Genome-Wide Analysis of Protein-Coding Variants in Leprosy

• Published in: Journal of investigative dermatology Vol. 137; no. 12; pp. 2544 - 2551
• Main Authors: Liu, Hong, Wang, Zhenzhen, Li, Yi, Yu, Gongqi, Fu, Xi’an, Wang, Chuan, Liu, Wenting, Yu, Yongxiang, Bao, Fangfang, Irwanto, Astrid, Liu, Jian, Chu, Tongsheng, Andiappan, Anand Kumar, Maurer-Stroh, Sebastian, Limviphuvadh, Vachiranee, Wang, Honglei, Mi, Zihao, Sun, Yonghu, Sun, Lele, Wang, Ling, Wang, Chaolong, You, Jiabao, Li, Jinghui, Foo, Jia Nee, Liany, Herty, Meah, Wee Yang, Niu, Guiye, Yue, Zhenhua, Zhao, Qing, Wang, Na, Yu, Meiwen, Yu, Wenjun, Cheng, Xiujun, Khor, Chiea Chuen, Sim, Kar Seng, Aung, Tin, Wang, Ningli, Wang, Deyun, Shi, Li, Ning, Yong, Zheng, Zhongyi, Yang, Rongde, Li, Jinlan, Yang, Jun, Yan, Liangbin, Shen, Jianping, Zhang, Guocheng, Chen, Shumin, Liu, Jianjun, Zhang, Furen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2017
• Subjects: Alleles; Asian Continental Ancestry Group; Autophagy; CARD Signaling Adaptor Proteins - genetics; Case-Control Studies; China; Cohort Studies; Endocytosis; Exome; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Leprosy - ethnology; Leprosy - genetics; Male; Phagocytosis; Polymorphism, Single Nucleotide; Reproducibility of Results; Skin - metabolism; GO; GWAS; MAF; OR; SNP
• ISSN: 0022-202X; 1523-1747; 1523-1747
• DOI: 10.1016/j.jid.2017.08.004

Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1.71 × 10–9, odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 × 10–8, OR = 4.75); three low-frequency variants: rs76418789 in IL23R (P = 1.03 × 10–10, OR = 1.36), rs146466242 in FLG (P = 3.39 × 10–12, OR = 1.45), and rs55882956 in TYK2 (P = 1.04 × 10–6, OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 × 10–9, OR = 1.14) and rs181206 in IL27 (P = 1.08 × 10–7, OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.