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A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals.
Genetic Epidemiology ( IF 2.1 ) Pub Date : 2019-06-06 , DOI: 10.1002/gepi.22214
Jenna C Carlson 1, 2 , Deepti Anand 3 , Azeez Butali 4 , Carmen J Buxo 5 , Kaare Christensen 6 , Frederic Deleyiannis 7 , Jacqueline T Hecht 8 , Lina M Moreno 9 , Ieda M Orioli 10, 11 , Carmencita Padilla 12, 13 , John R Shaffer 2, 14 , Alexandre R Vieira 14 , George L Wehby 15 , Seth M Weinberg 2, 14, 16 , Jeffrey C Murray 17 , Terri H Beaty 18 , Irfan Saadi 19 , Salil A Lachke 3, 20 , Mary L Marazita 2, 14, 16 , Eleanor Feingold 1, 2, 16 , Elizabeth J Leslie 21
Affiliation  

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.

中文翻译:

口面裂 GWAS 信号中表型异质性的系统遗传分析和可视化。

表型异质性是复杂性状的标志,这些性状的遗传学研究可能将其作为单一诊断实体或通过分析特定成分来关注。例如,在口面裂(OFC)中,三种亚型——唇裂(CL)、唇腭裂(CLP)和腭裂(CP)已经被单独和组合研究。为了进一步剖析 OFC 的遗传结构以及给定的相关位点如何促成性状的不同亚型,我们开发了一个框架,用于量化和解释复杂性状中亚型特异性或共享遗传效应的证据。我们应用这种技术创建了 30 个基因位点与三种 OFC 亚型关联的“裂缝图”。除了新的关联之外,我们还发现了具有亚型特异性效应的基因座(例如,GRHL3 [CP]、WNT5A [CLP]),以及与两种或所有三种亚型相关的基因座。我们将这些结果与小鼠颅面基因表达数据集进行交叉引用,从而确定了其他有希望的候选基因。然而,我们发现 OFC 亚型和表达模式之间没有很强的相关性。总的来说,裂隙图揭示了亚型特异性和共享遗传效应在 OFC 结构中都不是孤立运作的。我们的方法可以轻松应用于具有不同表型亚群的任何复杂性状。
更新日期:2019-11-01
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