Sandor Cynthia, Beer Nicola L, Webber Caleb
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
PLoS Comput Biol. 2017 Oct 23;13(10):e1005816. doi: 10.1371/journal.pcbi.1005816. eCollection 2017 Oct.
Type 2 Diabetes (T2D) constitutes a global health burden. Efforts to uncover predisposing genetic variation have been considerable, yet detailed knowledge of the underlying pathogenesis remains poor. Here, we constructed a T2D phenotypic-linkage network (T2D-PLN), by integrating diverse gene functional information that highlight genes, which when disrupted in mice, elicit similar T2D-relevant phenotypes. Sensitising the network to T2D-relevant phenotypes enabled significant functional convergence to be detected between genes implicated in monogenic or syndromic diabetes and genes lying within genomic regions associated with T2D common risk. We extended these analyses to a recent multiethnic T2D case-control exome of 12,940 individuals that found no evidence of T2D risk association for rare frequency variants outside of previously known T2D risk loci. Examining associations involving protein-truncating variants (PTV), most at low population frequencies, the T2D-PLN was able to identify a convergent set of biological pathways that were perturbed within four of five independent T2D case/control ethnic sets of 2000 to 5000 exomes each. These same pathways were found to be over-represented among both known monogenic or syndromic diabetes genes and genes within T2D-associated common risk loci. Our study demonstrates convergent biology amongst variants representing different classes of T2D genetic risk. Although convergence was observed at the pathway level, few of the contributing genes were found in common between different cohorts or variant classes, most notably between the exome variant sets which suggests that future rare variant studies may be better focusing their power onto a single population of recent common ancestry.
2型糖尿病（T2D）构成了一项全球健康负担。人们为揭示易感性基因变异付出了巨大努力，但对潜在发病机制的详细了解仍然匮乏。在此，我们构建了一个T2D表型连锁网络（T2D-PLN），通过整合多种基因功能信息来突出那些在小鼠中被破坏时会引发类似T2D相关表型的基因。使该网络对T2D相关表型敏感，能够检测到单基因或综合征性糖尿病相关基因与T2D常见风险相关基因组区域内的基因之间存在显著的功能趋同。我们将这些分析扩展到了一项针对12940名个体的近期多民族T2D病例对照外显子组研究，该研究未发现除先前已知的T2D风险位点之外的罕见频率变异与T2D风险存在关联的证据。在检查涉及蛋白截短变异（PTV）的关联时，大多数PTV在人群中的频率较低，T2D-PLN能够识别出一组在五个独立的T2D病例/对照种族组（每组2000至5000个外显子组）中的四个组内受到干扰的趋同生物途径。发现这些相同的途径在已知的单基因或综合征性糖尿病基因以及T2D相关常见风险位点内的基因中均过度富集。我们的研究证明了代表不同类别的T2D遗传风险的变异之间存在趋同生物学现象。尽管在途径水平上观察到了趋同，但在不同队列或变异类别之间，尤其是在外显子变异组之间，很少发现有共同的贡献基因，这表明未来的罕见变异研究可能最好将其研究重点放在具有近期共同祖先的单一人群上。
