Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose:Serum uric acid is an important biomarker for gout disease and kidney function. Genome-wide association study (GWAS) meta-analyses have identified 28 loci in European and Japanese population samples. Combined analysis of these summary data across populations offers the opportunity to discover new serum uric acid (SUA) associations through greater sample size and power, and trans-ancestral analyses provide the opportunity for fine-mapping associations with greater resolution given differing linkage disequilibrium patterns between populations.
Methods:Summary statistics from European (N=110,238) (PMID 23263486) and East Asian (N=21,268) (PMID 22797727) meta-analyses were obtained. We used ImpG v1.0 (PMID 24990607) to impute the results into 1000 Genomes phase 3 variants, and performed sample-size weighted z-score meta-analysis. LD-independent variants with PMETA < 5×10-8, not in LD (r2<0.1) with previously identified regions, were considered novel SUA loci. We used functional partitioned LD score regression (PMID 26414678) on all associated loci in the European GWAS to identify SNP-heritability enriched tissue-specific regulatory regions, for use as functional priors in PAINTOR (PMID 26189819) fine mapping analyses to identify putative causal variants.
Results:Trans-ancestral meta-analysis of European and East Asian GWAS revealed nine new SUA-associated loci (PMETA < 5×10-8). Three of the new loci are located in the 11q12.3-13.2 region near the established SLC22A11/12 association. Additional novel loci are located near the FGF5, LNC00603, HLA-DQB1, B4GALT1, BICC1 and USP2 genes. Tissue-focused functional partitioning of SNP-heritability indicated the strongest enrichments of kidney, GI and liver tissues (P<10-7), among other significant tissues (Figure 1). Trans-ancestral meta-analysis and functional fine-mapping decreases the numbers of SNPs in causal variant credible sets, and for example pinpoints the rs17632159 SNP as likely causal (posterior P>0.9) at the TMEM171/174 locus.
Conclusion:Meta-analysis of existing GWAS increases power and leads to the identification of nine new loci associated with serum uric acid levels. Increased resolution in trans-ancestral GWAS, with functional annotation enrichments, improves fine-mapping of serum urate GWAS loci.
Figure 1: Tissue-type SNP heritability enrichment P-values in serum uric acid GWAS.
To cite this abstract in AMA style:Boocock J, Stahl EA, Mount DB, Merriman TR, Choi HK, Okada Y, Cadzow M, Topless R. Trans-Ancestral Meta-Analysis Identifies Nine New Loci Associated with Serum Uric Acid Concentrations [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/trans-ancestral-meta-analysis-identifies-nine-new-loci-associated-with-serum-uric-acid-concentrations/. Accessed June 5, 2020.
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