调查老年痴呆症风险位点的转录调控。(S28.006)

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摘要目的:探讨晚发性阿尔茨海默氏症(负载)转录调控GWAS风险位点基因在人类的大脑。背景:我们之前确定的遗传关联的大脑的负载GWAS风险位点的基因水平ABCA7,BIN1 CLU, CR1和MS4A4AcisSNPs,包括一些高级广告风险变异。最近,11个额外风险位点被确定通过多个负载GWAS的大荟萃分析。在这项研究中,我们的第一个目标是调查协会的大脑这些11小说负荷风险位点基因的水平独联体单核苷酸多态性。我们的第二个目标是评估可变剪接的潜在作用在这些基因表达关联。设计/方法:我们已经获得的基因表达的措施~ 24000记录在两个脑区(颞叶皮层和小脑)200 ~ 200年的广告主题和~科目使用Illumina公司与其他病理WG-DASL化验。负载GWAS 11将小说位点分析的单核苷酸多态性与相应基因的表达水平独联体协变量,使用线性回归调整适当。评估可变剪接,我们将使用NanoString nCounter™技术来测量所有已知的候选基因的转录水平在所有负载GWAS位点在大脑~ 350 RNA样本。结果:之前我们已经证明了这种方法的实用程序和预测存在额外的负载基因,大脑同样受到snp的水平。我们也假定这些单核苷酸多态性赋予负荷表达式的风险和一些协会将外显子剪接的替代办法。结论:负载GWAS的许多基因位点与独联体单核苷酸多态性,其中一些是负载snp风险。这表明许多负载GWAS变异带来的风险在这些位点的基因的转录调控。解剖的转录调控有望在负载的理解病理生理学意义。研究支持:R01 AG032990 P50 AG016574

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