥重要作用。