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 ~6.5million 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