Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the FTO gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting IRX3 and IRX5 from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.

虽然编码变体通常在多个组织中具有多效性，但非编码变体被认为通过特定组织和基因表达的时间调节来介导其表型效应。在这里，我们研究了FTO基因内与肥胖风险密切相关的基因组区域的遗传和功能结构。我们表明，常见单倍型的多个变体改变了多个针对兆碱基距离的IRX3和IRX5增强子的调控特性。我们证明这些增强子影响多个组织（包括脂肪和大脑）的基因表达，并在有限的时间窗口内赋予调节作用。我们的数据表明，疾病相关位点的遗传结构可能涉及广泛的多效性、等位基因异质性、跨组织共享的等位基因效应以及时间限制效应。