Disease Studies

Sjögren’s Syndrome

Sjögren’s syndrome is an auto-immune disease affecting 0.1–3% of the population, with women 20 times more likely to develop symptoms characterized by dry eyes and dry mouth. However, the disease is highly heterogeneous and is often associated with other auto-immune diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Our analysis identified gene targets within these subpopulations that are involved in a variety of different mechanisms implicated in Sjögren’s syndrome, including Wnt/β-catenin signaling, T-cell-mediated auto-immunity, and endoplasmic reticulum (ER) stress and apoptosis.


Methodology

We analyzed a dataset that was generated from the UK Biobank consisting of 990 cases and 1,969 controls with genotype data on 547,197 SNPs. Cases with Sjögren’s syndrome (both primary and secondary) were identified using the ICD-10 code M350 and UK Biobank field 20002. An age- and gender-matched control set was generated consisting of randomly selected individuals who did not have any reported eye disorders and were not diagnosed with any auto-immune disease. The PrecisionLife platform took less than two days to identify the combinatorial genomic signatures in this dataset on a dual Xeon, 4x-GPU compute server.


Our results/findings

We found 299 risk-associated genes that are strongly associated with Sjögren’s syndrome. While several of the highest-scoring genes have already been implicated in driving other auto-immune diseases, either through regulation of the immune response or as the target of auto-antibodies, others encode more novel targets. These are involved in mechanisms such as cell adhesion, ER stress, and autophagy. Our study identified disease signatures representing different combinations of disease-associated SNPs within the Sjögren’s patient population. When these SNP networks were clustered based on their co-occurrence in patients, we generated 23 distinct patient communities. Functional analysis of these communities indicates that patients can be clustered based on differences in underlying disease mechanisms. Among a range of novel repurposing leads that were also identified, we also found several examples of targets with drugs that already been shown to protect against the development of auto-immune diseases in a range of mouse models. Although some of these genes are directly involved in T-cell-mediated auto-immunity and pro-inflammatory cytokine signaling, others are implicated in epithelial cell integrity and neurotransmission.

Graph showing SNP signatures (blue), risk-associated genes (pink), and existing drug options (yellow) in a community within the Sjögren’s syndrome disease population


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