Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls.
Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls.
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DOI：
10.1038/ng.3330
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发表时间：
2015-07
期刊：
影响因子：
30.8
通讯作者：
Wallace C
中科院分区：
文献类型：
--
作者：
Fortune MD;Guo H;Burren O;Schofield E;Walker NM;Ban M;Sawcer SJ;Bowes J;Worthington J;Barton A;Eyre S;Todd JA;Wallace C
确定相关疾病的潜在因果变异是否相同可以确定多因素疾病的重叠病因。共定位方法解开了共享和不同的因果变异。然而，现有的方法需要独立的数据集。在这里，我们扩展了两种共定位方法，以允许在比较跨疾病的全基因组关联研究结果时常用的共享控制设计。我们对 1 型糖尿病 (T1D)、类风湿性关节炎、乳糜泻和多发性硬化症等四种自身免疫性疾病的分析揭示了 90 个区域与至少一种疾病相关，其中 33 个区域 (37%) 与两种或多种疾病相关。然而，对于这 33 个共享区域中的 14 个区域，有证据表明因果变异存在差异。我们在 11 个区域中发现了先前与其他三种疾病中的一种或多种相关的新疾病关联。八个 T1D 特异性区域中的四个包含已知的 2 型糖尿病候选基因：COBL、GLIS3、RNLS 和 BCAR1，表明存在共同的细胞病因。
Identifying whether potential causal variants for related diseases are shared can identify overlapping etiologies of multifactorial disorders. Colocalization methods disentangle shared and distinct causal variants. However, existing approaches require independent datasets. Here we extend two colocalization methods to allow for the shared control design commonly used in comparison of genome-wide association study results across diseases. Our analysis of four autoimmune diseases, type 1 diabetes (T1D), rheumatoid arthritis, celiac disease and multiple sclerosis, revealed 90 regions that were associated with at least one disease, 33 (37%) of which with two or more disorders. Nevertheless, for 14 of these 33 shared regions there was evidence that causal variants differed. We identified novel disease associations in 11 regions previously associated with one or more of the other three disorders. Four of eight T1D-specific regions contained known type 2 diabetes candidate genes: COBL, GLIS3, RNLS and BCAR1, suggesting a shared cellular etiology.