Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
J Hum Genet. 2010 Oct;55(10):707-9. doi: 10.1038/jhg.2010.92. Epub 2010 Jul 29.
We developed and implemented software for the analysis of genome-wide association studies in the context of biological pathway enrichment and have here applied our algorithm to the study of Alzheimer disease (AD). Using genome-wide association data in a large French population, we observed a highly significant enrichment of genes involved in intracellular protein transmembrane transport, including several mitochondrial proteins and nucleoporins. An intriguing aspect of these findings is the implication that TOMM40, the channel-forming subunit of the translocase of the mitochondrial outer membrane complex, and a gene generally considered to be indiscernible from APOE because of linkage disequilibrium, may itself contribute to Alzheimer pathology. Results provide an indication that protein trafficking, in particular across the nuclear and mitochondrial membranes, may contribute to risk for AD.
我们开发并实现了用于生物途径富集的全基因组关联研究分析的软件，并且已经将我们的算法应用于阿尔茨海默病（AD）的研究。利用法国大型人群的全基因组关联数据，我们观察到参与细胞内蛋白跨膜运输的基因显著富集，包括几个线粒体蛋白和核孔蛋白。这些发现的一个有趣方面是，线粒体膜外转位复合物的通道形成亚基 TOMM40 以及一般由于连锁不平衡而被认为与 APOE 不可区分的基因，可能本身会导致阿尔茨海默病病理。结果表明，蛋白质转运，特别是核膜和线粒体膜之间的蛋白质转运，可能会增加患 AD 的风险。
