LoFtool: a gene intolerance score based on loss-of-function variants in 60 706 individuals
LoFtool: a gene intolerance score based on loss-of-function variants in 60 706 individuals
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DOI：
10.1093/bioinformatics/btv602
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发表时间：
2017-02-15
期刊：
影响因子：
5.8
通讯作者：
Groop, Leif
中科院分区：
文献类型：
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作者：
Fadista, Joao;Oskolkov, Nikolay;Groop, Leif
动机：损耗的功能（LoF）突变可以提供一个排名的基因功能不耐受，因此易感性diseases.Results：在这里，我们已经研究了LoF突变在60 706无关的个人，并表明，最不耐受的四分位数的排名基因是丰富的罕见和早发性疾病，并解释了87%的从头单倍不足OMIM突变，17%以上，比任何其他基因评分工具。我们检测到脑中耗尽的LoF基因表达的特定富集（比值比=1.5; P值= 4.2e-07）。通过在最近的四项研究中寻找与神经发育障碍相关的从头单倍不足突变，我们能够解释其中的81%。总之，这项研究提供了一种新的基因不耐受性排名系统，称为LoFtool，这可能有助于根据其LoF不耐受性和组织表达对感兴趣的基因进行排名。可用性和实施：LoFtool基因评分可在补充数据中获得。
Motivation: Depletion of loss-of-function (LoF) mutations may provide a rank of genic functional intolerance and consequently susceptibility to disease.Results: Here we have studied LoF mutations in 60 706 unrelated individuals and show that the most intolerant quartile of ranked genes is enriched in rare and early onset diseases and explains 87% of de novo haploinsufficient OMIM mutations, 17% more than any other gene scoring tool. We detected particular enrichment in expression of the depleted LoF genes in brain (odds ratio =1.5; P-value = 4.2e -07). By searching for de novo haploinsufficient mutations putatively associated with neurodevelopmental disorders in four recent studies, we were able to explain 81% of them. Taken together, this study provides a novel gene intolerance ranking system, called LoFtool, which may help in ranking genes of interest based on their LoF intolerance and tissue expression. Availability and implementation: The LoFtool gene scores are available in the Supplementary data.