Li Xin, Liang Liming, De Vivo Immaculata, Tang Jean Y, Han Jiali
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Oncotarget. 2016 Jun 14;7(24):36885-36895. doi: 10.18632/oncotarget.9212.
Genome-wide association studies (GWASs) have primarily focused on the association between individual genetic markers and risk of disease. We applied a novel approach that integrates skin expression-related single-nucleotide polymorphisms (eSNPs) and pathway analysis for GWAS of basal cell carcinoma (BCC) to identify potential novel biological pathways. We evaluated the associations between 70,932 skin eSNPs and risk of BCC among 2,323 cases and 7,275 controls of European ancestry, and then assigned them to the pathways defined by KEGG, GO, and BioCarta databases. Three KEGG pathways (colorectal cancer, actin cytoskeleton, and BCC), two GO pathways (cellular component disassembly in apoptosis, and nucleus organization), and four BioCarta pathways (Ras signaling, T cell receptor signaling, natural killer cell-mediated cytotoxicity, and links between Pyk2 and Map Kinases) showed significant association with BCC risk with p-value<0.05 and FDR<0.2. These pathways also ranked at top in sensitivity analyses. Two positive controls in KEGG, the hedgehog pathway and the BCC pathway, showed significant association with BCC risk in both main and sensitivity analyses. Our results indicate that SNPs that are undetectable by conventional GWASs are significantly associated with BCC when tested as pathways. Biological studies of these gene groups suggest their potential roles in the etiology of BCC.
全基因组关联研究（GWASs）主要聚焦于个体遗传标记与疾病风险之间的关联。我们应用了一种新方法，该方法整合了与皮肤表达相关的单核苷酸多态性（eSNPs）以及用于基底细胞癌（BCC）GWAS的通路分析，以识别潜在的新生物通路。我们评估了2323例BCC病例和7275例欧洲血统对照中70932个皮肤eSNPs与BCC风险之间的关联，然后将它们分配到由KEGG、GO和BioCarta数据库定义的通路中。三条KEGG通路（结直肠癌、肌动蛋白细胞骨架和BCC）、两条GO通路（细胞凋亡中的细胞成分分解和细胞核组织）以及四条BioCarta通路（Ras信号传导、T细胞受体信号传导、自然杀伤细胞介导的细胞毒性以及Pyk2与丝裂原活化蛋白激酶之间的联系）显示与BCC风险显著相关，p值<0.05且错误发现率<0.2。这些通路在敏感性分析中也排名靠前。KEGG中的两个阳性对照，即刺猬信号通路和BCC通路，在主要分析和敏感性分析中均显示与BCC风险显著相关。我们的结果表明，常规GWAS检测不到的SNPs作为通路进行测试时与BCC显著相关。对这些基因组的生物学研究表明它们在BCC病因学中的潜在作用。
