Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis.
Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis.
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DOI：
10.1038/s41431-018-0177-4
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发表时间：
2018-10
期刊：
影响因子：
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通讯作者：
Project MinE ALS Sequencing Consortium
中科院分区：
文献类型：
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作者：
Project MinE ALS Sequencing Consortium
最新的肌萎缩侧索硬化症 (ALS) 全基因组关联研究表明，低频变异对疾病遗传易感性的贡献不成比例。因此，我们启动了 MinE 项目，这是一项国际合作项目，旨在分析至少 15000 名 ALS 患者和 7500 名对照者的全基因组序列数据。在此，我们报告了 MinE 项目的设计以及对来自荷兰的 1169 名 ALS 患者和 608 名对照者进行成功测序的试点分析。正如测序研究的特点一样，我们发现了大量罕见的遗传变异（次要等位基因频率 < 0.1%），其中绝大多数在公共数据集中不存在。主成分分析揭示了这些变体在荷兰境内的本地地理聚类。我们使用全基因组序列数据来探索基于序列的疾病研究中病例和对照地理匹配不良的影响，并研究血统匹配的外部测序对照如何诱导假阳性关联。此外，我们还公开发布了病例和对照中的全基因组次要等位基因计数，以及基因负荷测试的结果。
The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public datasets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests.