Generating testable hypotheses for schizophrenia and rheumatoid arthritis pathogenesis by integrating epidemiological, genomic, and protein interaction data

Abstract

Patients with schizophrenia and their relatives have reduced prevalence of rheumatoid arthritis. Schizophrenia and rheumatoid arthritis genome-wide association studies also indicate negative genetic correlations, suggesting that there may be shared pathogenesis at the DNA level or downstream. A portion of the inverse prevalence could be attributed to pleiotropy, i.e., variants of a single nucleotide polymorphism that could confer differential risk for these disorders. To study the basis for such an interrelationship, we initially compared lists of single nucleotide polymorphisms with significant genetic associations (p < 1e-8) for schizophrenia or rheumatoid arthritis, evaluating patterns of linkage disequilibrium and apparent pleiotropic risk profiles. Single nucleotide polymorphisms that conferred risk for both schizophrenia and rheumatoid arthritis were localized solely to the extended HLA region. Among single nucleotide polymorphisms that conferred differential risk for schizophrenia and rheumatoid arthritis, the majority were localized to HLA-B, TNXB, NOTCH4, HLA-C, HCP5, MICB, PSORS1C1, and C6orf10; published functional data indicate that HLA-B and HLA-C have the most plausible pathogenic roles in both disorders. Interactomes of these eight genes were constructed from protein–protein interaction information using publicly available databases and novel computational predictions. The genes harboring apparently pleiotropic single nucleotide polymorphisms are closely connected to rheumatoid arthritis and schizophrenia associated genes through common interacting partners. A separate and independent analysis of the interactomes of rheumatoid arthritis and schizophrenia genes showed a significant overlap between the two interactomes and that they share several common pathways, motivating functional studies suggesting a relationship in the pathogenesis of schizophrenia/rheumatoid arthritis.

Altered expression of a unique set of genes reveals complex etiology of Schizophrenia

“…The linkage of the immune cell/chemokine mediated pathways (Table 3b) is strongly supported by literature [99][100][101]. An immunogenic basis of SCZ etiogenesis had also been brought forward [11,102] although counter to this hypothesis has also been placed which limits the role of immune function related genes as a solo or major factor in SCZ etiology [103]. Also, the involvement of growth, differentiation and survival of neurons in the specific brain regions (Table 3c) [104,105] (also discussed in subsection 'Involvement of the gene set in biological processes and events') and pathways related to apoptosis (Table 3d) [81, 82,106] (also discussed in subsection 'Involvement of the gene set in biological processes and events'), and related to protein synthesis (Table 3e) and degradation (Table 3f) [107,108] has been well documented in the literature (also discussed in subsection 'Involvement of the gene set in biological processes and events').…”

“…The linkage of the immune cell/chemokine mediated pathways (Table 3b) is strongly supported by literature (Jones, Mowry, Pender, & Greer, 2005;Müller & Schwarz, 2010;Reale et al, 2011). An immunogenic basis of SCZ etiogenesis had also been brought forward (Jones et al, 2005;Malavia et al, 2017) although counter to this hypothesis has also been placed which limits the role of immune function related genes as a solo or major factor in SCZ etiology (Pouget et al, 2016) (further discussed in subsections 4.5.2 and 4.6.3). Also, the involvement of growth, differentiation and survival of neurons in the specific brain regions (Table 3c) (A. S. Maschietto et al, 2015) (further discussed in subsection 4.2) and pathways related to apoptosis (Table 3d) (Jarskog et al, 2005(Jarskog et al, , 2004Lin et al, 2016) (also discussed in subsection 4.2), and related to protein synthesis (Table 3e) and degradation (…”

“…The genes linked with various acute and chronic inflammatory diseases (Kirkpatrick & Miller, 2013;Malavia et al, 2017;Müller, Myint, & Schwarz, 2012) (Fig. 3) hint for an inflammatory component involved in pathogenesis of SCZ (Hope et al, 2011;Kirkpatrick & Miller, 2013;Saetre et al, 2007).…”

Potentially repurposable drugs for schizophrenia identified from its interactome

“…Recently, the reduced prevalence of rheumatoid arthritis observed in schizophrenia patients was attributed to SNPs (single nucleotide polymorphisms) in the HLA region that conferred differential risk for schizophrenia and rheumatoid arthritis. 38 The interactomes of schizophrenia and rheumatoid arthritis genes also showed a significant overlap and shared common pathways. 38 The network of genes differentially expressed in alfacalcidol, cinnarizine and tetracycline were enriched in GWAS genes associated with inflammatory bowel disease (Supplementary File 2).…”

“…38 The interactomes of schizophrenia and rheumatoid arthritis genes also showed a significant overlap and shared common pathways. 38 The network of genes differentially expressed in alfacalcidol, cinnarizine and tetracycline were enriched in GWAS genes associated with inflammatory bowel disease (Supplementary File 2). The incidence of schizophrenia has been shown to be high in patients with immune-mediated inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis.…”