Characterizing the pathogenicity of genetic variants: the consequences of context.
Characterizing the pathogenicity of genetic variants: the consequences of context.
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DOI：
10.1038/s41525-023-00386-5
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发表时间：
2024-01-09
影响因子：
5.3
通讯作者：
Williams, Scott M.
中科院分区：
文献类型：
--
作者：
Ciesielski, Timothy H.;Sirugo, Giorgio;Iyengar, Sudha K.;Williams, Scott M.
除了最初发现致病性变异之外，确定变异与疾病复发相关对于理解临床影响和疾病病因学是重要的。令人遗憾的是，我们在不同情况下表征致病性的能力是有限的。在这里，我们将讨论遗传和环境背景的作用，以及它如何影响变异的突变率和结果。具体来说，遗传和环境的设置决定了遗传率，我们应该期待较低的遗传率，在不同的背景下。例如，当在两个大型生物库（UK Biobank和BioMe）中评估超过5000种ClinVar致病性和功能丧失变体时，平均外显率仅为7%。这表明，在以家庭为基础的，临床和病例对照研究，确定这些变异的参与者更同质和丰富的病因学辅助因素，和赢家的诅咒在发挥作用。我们还强调，利益的结果可能因条件而异。导致血红蛋白S的变异可以增加镰状化死亡的风险，降低疟疾死亡的风险，或增加肾脏疾病的风险，这取决于其他变异的存在，疟疾的地方性和一系列其他因素。总的来说，对从良性到致病的单一连续体的注释试图将一个复杂的现象硬塞进一个过于简单化的框架中。变异效应往往因环境而异，因此评估不同环境下的潜在致病性至关重要。没有灵丹妙药或简单的解决办法，但我们提出两项建议供考虑。首先，我们需要通过进行分层分析和开发可以检测异质性效应（例如女性与男性等位基因比例）的方法来常规评估性别和遗传祖先等背景。其次，我们需要在注释数据库中一致地记录我们所知道的关于效果修饰符的信息。这些不是唯一可能的方法，但它们开始提供创建致病性的强大注释的方法。
Beyond initial discovery of a pathogenic variant, establishing that a variant is recurrently associated with disease is important for understanding clinical impact and disease etiology. Disappointingly, our ability to characterize pathogenicity under varied circumstances is limited. Here we discuss the role of genetic and environmental background and how it affects variant penetrance and outcomes. Specifically, genetic and environmental settings determine penetrance, and we should expect lower penetrance where contexts are diverse. For example, when over 5000 ClinVar pathogenic and loss-of-function variants were assessed in two large biobanks, UK Biobank and BioMe, the mean penetrance was only 7%. This indicates that the participants in the family-based, clinical, and case-control studies that identified these variants were more homogenous and enriched for etiologic co-factors, and the winner’s curse was at play. We also emphasize that the outcome of interest can vary across conditions. The variant that causes hemoglobin S can increase the risk of death from sickling, lower the risk of death from malaria, or increase the risk of kidney disease, depending on the presence of other variants, the endemicity of malaria, and a suite of other factors. Overall, annotation on a single continuum from benign to pathogenic attempts to shoehorn a complex phenomenon into an overly simplistic framework. Variant effects often vary by context, and thus it is critical to assess potential pathogenicity in different settings. There is no panacea or easy fix, but we offer two recommendations for consideration. First, we need to routinely evaluate contexts such as sex and genetic ancestry by conducting stratified analyses and developing methods that can detect heterogenous effects (e.g. female-to-male allele proportion ratios). Second, we need to consistently document what we know about effect modifiers in our annotation databases. These are not the only possible approaches, but they begin to provide means to create robust annotations of pathogenicity.
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影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
4.5
作者：
Ciesielski TH;Pendergrass SA;White MJ;Kodaman N;Sobota RS;Huang M;Bartlett J;Li J;Pan Q;Gui J;Selleck SB;Amos CI;Ritchie MD;Moore JH;Williams SM
通讯作者：
Williams SM
影响因子：
3.7
作者：
Azevedo, Orleancio G. R.;Bolick, David T.;Guerrant, Richard L.
通讯作者：
Guerrant, Richard L.
DOI：
10.1111/ecoj.12433
发表时间：
2018-05
期刊：
Economic journal (London, England)
影响因子：
--
作者：
Depetris-Chauvin E;Weil DN
通讯作者：
Weil DN
影响因子：
--
作者：
Schiabor Barrett KM;Masnick M;Hatchell KE;Savatt JM;Banet N;Buchanan A;Willard HF
通讯作者：
Willard HF