The development of next-generation sequencing technologies has opened-up some new possibilities to explore the contribution of genetic variants to human diseases and in particular that of rare variants. Statistical methods have been developed to test for association with rare variants that require the definition of testing units and, in these testing units, the selection of qualifying variants to include in the test. In the coding regions of the genome, testing units are usually the different genes and qualifying variants are selected based on their functional effects on the encoded proteins. Extending these tests to the non-coding regions of the genome is challenging. Testing units are difficult to define as the non-coding genome organisation is still rather unknown. Qualifying variants are difficult to select as the functional impact of non-coding variants on gene expression is hard to predict. These difficulties could explain why very few investigators so far have analysed the non-coding parts of their whole genome sequencing data. These non-coding parts yet represent the vast majority of the genome and some studies suggest that they could play a major role in disease susceptibility. In this review, we discuss recent experimental and statistical developments to gain knowledge on the non-coding genome and how this knowledge could be used to include rare non-coding variants in association tests. We describe the few studies that have considered variants from the non-coding genome in association tests and how they managed to define testing units and select qualifying variants.

下一代测序技术的发展为探索遗传变异对人类疾病特别是稀有变异的贡献开辟了一些新的可能性。已经开发出统计方法来测试与稀有变异的关联，这些变异需要定义测试单位，并且在这些测试单位中，选择要包括在测试中的合格变异。在基因组的编码区域中，测试单位通常是不同的基因，并根据其对编码蛋白质的功能影响来选择合格的变体。将这些测试扩展到基因组的非编码区具有挑战性。由于非编码基因组的组织仍然相当未知，因此很难定义测试单位。很难选择合格的变体，因为很难预测非编码变体对基因表达的功能影响。这些困难可以解释为什么迄今为止很少有研究者分析了他们整个基因组测序数据的非编码部分。这些非编码部分仍然代表了基因组的绝大部分，一些研究表明它们可能在疾病易感性中起主要作用。在这篇综述中，我们讨论了最近的实验和统计发展，以获取有关非编码基因组的知识，以及如何将该知识用于在关联测试中包括罕见的非编码变体。我们描述了在关联测试中考虑非编码基因组变体的少数研究，以及它们如何设法定义测试单位和选择合格变体。