X-chromosome association study reveals genetic susceptibility loci of nasopharyngeal carcinoma

• Main Authors: Zuo, Xiao-Yu, Feng, Qi-Sheng, Sun, Jian, Wei, Pan-Pan, Chin, Yoon Ming, Guo, Yun-Miao, Xia, Yun-Fei, Li, Bo, Xia, Xiao-Jun, Jia, Wei-Hua, Liu, Jian-Jun, Khoo, Alan Soo-Beng, Mushiroda, Taisei, Ng, Ching Ching, Su, Wen-Hui, Zeng, Yi-Xin, Bei, Jin-Xin
• Format: Article
• Published: BMC 2019
• Subjects: Q Science (General); QH Natural history
• Online Access: http://eprints.um.edu.my/22883/; https://doi.org/10.1186/s13293-019-0227-9

Background: The male predominance in the incidence of nasopharyngeal carcinoma (NPC) suggests the contribution of the X chromosome to the susceptibility of NPC. However, no X-linked susceptibility loci have been examined by genome-wide association studies (GWASs) for NPC by far. Methods: To understand the contribution of the X chromosome in NPC susceptibility, we conducted an X chromosome-wide association analysis on 1615 NPC patients and 1025 healthy controls of Guangdong Chinese, followed by two validation analyses in Taiwan Chinese (n = 562) and Malaysian Chinese (n = 716). Results: Firstly, the proportion of variance of X-linked loci over phenotypic variance was estimated in the discovery samples, which revealed that the phenotypic variance explained by X chromosome polymorphisms was estimated to be 12.63% (non-dosage compensation model) in males, as compared with 0.0001% in females. This suggested that the contribution of X chromosome to the genetic variance of NPC should not be neglected. Secondly, association analysis revealed that rs5927056 in DMD gene achieved X chromosome-wide association significance in the discovery sample (OR = 0.81, 95% CI 0.73-0.89, P = 1.49 × 10 -5 ). Combined analysis revealed rs5927056 for DMD gene with suggestive significance (P = 9.44 × 10 -5 ). Moreover, the female-specific association of rs5933886 in ARHGAP6 gene (OR = 0.62, 95%CI: 0.47-0.81, P = 4.37 × 10 -4 ) was successfully replicated in Taiwan Chinese (P = 1.64 × 10 -2 ). rs5933886 also showed nominally significant gender × SNP interaction in both Guangdong (P = 6.25 × 10 -4 ) and Taiwan datasets (P = 2.99 × 10 -2 ). Conclusion: Our finding reveals new susceptibility loci at the X chromosome conferring risk of NPC and supports the value of including the X chromosome in large-scale association studies.