Q Zhen1,2,3,4, Y Zhang1, Y Yu1,2,3,4, H Yang1, T Zhang5, X Li13, X Mo1, B Li1,6, J Wu7, Y Liang1, H Ge1,2,3,4, Q Xu1,2,3,4, W Chen15, W Qian8, H Xu1, G Chen1,2,3,4, B Bai9, J Zhang10, Y Lu12, S Chen1,2,3,4, H Zhang1,2,3,4, Y Zhang1, X Chen12, X Li13, X Jin14, X Lin15, L Yong1,2,3,4, M Fang16, J Zhao17, Y Lu12, S Wu18, D Jiang16, J Shi19, H Cao1, Y Qiu20, S Li26, X Kang17, J Shen1, H Ma22, S Sun1, Y Fan21, W Chen15, M Bai1, Q Jiang23, W Li24, C Lv25, S Li26, M Chen27, F Li28, Y Li10, L Sun1,2,3,4. 1. Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, China. 2. Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China. 3. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China. 4. Anhui Provincial Institute of Translational Medicine, Hefei, China. 5. Department of Biology, University of Copenhagen, Copenhagen, Denmark. 6. The Comprehensive Lab, College of Basic, Anhui Medical University, Hefei, China. 7. Department of Dermatology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, China. 8. Institute of Dermatology, Guangzhou Medical University, Guangzhou, China. 9. Department of Dermatology at No.2 Hospital, Harbin Medical University, Harbin, Heilongjiang, China. 10. Department of Dermatology, The 195 Hospital of Chinese People's Liberation Army, Xianning, Hubei, China. 11. Dermatology Department of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. 12. Department of Dermatology at Chengdu Second People's Hospital, Sichuan, Chengdu, China. 13. Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. 14. School of Medicine, South China University of Technology, Guangzhou, Guangdong, China. 15. Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China. 16. Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture, Fisheries College, Jimei University, Xiamen, Fujian, China. 17. Department of Dermatology, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, Urumqi, China. 18. Urology Institute of Shenzhen University, The Luohu Affiliated Hospital of Shenzhen University, Shenzhen, China. 19. Department of Dermatology at the Second Affiliated Hospital, Baotou Medical College, University of Science and Technology of The Inner Mongolia, Baotou, Inner Mongolia, China. 20. Department of Dermatology, Jining No. 1 People's Hospital, Shandong, China. 21. Department of Dermatology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China. 22. Department of Dermatology, the 2nd Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China. 23. Donggang Center Hospital, Dandong, Liaoning, China. 24. Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, Shandong, China. 25. Dalian Dermatosis Hospital, Dalian, Liaoning, China. 26. Department of Dermatology at No.1 Hospital of Jilin University, Changchun, Jilin, China. 27. Dermatology Hospital, Peking Union Medical College, Beijing, China. 28. Department of Dermatology, The Second Hospital of Jilin University, Changchun, China.
Abstract
BACKGROUND: Structural variations (SVs; defined as DNA variants ≥ 50 base pairs) have been associated with various complex human diseases. However, research to screen the whole genome for SVs predisposing to psoriasis is lacking. OBJECTIVES: To investigate the association of SVs and psoriasis. METHODS: Using imputation, we performed a genome-wide screen of SVs on five independent cohorts with 45 386 participants from the Han Chinese population. Fine-mapping analysis, genetic interaction analysis and RNA expression analysis were conducted to explore the mechanism of SVs. RESULTS: In total, we obtained 4535 SVs and identified two novel deletions [esv3608550, odds ratio (OR) 2·73 (P < 2·00 × 10-308 ); esv3608542, OR 0·47 (P = 7·40 × 10-28 )] at 6q21·33 (major histocompatibility complex), one novel Alu element insertion [esv3607339; OR 1·22 (P = 1·18 × 10-35 )] at 5q33·3 (IL12B) and confirmed one previously reported deletion [esv3587563; OR 1·30 (P = 9·52 × 10-60 )] at 1q21·2 (late cornified envelope) for psoriasis. Fine-mapping analysis including single-nucleotide polymorphisms (SNPs) and small insertions/deletions revealed that esv3608550 and esv3608542 were independently associated with psoriasis, and a novel independent SNP [rs9378188; OR, 1·65 (P = 3·46 × 10-38 )] was identified at 6q21·33. By genetic interaction analysis and RNA expression analysis, we speculate that the association of two deletions at 6q21·33 with psoriasis might relate to their influence on the expression of HLA-C. CONCLUSIONS: We have constructed the most comprehensive SV map for psoriasis thus far and enriched the genetic architecture and pathogenesis of psoriasis, and highlight the non-negligible impact of SVs on complex diseases.
BACKGROUND: Structural variations (SVs; defined as DNA variants ≥ 50 base pairs) have been associated with various complex human diseases. However, research to screen the whole genome for SVs predisposing to psoriasis is lacking. OBJECTIVES: To investigate the association of SVs and psoriasis. METHODS: Using imputation, we performed a genome-wide screen of SVs on five independent cohorts with 45 386 participants from the Han Chinese population. Fine-mapping analysis, genetic interaction analysis and RNA expression analysis were conducted to explore the mechanism of SVs. RESULTS: In total, we obtained 4535 SVs and identified two novel deletions [esv3608550, odds ratio (OR) 2·73 (P < 2·00 × 10-308 ); esv3608542, OR 0·47 (P = 7·40 × 10-28 )] at 6q21·33 (major histocompatibility complex), one novel Alu element insertion [esv3607339; OR 1·22 (P = 1·18 × 10-35 )] at 5q33·3 (IL12B) and confirmed one previously reported deletion [esv3587563; OR 1·30 (P = 9·52 × 10-60 )] at 1q21·2 (late cornified envelope) for psoriasis. Fine-mapping analysis including single-nucleotide polymorphisms (SNPs) and small insertions/deletions revealed that esv3608550 and esv3608542 were independently associated with psoriasis, and a novel independent SNP [rs9378188; OR, 1·65 (P = 3·46 × 10-38 )] was identified at 6q21·33. By genetic interaction analysis and RNA expression analysis, we speculate that the association of two deletions at 6q21·33 with psoriasis might relate to their influence on the expression of HLA-C. CONCLUSIONS: We have constructed the most comprehensive SV map for psoriasis thus far and enriched the genetic architecture and pathogenesis of psoriasis, and highlight the non-negligible impact of SVs on complex diseases.