Pathogenicity of De Novo Rare Variants: Challenges and Opportunities.
Pathogenicity of De Novo Rare Variants: Challenges and Opportunities.
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新的罕见变异的致病性：挑战和机遇。
DOI：
10.1161/circgenetics.117.002013
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Mani,Arya
中科院分区：
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作者：
Mani,Arya
2 Mani De Novo 稀有变种：人口增长的利弊。 5 这些变体的效应大小明显大于常见变体的效应大小，但尚未达到独立因果关系的程度。因此，分离分析必须被突变负荷分析取代，成为主要的分析方法。由于效应大小适中且等位基因频率较低，因此疾病关联研究需要数万至数十万个体的大样本量。同样明显的是，用于测试遗传-表型关联的简单回归模型对于罕见变异的作用力不足。 6 具体而言，与常见变体相比，罕见独立变体的数量较多，这极大地增加了多次测试校正的要求。为了提高统计功效，通常使用基因内多个罕见变异的组合信息。这些方法分为 2 个主要类别：(1) 负担测试，将遗传变异分解为单个分数，假设测试的变异具有相同的方向和影响程度。这种方法忽略了同一基因中的某些变异可能是中性的或具有相反作用的可能性。(2)允许不同方向的影响的方差分量测试，即风险和保护性等位基因。不幸的是，这个分析工具以及该分析工具的许多分支都远非完美，并且已经显示出重大的实际局限性。事实上，该领域的大部分成功都来自于候选基因和 GWAS 位点基因中罕见变异的病例对照关联研究中的下一代测序。 7 毫不奇怪，分析技术的局限性导致基因研究中广泛使用宽松的标准，并随后产生假阳性结果。在单个病例和小规模研究中发现的许多遗传变异已被报告为独立致病，无需使用严格的标准。新生突变因其发生率极低而代表了罕见遗传变异的最独特形式。在小型家庭研究和大型病例对照三人研究中，这些唾手可得的成果实际上已被认为是致病的。在美国医学遗传学和基因组学学院的遗传分类指南中，这些变异被认为是致病性的有力支持证据。 1 这些变异的鉴定对于先天性心脏病 (CHD) 等严重性状的遗传研究非常重要：这是一种已知基因很少的复杂性状。三项研究使用了病例和父母的遗传数据，确实为各种先心病的致病性提供了重要的见解。 8 根据这些研究的估计，已识别的新发变异约占严重先心病的 10%。据估计，对于综合征型和孤立型 CHD，心脏高表达基因中破坏性从头变异的发生率分别高达 20% 和 2%。 9 一个尚未解答的关键问题是这些变异是否独立引起疾病或仅导致疾病。从头突变不能解释疾病在家族中的复发，因此，它们的因果关系无法通过分离分析来验证。由于众所周知的瓶颈效应或遗传漂变，罕见变异可以在某些群体中得到修复。这种限制可能会导致假阳性结果，特别是当病例对照人群种族不匹配或规模较小时。特别是，变体中存在许多与疾病相关的从头变体
2 Mani De Novo Rare Variants: The Pros and Cons population growth. 5 The effect sizes of these variants are significantly larger than those of common variants but not to the extent to be independently causal. Hence, segregation analysis had to be replaced by mutation burden analysis as the main analytic approach. Because of the modest effect sizes and low allele frequencies, large sample sizes of tens to hundreds of thousands of individuals became necessary for disease-association studies. It was also apparent that the simple regression models used for testing of genetic–phenotype associations are underpowered for rare variants. 6 Specifically, the higher number of rare independent variants compared with common variants dramatically increases the requirement for multiple testing corrections. To increase the statistical power, combined information from multiple rare variants within a gene is often used. These approaches are grouped in 2 main categories:(1) the burden test that collapses genetic variants into a single score, assuming that tested variants have the same direction and magnitude of effect. This approach ignores the possibility that certain variants in the same gene may be neutral or have opposite effects.(2) Variance-component test that allows for different directions of effect, that is, risk and protective alleles. Unfortunately, this and many offshoots of this analytic tool are all far from perfection and have shown major practical limitations. In fact, most success in this venue has come from nextgeneration sequencing in case–control association studies of rare variants in candidate genes and genes in GWAS loci. 7 Not unexpectedly, the limitations of the analytic techniques have led to widespread use of lenient criteria in genetic studies and subsequent generation of false-positive results. Many genetic variants identified in single cases and small-size studies have been reported as independently disease causing without use of stringent criteria.De novo mutations represent the most unique form of rare genetic variation because of their extremely low incidence. These low hanging fruits have been practically considered as pathogenic, in both small family-based and large case–control trio studies. In genetic classification guidelines of the American College of Medical Genetics and Genomics, these variants have been considered strong supporting evidence for pathogenicity. 1 Identification of these variants has been of great interest for genetic studies of severe traits such as congenital heart disease (CHD): a complex trait with few known genes. Trio studies, which use genetic data from case and parents, have indeed provided important insight into the pathogenicity of various CHD. 8 As estimated by these studies, the identified de novo variants account for≈ 10% of severe CHD. The prevalence of damaging de novo variants in highly heart expressed genes have been estimated to be as high as 20% and 2% for syndromic and isolated CHD, respectively. 9 One key unanswered question is whether these variants are independently disease causing or only contributing to the disease. De novo mutations do not explain the recurrence of the disease in families, and consequently, their causality cannot be verified by segregation analysis. Rare variants can be fixed in certain populations because of well-known bottle-neck effect or genetic drift. Such limitation can give rise to false-positive results, especially when case–control populations are not ethnically matched or are small in size. Particularly, the presence of numerous disease-associated de novo variants in variant