Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.
Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.
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对 208370 名东亚人的荟萃分析确定了 113 个系统性红斑狼疮易感位点
DOI：
10.1136/annrheumdis-2020-219209
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发表时间：
2021-05
影响因子：
27.4
通讯作者：
Bae SC
中科院分区：
文献类型：
--
作者：
Yin X;Kim K;Suetsugu H;Bang SY;Wen L;Koido M;Ha E;Liu L;Sakamoto Y;Jo S;Leng RX;Otomo N;Laurynenka V;Kwon YC;Sheng Y;Sugano N;Hwang MY;Li W;Mukai M;Yoon K;Cai M;Ishigaki K;Chung WT;Huang H;Takahashi D;Lee SS;Wang M;Karino K;Shim SC;Zheng X;Miyamura T;Kang YM;Ye D;Nakamura J;Suh CH;Tang Y;Motomura G;Park YB;Ding H;Kuroda T;Choe JY;Li C;Niiro H;Park Y;Shen C;Miyamoto T;Ahn GY;Fei W;Takeuchi T;Shin JM;Li K;Kawaguchi Y;Lee YK;Wang Y;Amano K;Park DJ;Yang W;Tada Y;Yamaji K;Shimizu M;Atsumi T;Suzuki A;Sumida T;Okada Y;Matsuda K;Matsuo K;Kochi Y;Japanese Research Committee on Idiopathic Osteonecrosis of the Femoral Head;Kottyan LC;Weirauch MT;Parameswaran S;Eswar S;Salim H;Chen X;Yamamoto K;Harley JB;Ohmura K;Kim TH;Yang S;Yamamoto T;Kim BJ;Shen N;Ikegawa S;Lee HS;Zhang X;Terao C;Cui Y;Bae SC
目的系统性红斑狼疮(SLE)是一种自身免疫性疾病，与近100个易感基因有关。然而，这些基因座只能部分解释系统性红斑狼疮的遗传性，其假定的因果变异很少被优先考虑，这给阐明疾病生物学带来了挑战。为了检测新的系统性红斑狼疮基因座和因果变异，我们对东亚人群中的系统性红斑狼疮进行了最大的全基因组荟萃分析。方法我们在东亚人群中对10例 029例SLE和180例 167对照进行了新的基因分型，并与3348例SLE病例和14名 826对照进行了Meta分析。我们进一步应用贝叶斯统计方法来定位SLE关联的假定因果变量。结果共鉴定出113个基因区，其中46个新基因座具有全基因组意义(p<；5×10−8)。条件分析在这些基因座内检测到233个关联信号，表明存在广泛的等位基因异质性。我们在六个新的错义变异中检测到全基因组的关联。贝叶斯统计精细映射分析将28个关联信号的假定因果变量优先排序为一小组变量(95%可信集合大小≤10)。我们确定了57个系统性红斑狼疮基因座的110个假设因果变量，后验概率≥为0.1%，其中我们优先选择了10个最可能的因果变量(后验概率≥为0.8%)。连锁不平衡分数回归分析发现，白蛋白/球蛋白比值(Rg=−0.242)和非白蛋白(Rg=0.238)与系统性红斑狼疮存在遗传相关性。结论本研究重申了大规模全基因组荟萃分析对新的基因发现的威力。这些发现有助于从遗传学和生物学角度理解系统性红斑狼疮。
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<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). 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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中国和欧洲个体的全基因组关联荟萃分析确定了与系统性红斑狼疮相关的十个新位点
影响因子：
30.8
作者：
Morris DL;Sheng Y;Zhang Y;Wang YF;Zhu Z;Tombleson P;Chen L;Cunninghame Graham DS;Bentham J;Roberts AL;Chen R;Zuo X;Wang T;Wen L;Yang C;Liu L;Yang L;Li F;Huang Y;Yin X;Yang S;Rönnblom L;Fürnrohr BG;Voll RE;Schett G;Costedoat-Chalumeau N;Gaffney PM;Lau YL;Zhang X;Yang W;Cui Y;Vyse TJ
通讯作者：
Vyse TJ
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
4.6
作者：
Morimoto K;Baba Y;Shinohara H;Kang S;Nojima S;Kimura T;Ito D;Yoshida Y;Maeda Y;Sarashina-Kida H;Nishide M;Hosokawa T;Kato Y;Hayama Y;Kinehara Y;Okuno T;Takamatsu H;Hirano T;Shima Y;Narazaki M;Kurosaki T;Toyofuku T;Kumanogoh A
通讯作者：
Kumanogoh A