Genome-Wide Search for Gene-Gene Interactions in Colorectal Cancer

Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<10−4). For the known locus rs10795668 (10p14), we found an interacting SNP rs367615 (5q21) with replication p = 0.01 and combined p = 4.19×10−8. Among the top marginal SNPs after LD pruning (n = 163), we identified an interaction between rs1571218 (20p12.3) and rs10879357 (12q21.1) (nominal combined p = 2.51×10−6; Bonferroni adjusted p = 0.03). Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.

全基因组关联研究（Genome-wide association studies, GWAS）已成功鉴定出多个与结直肠癌（colorectal cancer, CRC）风险相关的单核苷酸多态性（single-nucleotide polymorphisms, SNPs）。然而，当前已知的此类易感位点仅能解释极小一部分遗传风险。基因-基因交互作用（gene-gene interaction, GxG）被认为是缺失遗传力的重要来源之一。为解决这一遗传风险解释度不足的问题，本研究在发现阶段纳入8380例病例与10558例对照、验证阶段纳入2527例病例与2658例对照，开展了全基因组范围内与结直肠癌风险相关的成对GxG搜索。本研究开发了一种简便却高效的交互作用检验方法，将其命名为交互作用平均风险（Average Risk Due to Interaction, ARDI）。依托该方法，我们完成了全基因组搜索，以筛选出与14个独立区域中已报道的CRC易感位点存在GxG效应的SNPs。同时，我们还通过边际关联筛选策略，对通过筛选阈值（P<10⁻⁴）的SNPs间的交互作用进行检验，开展了另一项全基因组GxG搜索。针对已知位点rs10795668（10p14），我们发现了一个存在交互作用的SNP rs367615（5q21），其验证P值为0.01，合并P值为4.19×10⁻⁸。在经过连锁不平衡修剪（LD pruning）后的顶级边际SNPs（n=163）中，我们鉴定出rs1571218（20p12.3）与rs10879357（12q21.1）之间存在显著交互作用（名义合并P值=2.51×10⁻⁶；邦费罗尼校正P值=0.03）。本研究是首个针对CRC开展的全面GxG搜索，其研究结果可为结直肠癌的遗传病因学研究提供全新视角。