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

Abstract

ObjectiveImmune-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.MethodsWe 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.ResultsOur 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.ConclusionsWe 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.

Shared genetic factors and their causality in autoimmune diseases

“…In Annals of Rheumatic Diseases , Acosta-Herrera et al have reported their results from a genome-wide meta-analysis of four systemic seropositive rheumatological immune-mediated inflammatory diseases (IMIDs) including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), RA and idiopathic inflammatory myopathies (IIM) 9. Autoantibody production is one of the main features of these diseases.…”

Genetic architecture study of rheumatoid arthritis and juvenile idiopathic arthritis

“…Here, we adopted the fastBAT method which was a robust set-based association test computing the P-value of a gene with a number of SNPs from an approximated distribution (Bakshi et al, 2016). 431 genes located at 50 loci reached genome-wide significance in the RA dataset, including 17 known loci (Acosta-Herrera et al, 2019;Buniello et al, 2019;Eyre et al, 2012;Plenge et al, 2005;Raychaudhuri et al, 2009;Zhu et al, 2016) and 33 novel loci which should be examined in future replication studies (Table S4).…”

Genomic opportunities for drug repositioning in systemic seropositive rheumatic diseases

“…Autoimmune diseases are a group of disorders characterized by the loss of immune self-tolerance of the organism, generating autoantibodies against its own tissues [8]. In the cases where there is a systemic autoantibody response and the musculoskeletal system is affected, the disorders are known as 'systemic seropositive rheumatic diseases', which includes rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), among others [8,9]. In general, these conditions are considered as seropositive, however it is worth mentioning that they can manifest without the presence of autoantibodies in a smaller proportion of patients.…”

“…A recent report by Acosta-Herrera et al summarizes the main findings in the cross-disease meta-analysis in systemic seropositive rheumatic diseases to date [16]. An interesting study to highlight is the one combining four of these conditions, namely SSc, SLE, IIM and RA, where the authors evaluate drug targets indicated for prevalent diseases such as RA, and provide possibilities of being repurposed in genetically related, less prevalent or rare diseases such as SSc [8]. The main results of these studies are summarized in Table 1.…”