A two-stage inter-rater approach for enrichment testing of variants associated with multiple traits.
A two-stage inter-rater approach for enrichment testing of variants associated with multiple traits.
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DOI：
10.1038/ejhg.2016.171
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Barroso I
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文献类型：
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作者：
Asimit JL;Payne F;Morris AP;Cordell HJ;Barroso I
共同的基因病因学可能解释了疾病在个体中共同发生的频率比预期的更高。在确定两个性状之间共有的相关变异时，一个目标是确定这种重叠是否可以用特定的基因组特征(如功能注释)来解释。在临床研究中，评价者之间达成一致的方法评估专家对每个受试者是否存在复杂疾病的意见的一致性。我们将两阶段评分者间协议模型应用于遗传关联设置，以识别预测重叠变异的特征，同时考虑它们的边缘特征关联。由此产生的校正重叠和边际富集度检验(COMET)也评估了个体性状水平的富集度。可以同时测试多个类别，并且该方法在计算上是有效的，不需要排列来评估重要性。在一项广泛的模拟研究中，彗星以高功率确定了预测浓缩的特征，并具有经过很好校准的I类误差。相比之下，与单一性状丰富测试重叠的测试夸大了第一类错误。使用一组功能注释类别作为预测因子，Comet被应用于三个血糖性状，随后进一步分析了组织特定的调节变体。这一结果支持了先前的发现，即胰岛中的调节变量富含与空腹血糖相关的变量，并揭示了与血糖相关的变量特征之间的差异/相似之处。此外，尽管胰岛的调控变异与空腹血糖和空腹胰岛素略有关联，但这些特征之间的共同变异并没有丰富。
Shared genetic aetiology may explain the co-occurrence of diseases in individuals more often than expected by chance. On identifying associated variants shared between two traits, one objective is to determine whether such overlap may be explained by specific genomic characteristics (eg, functional annotation). In clinical studies, inter-rater agreement approaches assess concordance among expert opinions on the presence/absence of a complex disease for each subject. We adapt a two-stage inter-rater agreement model to the genetic association setting to identify features predictive of overlap variants, while accounting for their marginal trait associations. The resulting corrected overlap and marginal enrichment test (COMET) also assesses enrichment at the individual trait level. Multiple categories may be tested simultaneously and the method is computationally efficient, not requiring permutations to assess significance. In an extensive simulation study, COMET identifies features predictive of enrichment with high power and has well-calibrated type I error. In contrast, testing for overlap with a single-trait enrichment test has inflated type I error. COMET is applied to three glycaemic traits using a set of functional annotation categories as predictors, followed by further analyses that focus on tissue-specific regulatory variants. The results support previous findings that regulatory variants in pancreatic islets are enriched for fasting glucose-associated variants, and give insight into differences/similarities between characteristics of variants associated with glycaemic traits. Also, despite regulatory variants in pancreatic islets being enriched for variants that are marginally associated with fasting glucose and fasting insulin, there is no enrichment of shared variants between the traits.