Objective Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. Methods We built gene expression predictive models in blood B cells, CD4 + and CD8 + T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. Results TWAS identified 171 genes for SLE (p<1.0×10 -5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10 -8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10 -9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. Conclusions Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.
|Number of pages||8|
|Journal||Annals of the Rheumatic Diseases|
|Publication status||Published - 2022 Sept 1|
Bibliographical noteFunding Information:
Contributors XY, KKim and HS contributed equally to this work, and either has the right to list himself first in bibliographic documents. SCB, YC, CT, XZhang, XY, KKim and HS conceived the study design. SCB, YC, XZhang, SY, KKim and CT acquainted the financial support. XY, KKim, HS, CT, YC and SCB wrote the manuscript. XY, KKim, HS, EH, XZheng, and YW conducted all of the analyses with the help of KT, NO, MK, KI and CTerao, KKim, SYB, LW, LL, RXL, YSheng, MYH, WL, KYoon, MC, HH, MW, YTang, ZZ, HD, CL, CS, WF, KL, BJK, HSL, SCB, SH, YSakamoto, NSugano, MM, DT, KKarino, TMiyamura, JN, GM, TKuroda, HN, TMiyamoto, TT, YKawaguchi, KA, YTada, KYamaji, MS, TA, AS, TSumida, YOkada, KMatsuda, KMatsuo, YKochi, TSeki, YTanaka, TKubo, RH, TYoshioka, MY, TKabata, YA, YOhta, TO, YN, AK, YY, KOhzono, KYamamoto, KOhmura, TYamamoto and SI generated genetic data. LL and HH contributed to ATAC-seq experiment. SJ and THK performed luciferase reporter assays and EMSAs. SYB, SJ, YCK, WTC, SSL, SCS, YMK, DY, CHS, YBP, JYC, YP, GYA, JMS, YKL, DJP, WY, THK, SY, BJK, NShen, HSL, XZhang, CT and SCB managed the cohort data. SCB, YC and CT had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Biochemistry, Genetics and Molecular Biology(all)