GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region

Abstract

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Fig. 1. Five significant non-HLA loci identified by the ever-largest Asian GWAS for systemic sclerosis.

a A Manhattan plot of the GWAS for systemic sclerosis (SSc) in the Japanese population. The novel risk loci are red-highlighted and SNPs with genome wide-significance (threshold p = 5.0 × 10⁻⁸; the black dotted line) are indicated by light green. b–d Regional locus zoom plots for novel single nucleotide polymorphisms (SNPs) identified by the GWAS for Japanese SSc. Each dot is colored by r² of linkage disequilibrium (LD) with the purple-colored lead SNPs indicated with texts (chromosome position). 1428 cases and 112,599 controls were analyzed by logistic regression. Source data are provided as a Source Data file.

Fig. 2. Regional plots of credible sets fine-mapped in each GWAS locus.

The regional plot of each significant locus of the Japanese GWAS for SSc is presented. Each dot represents each SNP colored by the posterior probability (pp). Lead SNPs highlighted in bold and SNPs with pp > 0.3 are specified in each graph. a FCGR/FCRL, (b) STAT4, (c) TNFAIP3, (d) IRF5, (e) AHNAK2-PLD4. The left y-axis indicates -log10 (p-value) and the right y-axis indicates recombination rate (cM/Mb). Approximate Bayesian factors calculated for each locus and 95% credible set was created based on posterior inclusion probabilities (PIPs). 1428 cases and 112,599 controls were included. Source data are provided as a Source Data file.

Fig. 3. Twenty-eight significant signals including four novel SNPs identified by the meta-analysis for the Japanese and the European GWASs.

a A Manhattan plot representing the lead signals identified in the meta-analysis for GWASs of European and Japanese SSc. b–d Regional locus zoom plots for novel significant SNPs identified by the trans-ethnic meta-GWAS (A). For each SNP, regional plots for European and Japanese populations are presented on the left and right, respectively. Inverse-variance fixed effect model was utilized for a meta-analysis of Japanese (1428 cases and 112,599 controls) and European (9095 cases and 17,584 controls) GWAS datasets. Source data are provided as a Source Data file.

Fig. 4. An association of rs10917688 on IRF8 binding to the candidate cis-regulatory element.

a Relative positions of the predicted IRF8 binding site within the candidate cis-regulatory element (cCRE) is presented. The rs10917688 with the reference (REF: C) and alternative (ALT: T) alleles are indicated. b Odds ratio (OR) of each genotype combination relative to the control genotypes CC for rs10917688 in FCGR/FCRL and CC or GC for rs11117420 in IRF8 is presented. Protective and risk genotypes are colored blue and red, respectively. Mean ORs and 95% confidence intervals are presented by black dots and blue bars, respectively. T-test was utilized and two-sided p-values were calculated. The sample number of each genotype is indicated at the bottom of the panel. Source data are provided as a Source Data file.

Fig. 5. Different patterns of association observed between the diffuse and the limited forms of SSc.

a Association test results by logistic regression for the major clinical phenotypes, lcSSc (n = 679), dcSSc (n = 575), ACA-positive SSc (n = 429), ATA-positive SSc (n = 463), and SSc complicated with ILD (n = 625) are presented. The blue lines indicate genome-wide significance (p = 5.0 × 10⁻⁸) threshold line. b A heatmap of the effect sizes (odds ratios) of lead variants for each subset is presented. Source data are provided as a Source Data file.

Fig. 6. Partitioned heritability enrichment analysis for European and Japanese SSc.

Heritability enrichment of active histone marks (H3K9ac, H3K27ac, H3K4me3, H3K4me1) in different tissue types (a) corresponding to Supplementary Data 20 and cell types (b) corresponding to Supplementary Data 21 and 22 by LD-score regression are presented. The dashed lines indicate the thresholds of significance based on the Bonferroni correction (P < 0.05/10 for (a), P < 0.05/220 for (b)). Primary B cells are indicated by red arrows. EUR European (9095 cases and 17,584 controls); JPN Japanese (1428 cases and 112,599 controls). Source data are provided as a Source Data file.

Fig. 7. Application of polygenic risk scores to Japanese SSc.

Set 2 Japanese samples (734 cases and 110,504 controls) are stratified into 20 quantiles based on the individual polygenic risk scores (PRSs) calculated without prioritizing SNPs with the use of effect sizes of the European GWAS (a), without prioritizing SNPs with the use of effect sizes of the meta-analysis of the European (9095 cases and 17,584 controls) and Set 1 Japanese (694 cases and 2095 controls) dataset (b), or by prioritizing the top 5% of SNPs for IRF8-binding in RAMOS cells identified by IMPACT (see Methods for detail) and the lead SNPs of the meta-analysis with the use of the effect sizes of the meta-analysis (c). The odds ratio, the 95% confidence intervals, and the p-value of the top 5% quantile relative to those of median quantiles (the 10th and 11th quantile) are presented. The significant threshold is determined by Bonferroni correction (0.05/18). Source data are provided as a Source Data file.