Yan Zhang1, Jing Yang1, Jing Zhang1, Liangdan Sun2, Nattiya Hirankarn3, Hai-Feng Pan4, Chak Sing Lau5, Tak Mao Chan5, Tsz Leung Lee1, Alexander Moon Ho Leung6, Chi Chiu Mok7, Lu Zhang1, Yongfei Wang1, Jiangshan Jane Shen1, Sik Nin Wong8, Ka Wing Lee9, Marco Hok Kung Ho1, Pamela Pui Wah Lee1, Brian Hon-Yin Chung1, Chun Yin Chong1, Raymond Woon Sing Wong5, Mo Yin Mok5, Wilfred Hing Sang Wong1, Kwok Lung Tong10, Niko Kei Chiu Tse11, Xiang-Pei Li12, Yingyos Avihingsanon13, Pornpimol Rianthavorn14, Thavatchai Deekajorndej14, Kanya Suphapeetiporn14, Vorasuk Shotelersuk14, Shirley King Yee Ying10, Samuel Ka Shun Fung10, Wai Ming Lai11, Chun-Ming Wong15, Irene Oi Lin Ng15, Maria-Merce Garcia-Barcelo16, Stacey S Cherny17, Yong Cui2, Pak Chung Sham18, Sen Yang2, Dong-Qing Ye3, Xue-Jun Zhang2, Yu Lung Lau1, Wanling Yang19. 1. Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong. 2. State Key Laboratory Incubation Base of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China. 3. Lupus Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 4. Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China. 5. Department of Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong. 6. Department of Medicine, Queen Elizabeth Hospital, Hong Kong, Hong Kong. 7. Department of Medicine, Tuen Mun Hospital, New Territory, Hong Kong, Hong Kong. 8. Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong, Hong Kong. 9. Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, Hong Kong. 10. Department of Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong. 11. Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong. 12. Department of Rheumatology, Anhui Provincial Hospital, Hefei, China. 13. Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 14. Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 15. Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong. 16. Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong. 17. Department of Psychiatry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong. 18. Department of Psychiatry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong LKS Faculty of Medicine, Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, Hong Kong. 19. Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong LKS Faculty of Medicine, Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, Hong Kong.
Abstract
OBJECTIVES: Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility. METHODS: The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction. RESULTS: Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets. CONCLUSIONS: Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
OBJECTIVES: Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility. METHODS: The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction. RESULTS: Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets. CONCLUSIONS: Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Agnieszka H Ludwig-Słomczyńska; Michał T Seweryn; Przemysław Kapusta; Ewelina Pitera; Urszula Mantaj; Katarzyna Cyganek; Paweł Gutaj; Łucja Dobrucka; Ewa Wender-Ożegowska; Maciej T Małecki; Paweł P Wołkow Journal: Mol Med Date: 2021-01-20 Impact factor: 6.354
Authors: Xiaoming Lu; Xiaoting Chen; Carmy Forney; Omer Donmez; Daniel Miller; Sreeja Parameswaran; Ted Hong; Yongbo Huang; Mario Pujato; Tareian Cazares; Emily R Miraldi; John P Ray; Carl G de Boer; John B Harley; Matthew T Weirauch; Leah C Kottyan Journal: Nat Commun Date: 2021-03-12 Impact factor: 17.694