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

• Published in: Annals of the rheumatic diseases Vol. 80; no. 5; pp. 632 - 640
• Main Authors: Yin, Xianyong, Kim, Kwangwoo, Suetsugu, Hiroyuki, Bang, So-Young, Wen, Leilei, Koido, Masaru, Ha, Eunji, Liu, Lu, Sakamoto, Yuma, Jo, Sungsin, Leng, Rui-Xue, Otomo, Nao, Laurynenka, Viktoryia, Kwon, Young-Chang, Sheng, Yujun, Sugano, Nobuhiko, Hwang, Mi Yeong, Li, Weiran, Mukai, Masaya, Yoon, Kyungheon, Cai, Minglong, Ishigaki, Kazuyoshi, Chung, Won Tae, Huang, He, Takahashi, Daisuke, Lee, Shin-Seok, Wang, Mengwei, Karino, Kohei, Shim, Seung-Cheol, Zheng, Xiaodong, Miyamura, Tomoya, Kang, Young Mo, Ye, Dongqing, Nakamura, Junichi, Suh, Chang-Hee, Tang, Yuanjia, Motomura, Goro, Park, Yong-Beom, Ding, Huihua, Kuroda, Takeshi, Choe, Jung-Yoon, Li, Chengxu, Niiro, Hiroaki, Park, Youngho, Shen, Changbing, Miyamoto, Takeshi, Ahn, Ga-Young, Fei, Wenmin, Takeuchi, Tsutomu, Shin, Jung-Min, Li, Keke, Kawaguchi, Yasushi, Lee, Yeon-Kyung, Wang, Yongfei, Amano, Koichi, Park, Dae Jin, Yang, Wanling, Tada, Yoshifumi, Yamaji, Ken, Shimizu, Masato, Atsumi, Takashi, Suzuki, Akari, Sumida, Takayuki, Okada, Yukinori, Matsuda, Koichi, Matsuo, Keitaro, Kochi, Yuta, Kottyan, Leah C, Weirauch, Matthew T, Parameswaran, Sreeja, Eswar, Shruti, Salim, Hanan, Chen, Xiaoting, Yamamoto, Kazuhiko, Harley, John B, Ohmura, Koichiro, Kim, Tae-Hwan, Yang, Sen, Yamamoto, Takuaki, Kim, Bong-Jo, Shen, Nan, Ikegawa, Shiro, Lee, Hye-Soon, Zhang, Xuejun, Terao, Chikashi, Cui, Yong, Bae, Sang-Cheol
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.05.2021; BMJ Publishing Group
• Subjects: Adult; Albumin; Asia, Eastern - ethnology; Asian people; Asian People - genetics; Bayes Theorem; Bayesian analysis; Case-Control Studies; China - epidemiology; China - ethnology; Datasets; Disease; Female; Gene mapping; Genetic analysis; Genetic Loci - genetics; Genetic Predisposition to Disease - epidemiology; Genetic Predisposition to Disease - ethnology; Genetic Variation; Genome-Wide Association Study; Genomes; Genotype; Genotype & phenotype; Globulins; Heritability; Humans; Japan - epidemiology; Japan - ethnology; Linkage disequilibrium; Lupus; Lupus Erythematosus, Systemic - epidemiology; Lupus Erythematosus, Systemic - ethnology; Lupus Erythematosus, Systemic - genetics; Male; Meta-analysis; Middle Aged; Prevalence; Republic of Korea - epidemiology; Republic of Korea - ethnology; Rheumatology; Statistics; Systemic Lupus Erythematosus; Asia, Eastern; China; Japan; Republic of Korea; genetic; epidemiology; systemic; polymorphism; lupus erythematosus
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2020-219209

ObjectiveSystemic 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.MethodsWe 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.ResultsWe identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10−8). 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 (rg=−0.242) and non-albumin protein (rg=0.238).ConclusionThis 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.