Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types.
Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types.
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DOI：
10.1038/ng.3795
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发表时间：
2017-04
期刊：
影响因子：
30.8
通讯作者：
Cotsapas C
中科院分区：
文献类型：
--
作者：
Chun S;Casparino A;Patsopoulos NA;Croteau-Chonka DC;Raby BA;De Jager PL;Sunyaev SR;Cotsapas C
由全基因组关联研究（GWAS）确定的大多数自身免疫疾病风险效应定位于具有基因调控活性的开放染色质。GWAS基因座还富含表达数量性状位点（eqtl），这表明大多数风险变异改变了基因表达。然而，由于因果变异难以识别，而且cis- eqtl频繁发生，因此确定与疾病相关的基因调控变化的具体实例仍然具有挑战性。在这里，我们使用了一种新的联合似然框架，其分辨率比以前的方法更高，以确定自身免疫性疾病风险和eQTL由单一共享遗传效应驱动的位点。使用来自三个主要免疫亚群的eqtl，我们发现只有~ 25%的基因座具有相同的效应。因此，我们表明，一小部分基因调控变化提示了疾病风险的强有力的机制假设，但我们得出结论，大多数风险机制不太可能涉及基础基因表达的变化。
Most autoimmune-disease-risk effects identified by genome-wide association studies (GWAS) localize to open chromatin with gene-regulatory activity. GWAS loci are also enriched in expression quantitative trait loci (eQTLs), thus suggesting that most risk variants alter gene expression,. However, because causal variants are difficult to identify, andcis-eQTLs occur frequently, it remains challenging to identify specific instances of disease-relevant changes to gene regulation. Here, we used a novel joint likelihood framework with higher resolution than that of previous methods to identify loci where autoimmune-disease risk and an eQTL are driven by a single shared genetic effect. Using eQTLs from three major immune subpopulations, we found shared effects in only ∼25% of the loci examined. Thus, we show that a fraction of gene-regulatory changes suggest strong mechanistic hypotheses for disease risk, but we conclude that most risk mechanisms are not likely to involve changes in basal gene expression.