Genetics of neurodegenerative diseases: insights from high-throughput resequencing.
Genetics of neurodegenerative diseases: insights from high-throughput resequencing.
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DOI：
10.1093/hmg/ddq162
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发表时间：
2010-04-15
影响因子：
3.5
通讯作者：
Tsuji S
中科院分区：
文献类型：
--
作者：
Tsuji S
在过去的三十年中，我们已经目睹了显着的进步，我们的遗传性神经退行性疾病，这已经完成了“定位克隆”策略的分子病因的理解。遗传性神经退行性疾病致病基因的发现，不仅促进了对疾病病理生理机制的研究，而且也促进了疾病改善疗法的研究。全基因组关联研究（GWAS）的基础上的“常见疾病常见变异假说”，目前正在进行阐明疾病相关的等位基因。虽然GWAS已经成功地揭示了许多神经退行性疾病的易感基因，但与风险等位基因相关的比值比通常较低，仅占估计遗传力的一小部分。最近的研究表明，基于对帕金森病的大数据集进行全面重测序而确定的疾病相关等位基因的效应量远大于GWAS确定的效应量。这些发现有力地证明了“常见病-多种罕见变异假说”在散发性神经退行性疾病中的作用。鉴于下一代测序（NGS）技术的快速改进，我们预计NGS最终将使我们能够识别个体基因组中的所有变体，特别是临床相关等位基因。除此之外，全基因组重测序预计将带来临床实践的范式转变，其中临床实践包括诊断和适当治疗程序的决策是基于“个人基因组”。个人基因组时代有望在不久的将来实现，社会需要为这个新时代做好准备。
During the past three decades, we have witnessed remarkable advances in our understanding of the molecular etiologies of hereditary neurodegenerative diseases, which have been accomplished by ‘positional cloning’ strategies. The discoveries of the causative genes for hereditary neurodegenerative diseases accelerated not only the studies on the pathophysiologic mechanisms of diseases, but also the studies for the development of disease-modifying therapies. Genome-wide association studies (GWAS) based on the ‘common disease–common variants hypothesis’ are currently undertaken to elucidate disease-relevant alleles. Although GWAS have successfully revealed numerous susceptibility genes for neurodegenerative diseases, odds ratios associated with risk alleles are generally low and account for only a small proportion of estimated heritability. Recent studies have revealed that the effect sizes of the disease-relevant alleles that are identified based on comprehensive resequencing of large data sets of Parkinson disease are substantially larger than those identified by GWAS. These findings strongly argue for the role of the ‘common disease–multiple rare variants hypothesis’ in sporadic neurodegenerative diseases. Given the rapidly improving technologies of next-generation sequencing next-generation sequencing (NGS), we expect that NGS will eventually enable us to identify all the variants in an individual's personal genome, in particular, clinically relevant alleles. Beyond this, whole genome resequencing is expected to bring a paradigm shift in clinical practice, where clinical practice including diagnosis and decision-making for appropriate therapeutic procedures is based on the ‘personal genome’. The personal genome era is expected to be realized in the near future, and society needs to prepare for this new era.
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影响因子：
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作者：
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DOI：
10.1073/pnas.0903103106
发表时间：
2009-06-09
影响因子：
11.1
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通讯作者：
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