Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci.
Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci.
复制标题
进行性核上麻痹危险基因座的基因表达，甲基化和神经病理相关性。
DOI：
10.1007/s00401-016-1576-7
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发表时间：
2016-08
影响因子：
12.7
通讯作者：
Ertekin-Taner N
中科院分区：
文献类型：
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作者：
Allen M;Burgess JD;Ballard T;Serie D;Wang X;Younkin CS;Sun Z;Kouri N;Baheti S;Wang C;Carrasquillo MM;Nguyen T;Lincoln S;Malphrus K;Murray M;Golde TE;Price ND;Younkin SG;Schellenberg GD;Asmann Y;Ordog T;Crook J;Dickson D;Ertekin-Taner N
为了确定进行性核上性麻痹（PSP）全基因组关联研究中确定的单核苷酸多态性（SNP）的影响，我们测试了它们与脑基因表达，CpG甲基化和神经病理学的关联。在175例尸检的PSP受试者中，我们在±100 kb内进行了7种PSP风险变体与20个基因的颞叶皮层水平之间的关联。甲基化措施，收集减少代表亚硫酸氢盐测序在43 PSP的大脑。为了确定SNP/表达关联是否是由于表观遗传修饰，针对相关变体测试了相关基因的CpG甲基化水平。在422名PSP受试者中测试了定量神经病理学内表型的SNP相关性。LRRC 37 A4和ARL 17 B的脑水平与rs 8070723相关; MOBP与rs 1768208相关，ARL 17 A和ARL 17 B均与rs 242557相关。在另外100名PSP受试者中可获得LRRC 37 A4和MOBP的表达关联。荟萃分析显示rs 8070723和rs 1768208的PSP风险等位基因分别与较高的LRRC 37 A4和MOBP脑水平高度显著相关。ARL 17 B基因3′区一个CpG的甲基化水平与rs 242557和rs 8070723相关此外，内含子ARL 17 A CpG的甲基化水平与rs 242557相关，内含子MOBP CpG的甲基化水平与rs 1768208相关。MAPT和MOBP区域风险等位基因也与较高水平的神经病理学相关。观察到rs 242557/卷曲体和簇状星形胶质细胞以及rs 1768208/卷曲体和tau线程的最强关联。这些研究结果表明，PSP变异MAPT和MOBP基因座可能会通过影响基因表达和tau神经病理赋予PSP的风险。MOBP、LRRC 37 A4、ARL 17 A和ARL 17 B作为PSP的候选风险基因值得进一步评估。我们的研究结果对某些最高PSP风险位点的变异的作用机制有影响。
To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3′ region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci.