Objective Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. Methods We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. Results We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5x10(-8)). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size <= 10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities >= 0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability >= 0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r(g)=-0.242) and non-albumin protein (r(g)=0.238). Conclusion This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.
基金:
National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [81872516, 81573033, 81872527, 81830019, 81421001, 81803117, 82003328, 81881340424, 31630021]; Distinguished Young Scholar of Provincial Natural Science Foundation of Anhui [1808085J08]; National Program on Key Basic Research Project of China (973 Program)National Basic Research Program of China [2014CB541901]; China National Key RD Program [2016YFC0906100]; Science Foundation of Ministry of Education of ChinaMinistry of Education, China [213018A]; Program for New Century Excellent Talents in University of Ministry of Education of ChinaProgram for New Century Excellent Talents in University (NCET) [NCET-12-0600]; Bio & Medical Technology Development Program of the National Research Foundation - Ministry of Science & ICT of the Republic of Korea [NRF--2017M3A9B4050355]; Basic Science Research Program through the National Research Foundation of Korea - Ministry of Science, ICT and Future Planning [2015R1C1A1A02036527, 2017R1E1A1A01076388]; National BioBank of Korea; Centers for Disease Control and Prevention, Republic of Korea [KBN-2018-031]; Center for Genome Science, Korea National Institute of Health, Republic of Korea [4845-301, 3000-3031]; Japan Agency for Medical Research and Development (AMED)Japan Agency for Medical Research and Development (AMED); BioBank Japan project - Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese GovernmentMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT); AMED [17km0305002, 18km0605001]; Grant of Japan Orthopaedics and Traumatology Research Foundation, lnc [350]; RIKEN Junior Research Associate Program; US NIH grantsUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI024717, AI130830, AI148276, HG172111, AR070549]; US Department of Veterans AffairsUS Department of Veterans Affairs [BX001834]; Center for Pediatric Genomics Award; CCRF Endowed Scholar Award of Cincinnati Children's Hospital
第一作者单位:[1]Anhui Med Univ, Affiliated Hosp 1, Dept Dermatol, Hefei, Anhui, Peoples R China[2]Anhui Med Univ, Inst Dermatol, Hefei, Anhui, Peoples R China[3]Anhui Med Univ, Key Lab Dermatol, Minist Educ, Hefei, Anhui, Peoples R China[4]Inflammat & Immune Mediated Dis Lab Anhui Prov, Hefei, Anhui, Peoples R China[5]China Japan Friendship Hosp, Dept Dermatol, Beijing, Peoples R China[6]Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA
通讯作者:
通讯机构:[10]RIKEN Ctr Integrat Med Sci, Lab Stat & Translat Genet Anal, Yokohama, Kanagawa, Japan[12]Hanyang Univ, Dept Rheumatol, Hosp Rheumat Dis, Seoul, South Korea[13]Hanyang Univ, Inst Rheumatol Res, Seoul, South Korea[67]Shizuoka Prefectural Gen Hosp, Clin Res Ctr, Shizuoka, Japan[68]Univ Shizuoka, Sch Pharmaceut Sci, Dept Appl Genet, Shizuoka, Japan[*1]Hanyang Univ Hosp Rheumat Dis, Rheumatol, Seoul, South Korea
推荐引用方式(GB/T 7714):
Yin Xianyong,Kim Kwangwoo,Suetsugu Hiroyuki,et al.Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus[J].ANNALS of the RHEUMATIC DISEASES.2021,80(5):632-640.doi:10.1136/annrheumdis-2020-219209.
APA:
Yin, Xianyong,Kim, Kwangwoo,Suetsugu, Hiroyuki,Bang, So-Young,Wen, Leilei...&Bae, Sang-Cheol.(2021).Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.ANNALS of the RHEUMATIC DISEASES,80,(5)
MLA:
Yin, Xianyong,et al."Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus".ANNALS of the RHEUMATIC DISEASES 80..5(2021):632-640