A large-scale genome-wide association meta-analysis study, initiated in 2017 and conducted by 102 contributors, made a wonderful story in lupus genetics field, identifying 46 novel loci in the human genome in East Asian populations. This study has been led by Kwangwoo and Prof. Sang-Cheol Bae in Korea; Prof. Xianyong Yin and Prof. Yong Cui in China; and Dr. Hiroyuki Suetsugu and Dr. Chikashi Terao in Japan. Eunji Ha (at KimLab) participated as a co-author by performing several important computational analyses.
Through the collaborative effort of the East Asian SLE genetics network, we newly genotyped 10,029 SLE cases and 180,167 controls and subsequently meta-analyzed them jointly with 3,348 SLE cases and 14,826 controls from published studies in East Asians. We identified 113 SLE susceptibility loci including 46 novel loci at genome-wide significance, with 169 association signals within non-HLA loci. Bayesian statistical fine-mapping analysis prioritized the putative causal variants to a small set of variants and identified putative causal variants with relatively high posterior probabilities.
This work was published online ahead of print in Annals of the Rheumatic Diseases on Dec 3, 2020. https://ard.bmj.com/content/early/2020/12/02/annrheumdis-2020-219209
Abstract
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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