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Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus

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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 [7]Kyung Hee Univ, Dept Biol, Seoul, South Korea [8]Kyung Hee Univ, Dept Life & Nanopharmaceut Sci, Seoul, South Korea [9]RIKEN Ctr Med Sci, Lab Bone & Joint Dis, Yokohama, Kanagawa, Japan [10]RIKEN Ctr Integrat Med Sci, Lab Stat & Translat Genet Anal, Yokohama, Kanagawa, Japan [11]Kyushu Univ, Grad Sch Med Sci, Dept Orthopaed Surg, Fukuoka, Japan [12]Hanyang Univ, Dept Rheumatol, Hosp Rheumat Dis, Seoul, South Korea [13]Hanyang Univ, Inst Rheumatol Res, Seoul, South Korea [14]Univ Tokyo, Inst Med Sci, Dept Canc Biol, Div Mol Pathol, Tokyo, Japan [15]Koga Hosp 21, Fukuoka, Japan [16]Anhui Med Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Hefei, Anhui, Peoples R China [17]Keio Univ, Dept Orthoped Surg, Sch Med, Tokyo, Japan [18]Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol CAGE, Cincinnati, OH 45229 USA [19]Osaka Univ, Dept Orthopaed Med Engn, Grad Sch Med, Osaka, Japan [20]Osong Hlth Technol Adm Complex, Natl Inst Hlth, Ctr Genome Sci, Div Genome Res, Cheongju, South Korea [21]Sapporo City Gen Hosp, Dept Rheumatol & Clin Immunol, Sapporo, Hokkaido, Japan [22]Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA [23]Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA [24]Harvard Med Sch, Ctr Data Sci, Boston, MA 02115 USA [25]Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA [26]Dong A Univ Hosp, Dept Internal Med, Busan, South Korea [27]Hokkaido Univ, Fac Med, Dept Orthopaed Surg, Sapporo, Hokkaido, Japan [28]Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan [29]Chonnam Natl Univ Med Sch & Hosp, Dept Internal Med, Div Rheumatol, Gwangju, South Korea [30]Hokkaido Univ, Dept Rheumatol Endocrinol & Nephrol, Fac Med, Sapporo, Hokkaido, Japan [31]Chungnam Natl Univ Hosp, Dept Internal Med, Div Rheumatol, Daejeon, South Korea [32]Natl Hosp Org, Kyushu Med Ctr, Dept Internal Med & Rheumatol, Fukuoka, Japan [33]Kyungpook Natl Univ Hosp, Dept Internal Med, Div Rheumatol, Daegu, South Korea [34]Chiba Univ, Grad Sch Med, Dept Orthopaed Surg, Chiba, Japan [35]Ajou Univ, Dept Rheumatol, Sch Med, Suwon, South Korea [36]Shanghai Jiao Tong Univ, Shanghai Inst Rheumatol, Sch Med SJTUSM, Renji Hosp, Shanghai, Peoples R China [37]Yonsei Univ, Dept Internal Med, Coll Med, Seoul, South Korea [38]Niigata Univ, Hlth Adm Ctr, Niigata, Japan [39]Catholic Univ Daegu, Dept Rheumatol, Sch Med, Daegu, South Korea [40]Kyushu Univ, Dept Med Educ, Grad Sch Med Sci, Fukuoka, Japan [41]Peking Univ, Dept Dermatol, Shenzhen Hosp, Shenzhen, Guangdong, Peoples R China [42]Hong Kong Univ Sci & Technol, Shenzhen Key Lab Translat Med Dermatol, Shenzhen Peking Univ, Med Ctr, Shenzhen, Guangdong, Peoples R China [43]Kumamoto Univ, Dept Orthopaed Surg, Fac Life Sci, Kumamoto, Japan [44]Keio Univ, Dept Internal Med, Div Rheumatol, Sch Med, Tokyo, Japan [45]Tokyo Womens Med Univ, Inst Rheumatol, Tokyo, Japan [46]Univ Hong Kong, Dept Paediat & Adolescent Med, Pok Fu Lam, Hong Kong, Peoples R China [47]Saitama Med Univ, Saitama Med Ctr, Dept Rheumatol & Clin Immunol, Saitama, Japan [48]Saga Univ, Dept Rheumatol, Fac Med, Saga, Japan [49]Juntendo Univ, Dept Internal Med & Rheumatol, Sch Med, Tokyo, Japan [50]Hokkaido Med Ctr Rheumat Dis, Sapporo, Hokkaido, Japan [51]Showa Univ, Dept Orthopaed Surg, Sch Med, Tokyo, Japan [52]RIKEN Ctr Integrat Med Sci, Lab Autoimmune Dis, Yokohama, Kanagawa, Japan [53]Univ Tsukuba, Dept Internal Med, Fac Med, Ibaraki, Japan [54]Osaka Univ, Dept Stat Genet, Grad Sch Med, Osaka, Japan [55]Osaka Univ, Immunol Frontier Res Ctr WPi iFReC, Lab Stat Immunol, Osaka, Japan [56]Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Genome Technol, Tokyo, Japan [57]Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Lab Clin Genome Sequencing, Tokyo, Japan [58]Aichi Canc Ctr Res Inst, Div Canc Epidemiol & Prevent, Nagoya, Aichi, Japan [59]Nagoya Univ, Dept Epidemiol, Grad Sch Med, Nagoya, Aichi, Japan [60]Tokyo Med & Dent Univ, Med Res Inst, Dept Genom Funct & Divers, Tokyo, Japan [61]Univ Cincinnati, Dept Pediat, Cincinnati, OH USA [62]US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA [63]Kyoto Univ, Dept Rheumatol & Clin immunol, Grad Sch Med, Kyoto, Japan [64]Fukuoka Univ, Dept Orthopaed Surg, Fac Med, Fukuoka, Japan [65]Shanghai Jiao Tong Univ, Sch Med SJTUSM, State Key Lab Oncogenes & Related Genes, Shanghai Canc Inst,Renji Hosp, Shanghai, Peoples R China [66]Fudan Univ, Inst Dermatol, Huashan Hosp, Dept Dermatol, Shanghai, Peoples R China [67]Shizuoka Prefectural Gen Hosp, Clin Res Ctr, Shizuoka, Japan [68]Univ Shizuoka, Sch Pharmaceut Sci, Dept Appl Genet, Shizuoka, Japan
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关键词: lupus erythematosus systemic polymorphism genetic epidemiology

摘要:
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.

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出版当年[2020]版:
大类 | 1 区 医学
小类 | 1 区 风湿病学
最新[2025]版:
大类 | 1 区 医学
小类 | 1 区 风湿病学
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出版当年[2019]版:
Q1 RHEUMATOLOGY
最新[2023]版:
Q1 RHEUMATOLOGY

影响因子: 最新[2023版] 最新五年平均[2021-2025] 出版当年[2019版] 出版当年五年平均[2015-2019] 出版前一年[2018版] 出版后一年[2020版]

第一作者:
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
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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
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