Identification of novel susceptibility genes associated with seven autoimmune disorders using whole genome molecular interaction networks. (February 2019)

• Record Type: Journal Article
• Authors: Kara, Sam; Pirela-Morillo, Gerardo A.; Gilliam, Conrad T.; Wilson, George D.
• Is Part Of: Journal of autoimmunity. Volume 97(2019)
• Page Start: 48
• Page End: 58
• Publication Date: 2019-02
• Subjects: Autoimmune disorders -- Crohn's disease -- Molecular network -- Psoriasis -- Type-1 diabetes -- Rheumatoid arthritis; AuD autoimmune disorders -- GWAS genome wide association studies -- SNPs single nucleotide polymorphisms -- CD Crohn's disease -- RA rheumatoid arthritis -- SLE systemic lupus erythematosus -- T1D type-1 diabetes -- T2D type-2 diabetes -- CeD celiac disease -- MS multiple sclerosis -- TRIDOM Translational Research Initiative in the Department of Medicine at the University of Chicago -- IPA Ingenuity Pathway Analysis -- WTCCC the Wellcome Trust Case-Control Consortium -- NIDDK the National Institute of Digestive Disorders and Kidney Disease -- IMSGC the International Multiple Sclerosis Genomics Consortium -- SLEGEN the Whole Genome Association Study of Systemic Lupus Erythematosus -- PSO Psoriasis -- LD linkage disequilibrium; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2018.10.002
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Convergent evidence from multiple and independent genetics studies implicate a small number of genes that predispose individuals to multiple autoimmune disorders (AuD). These intersecting loci reinforced the hypothesis that disorders with overlapping etiology group into a cluster of closely related genes within a whole genome molecular interaction network. We tested the hypothesis that "biological network proximity" within a whole genome molecular interaction network can be used to inform the search for multigene inheritance. Using a set of nine previously published genome wide association studies (GWAS) of AuD genes, we generated AuD-specific molecular interaction networks to identify networks of associated genes. We show that all nine "seed genes" can be connected within a 35-member network via interactions with 26 connecting genes. We show that this network is more connected than expected by chance, and 13 of the connecting genes showed association with multiple AuD upon GWAS reanalysis. Furthermore, we report association of SNPs in five new genes (IL10RA, DGKA, GRB2, STAT5A, and NFATC2) which were not previously considered as AuD candidates, and show significant association in novel disease samples of Crohn's disease and systemic lupus erythematosus. Furthermore, we show that the connecting genes show no association in four non-AuD GWAS. Finally, we test the connecting genes in psoriasis GWAS, and show association to previously identified loci and report new loci. These findings support the hypothesis that molecular interaction networks can be used to inform the search for multigene disease etiology, especially for disorders with overlapping etiology. Highlights: Molecular interaction networks can be used to inform the search for multigene disease etiology. Network topology used to map a 35-gene network of six autoimmune diseases. GWAS are used to identify SNPs within each identified gene within the autoimmune disease network. NFATC2 showed association to Crohn's disease, SLE, Diabetes type-1, and Psoriasis. IL12RB2 showed association to Crohn's disease, SLE, and Psoriasis.