Pervasive Sharing of Causal Genetic Risk Factors Contributes to Clinical and Molecular Overlap between Sjögren's...

SjD (Sjögren's Disease) and SLE (Systemic Lupus Erythematosus) are similar diseases. There is extensive overlap between the two in terms of both clinical features and pathobiologic mechanisms. Shared genetic risk is a potential explanation of this overlap. In this study, we evaluated whether these diseases share causal genetic risk factors. We compared the causal genetic risk for SLE and SjD using three complementary approaches. First, we examined the published GWAS results for these two diseases by analyzing the predicted causal gene protein-protein interaction networks of both diseases. Since this method does not account for overlapping risk intervals, we examined whether such intervals also overlap. Third, we used two-sample Mendelian randomization (two sample MR) using GWAS summary statistics to determine whether risk variants for SLE are causal for SjD and vice versa. We found that both the putative causal genes and the genomic risk intervals for SLE and SjD overlap 28- and 130-times more than expected by chance (p < 1.1 × 10^-24 and p < 1.1 × 10^-41, respectively). Further, two sample MR analysis confirmed that alone or in aggregate, SLE is likely causal for SjD and vice versa. [SjD variants predicting SLE: OR = 2.56; 95% CI (1.98-3.30); p < 1.4 × 10^-13, inverse-variance weighted; SLE variants predicting SjD: OR = 1.36; 95% CI (1.26-1.47); p < 1.6 × 10^-11, inverse-variance weighted]. Notably, some variants have disparate impact in terms of effect size across disease states. Overlapping causal genetic risk factors were found for both diseases using complementary approaches. These observations support the hypothesis that shared genetic factors drive the clinical and pathobiologic overlap between these diseases. Our study has implications for both differential diagnosis and future genetic studies of these two conditions.