Meta-analysis of 208,370 East Asians identifies 113 genomic loci and yields new non-immune cell relevant biological insights for systemic lupus erythematosus

Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci[1][1]-[8][2]. Nevertheless, these loci only partially explain SLE heritability and provide limited biological insight. We report the largest study of SLE in East Asians (13,377 cases and 194,993 controls), identifying 233 association signals within 113 (46 novel) genetic loci. We detect six new lead missense variants and prioritize ten most likely putative causal variants, one of which we demonstrate exhibits allele-specific regulatory effect on ACAP1 in vitro. We suggest 677 effector genes with potential for drug repurposing, and provide evidence that two distinct association signals at a single locus act on different genes ( NCF2 and SMG7) . We demonstrate that SLE-risk variants overlap with cell-specific active regulatory elements, notably EBNA2-mediated super-enhancers in Epstein-Barr Virus-transformed B cells, and implicate the role for non-immune cells in SLE biology. These findings shed light on genetic and biological understandings of SLE. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We acknowledged the participants in this study. We appreciate the contribution of Japanese Research Committee on Idiopathic Osteonecrosis of the Femoral Head. We appreciate all contributors to BioBank Japan. Details are included in supplementary material. This research was supported by General Program (81872516, 81573033, 81872527, 81830019, 81421001), Young Program (81803117), Exchange Program (81881340424), and Science Fund for Creative Research Groups (31630021) of National Natural Science Foundation of China (NSFC), Distinguished Young Scholar of Provincial Natural Science Foundation of Anhui (1808085J08), National Program on Key Basic Research Project of China (973 Program) (2014CB541901), Science Foundation of Ministry of Education of China (213018A), Program for New Century Excellent Talents in University of Ministry of Education of China (NCET-12-0600), The Bio & Medical Technology Development Program of the National Research Foundation, funded by the Ministry of Science & ICT of the Republic of Korea (NRF-2017M3A9B4050355 to S.C.B.), Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning (2015R1C1A1A02036527 and 2017R1E1A1A01076388 to K. Kim), National BioBank of Korea, the Centers for Disease Control and Prevention, Republic of Korea (KBN-2018-031 to S.S.L.), Center for Genome Science, Korea National Institute of Health, Republic of Korea (4845-301, 3000-3031 to M.Y.H., K. Yoon and B.J.K.), Japan Agency for Medical Research and Development (AMED) and the BioBank Japan project supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese Government and AMED under grant numbers (17km0305002 and 18km0605001), Grant of Japan Orthopaedics and Traumatology Research Foundation, lnc, (No.350 to Y.Sakamoto), RIKEN Junior Research Associate Program (to H.S.), US NIH grants (AI024717, AI130830, AI148276, HG172111 and AR070549 to J.B.H.), US Department of Veterans Affairs (BX001834 to J.B.H.), and Center for Pediatric Genomics Award and CCRF Endowed Scholar Award of Cincinnati Children’s Hospital (to M.T.W.). We appreciate the generous gift of pGL4.26 vector from Prof. Joon Kim at Graduate School of Medical Science Engineering, KAIST, Daejeon, South Korea. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: institutional review boards in participating institutions All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The ATAC-seq data for human blood B and T cells have been deposited with the China National Genomics Data Center (https://bigd.big.ac.cn/gsa-human/browse) under accession no. HRA000271. The expression quantitative trait loci summary-level data in blood immune cells are publicly available from our website (JENGER; http://jenger.riken.jp/en/). The meta-analysis summary-level results will be publicly available following 6 month embargo from the date of publication. All other data supporting the findings of this study are available within the paper and its supplementary information files and from the corresponding author upon reasonable request. [1]: #ref-1 [2]: #ref-8