Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.
Fano Labs, Hong Kong SAR, China.
Sci Rep. 2022 Nov 28;12(1):20423. doi: 10.1038/s41598-022-24077-w.
Common variants in RET and NRG1 have been associated with Hirschsprung disease (HSCR), a congenital disorder characterised by incomplete innervation of distal gut, in East Asian (EA) populations. However, the allelic effects so far identified do not fully explain its heritability, suggesting the presence of epistasis, where effect of one genetic variant differs depending on other (modifier) variants. Few instances of epistasis have been documented in complex diseases due to modelling complexity and data challenges. We proposed four epistasis models to comprehensively capture epistasis for HSCR between and within RET and NRG1 loci using whole genome sequencing (WGS) data in EA samples. 65 variants within the Topologically Associating Domain (TAD) of RET demonstrated significant epistasis with the lead enhancer variant (RET+3; rs2435357). These epistatic variants formed two linkage disequilibrium (LD) clusters represented by rs2506026 and rs2506028 that differed in minor allele frequency and the best-supported epistatic model. Intriguingly, rs2506028 is in high LD with one cis-regulatory variant (rs2506030) highlighted previously, suggesting that detected epistasis might be mediated through synergistic effects on transcription regulation of RET. Our findings demonstrated the advantages of WGS data for detecting epistasis, and support the presence of interactive effects of regulatory variants in RET for HSCR.
RET 和 NRG1 中的常见变异与先天性巨结肠症（HSCR）有关，这是一种以远端肠道神经支配不完全为特征的先天性疾病，在东亚（EA）人群中较为常见。然而，迄今为止发现的等位基因效应并不能完全解释其遗传性，这表明存在上位性，即一种遗传变异的效应取决于其他（修饰）变异。由于建模复杂性和数据挑战，在复杂疾病中很少有上位性的例子被记录下来。我们提出了四个上位性模型，使用 EA 样本中的全基因组测序（WGS）数据，全面捕捉 RET 和 NRG1 基因座之间和内部的 HSCR 上位性。在 RET 的拓扑关联域（TAD）内的 65 个变异与主要增强子变异（RET+3；rs2435357）表现出显著的上位性。这些上位性变异形成了两个连锁不平衡（LD）簇，由 rs2506026 和 rs2506028 代表，它们在次要等位基因频率和最佳支持的上位性模型上存在差异。有趣的是，rs2506028 与之前突出显示的一个顺式调节变异（rs2506030）高度 LD，这表明检测到的上位性可能是通过对 RET 转录调控的协同作用介导的。我们的研究结果表明，WGS 数据在检测上位性方面具有优势，并支持 RET 对 HSCR 的调节变异存在相互作用效应。
