GWAS of Clinically Defined Gout Identifies Non-Urate-Related Loci and Implicates Novel Gene, Pathway and Cell Type Associations

Background: Gout is most common inflammatory arthritis characterized by deposition of monosodium urate crystals in joints. Several genome-wide association studies (GWAS) have reported associations between common genetic variants and gout status. This study aimed to further elucidate the genetic architecture of gout for better understanding of pathogenesis. Methods: We conducted a large clinically defined gout GWAS in Chinese male descent (n case=3,669, n control=8,838) by using genome-wide genotyping arrays. Additional comprehensive analyses, including eQTL, pathway enrichment and connectivity enrichment analyses, were performed to further prioritize relevant genes, pathways and cell types that contributed to pathogenesis. The cell type intervention experiments were further performed in a MSU induced air-pouch mouse model of acute gouty arthritis to identify the role of different cell types in the gout pathogenesis. Findings: In addition to five previously reported urate- and gout-related loci, we detected four novel genome-wide significant (GWS, p<5.0×10-8) risk loci (1p35.2, 5q35.1, 7p13 and 22q12.3). For the GWS variants and their proxy (r 2 >0.8), 11 missense variants in 7 genes were identified, and eQTL analysis suggested involvement of MAPK signaling pathway. Genome-wide gene and gene-set analyses revealed novel gene and pathway associations (eg. T cell lineage commitment) with gout and also highlighted urate-related findings by single-SNP analysis. We also confirmed that CD4 T cell blockade can effectively alleviate the pathological process of gout. Interpretation: Our largest genome-wide data of clinically defined gout identified non urate-related associations at the variant, gene, pathway and cell type levels, and provided a better understanding of the pathogenesis of gout. Fundings: This work was supported by research project grants from National Natural Science Foundation of China, Shandong Province Key Research and Development Program, Taishan Scholar Program of Shandong Province, Shandong Province Natural Science Foundation, Shandong Provincial Science Foundation for Outstanding Youth Scholars, National Key R&D Program of China.Declaration of Interest: None declared.Ethical Approval: The study procedure complied with the Declaration of Helsinki and obtained ethical approval from the ethics committee of the Affiliated Hospital of Qingdao University.