Table 1.
Summary statistics of SS phenotypes, potential confounders, and co-morbidities.
Fig 1.
(A) Proportion of SS DMR locations relative to closest gene, and CpG type proportions at each DMR location; most DMRs are located either in the gene body (inside) or promoter, and most DMR CpG sites are either in the CpG island or the open sea. (B) Density plot of SS DMR locations on chromosome 6, where a DMR’s location is represented by GRCh37 genetic coordinates of its first CpG site to last CpG site. The shaded red region denotes the MHC region (28,477,797 bp—33,448,354 bp on chromosome 6). mb = megabase pairs.
Table 2.
Top gene sets enriched for hypomethylated genes in SS.
Table 3.
Top gene sets enriched for hypermethylated genes in SS.
Fig 2.
MeQTLs associated with SS DMR methylation M-values.
(A) SNP rs9275224 is a meQTL associated with average M-value of the DMR at genetic positions 32,810,706–32,810,742 (GRCh37) on chromosome 6. See S3 Table for the remaining meQTL-DMR pairs. (B) Density plot of associated and unassociated SNP-DMR pairs by absolute distance. The significance criteria for association is having a Benjamini-Hochberg adjusted p-value (p) ≤ 0.05. While distance is approximately uniformly distributed for unassociated SNP-DMR pairs, the distances of associated SNP-DMR pairs is concentrated around 153 kb. (C) MHC region spanning the HLA-DQA1, HLA-DQB1, and HLA-DQA2 loci with high density of the meQTL-DMR pairs. Each DMR is specified by its chromosome, starting position, and ending position, in GRCh37 genetic coordinates.
Table 4.
Top causal inference test results for meQTLs of SS DMRs.
Fig 3.
Manhattan plot of SS GWAS results at the MHC.
European SS GWAS results at the MHC from Taylor et al. [7], with mediating meQTL p-values from this study colored in yellow. SS case status was determined based on the 2016 ACR/EULAR classification criteria [32]. The red horizontal line indicates genome-wide significance level of p-value < 5 × 10−8.
Table 5.
Association of meQTLs with SS in European GWAS.
Fig 4.
LD heatmap for MHC meQTLs supporting the causal mediation model.
Heatmap of the LD measure of R2 statistics, based on European populations from the 1000 Genomes Project [55]. (A) LD among meQTLs and (B) LD between meQTLs and established SS-associated SNPs at the MHC, for Europeans [7, 8].
Table 6.
Multivariate logistic regression of SS status against MHC meQTLs.