Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Neuron. 2010 Oct 21;68(2):270-81. doi: 10.1016/j.neuron.2010.10.013.
Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and dementia. Positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 causing early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. Recent genome-wide association approaches have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. It seems likely that much of this "missing heritability" may be accounted for by rare sequence variants, which, owing to recent advances in high-throughput sequencing technologies, can now be assessed in unprecedented detail.
三十年来，阿尔茨海默病（AD）的遗传学研究极大地拓宽了我们对导致神经退行性变和痴呆的发病机制的理解。定位克隆导致了 APP、PSEN1 和 PSEN2 中罕见的、致病的突变的鉴定，这些突变导致早发性家族性 AD，随后发现 APOE 是晚发性 AD 的唯一最重要的风险因素。最近的全基因组关联研究方法发现了几个在普通人群中常见的 AD 易感性位点，但仅具有非常小的风险效应。因此，目前已知的疾病基因只能解释 AD 遗传率的很大一部分。由于高通量测序技术的最新进展，现在可以以前所未有的细节评估这些罕见的序列变异，这些罕见的序列变异很可能在很大程度上解释了“缺失的遗传率”。
