Session Type: Abstract Submissions (ACR)
Background/Purpose: Genome-wide association studies (GWASs) have been successfully used to identify novel common genetic variants that contribute to susceptibility to complex diseases, but individual GWASs are limited in terms of identifying new loci. Thus, pathway-based analysis is required to identify further new loci that contribute to susceptibility to complex diseases. The aims of this study were to identify candidate causal single nucleotide polymorphisms (SNPs) and candidate causal mechanisms of rheumatoid arthritis (RA) and generate hypothesis for SNP à gene à pathways.
Methods: An meta-analysis dataset of RA GWASs was used that included 2,554,714 SNPs in 5,539 RA cases and 20,169 controls of European descent. ICSNPathway (Identify candidate Causal SNPs and Pathways) analysis was applied to meta-analysis results of the RA GWAS dataset.
Results: ICSNPathway analysis identified 49 candidate causal SNPs and 37 candidate causal pathways. The top 5 candidate causal SNPs, rs1063478 (p = 5.40E-09), rs375256 (p = 3.44E-09), rs365066 (p = 3.60E-30), rs2581 (p = 2.7E-25), and rs1059510 (p = 2.52E-06) were all at human leukocyte antigen (HLA) loci. These candidate causal SNPs and pathways provide 22 hypothetical biological mechanisms. The most strongly associated pathway concerned HLA: rs1063478 (nonsynonymous coding) à HLA-DMA à antigen processing and presentation of peptide antigen. ICSNPathway analysis identified two candidate causal non-HLA SNPs and ten candidate causal pathways, which provided two hypothetical biological mechanisms. First, rs2476601 (nonsynonymous coding [deleterious]) (p = 6.22E-71) à protein tyrosine phosphatase nonreceptor 22 (PTPN22) à immune response-activation cell surface receptor signaling pathway, and, rs2230926 (nonsynonymous coding) (p = 1.26E-07) à tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) à the CD40L signaling pathway.
Conclusion: The application of ICSNPathway analysis to meta-analysis results of RA GWAS datasets resulted in the identification of candidate causal SNPs and pathways involving HLA-DMA, PTPN22, and TNAIP3 that might contribute to RA susceptibility.
Y. H. Lee,
S. J. Choi,
J. D. Ji,
G. G. Song,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pathway-analysis-of-genome-wide-association-studies-on-rheumatoid-arthritis/