Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Abstract

Objective: Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.

Methods: We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.

Results: Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.

Conclusions: We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.

Keywords: autoimmune diseases; autoimmunity; gene polymorphism.

Figure 1.. Meta-analysis results for the four systemic immune-mediated inflammatory diseases (IMIDs).

The Manhattan plot displays the -log10 transformed p-values (y-axis) by position on each chromosome (x-axis). The red line depicts the genome-wide significance threshold (p-value=5×10⁻⁸). A total of 26 SNPs were independently associated with at least two systemic IMIDs. Most of the signals map to known susceptibility loci in autoimmunity (e.g. PTPN22, STAT4, TNPO3, FAM167A-BLK) and five loci have never been reported before.

Figure 2.. GARFIELD functional enrichment analyses in DHS hotspots.

The wheel plot shows functional enrichment in systemic IMIDs within DHS hotspot regions in ENCODE and Roadmap Epigenomics. The radial axis depicts the fold enrichment (FE) calculated at different meta-analysis p-value thresholds. The font size is proportional to the number of cell types from the tissue, mainly enriched in blood cell types including a repertoire of immune cell lines.