Background/Purpose: Single variants in 30 genetic loci have been associated with serum urate levels in Europeans by meta-analysis of summary statistics of 48 individual genome-wide association study (GWAS) data sets.¹ Identifying independent effects can help fine map causal genes and reveal functional mechanisms of genetic variation, and has been successful in other complex phenotypes. Our aim was to test for the presence of independent effects at the 30 urate loci.

Methods: Summary level statistics from the Kottgen et al. GWAS¹ were used in collaboration with the Global Urate Genetics Consortium. The Genome-Wide Complex Trait Analysis (GCTA) package² was used to test for association conditional on the lead single nucleotide polymorphism (SNP). A total of 9713 HapMap2 genome-wide imputed genotypes from European participants of the Atherosclerosis Risk in Communities study were used as a reference. An independent effect at each locus was defined as an association signal, after conditional analysis, of P<0.05 divided by the number of SNPs analyzed. Further rounds of analysis were conducted if SNPs remained significant after conditioning. The percent variance explained for each SNP was calculated by the formula b^2*(var(X) / var(Y)).

Results: Twenty-five additional independent effects were detected at 14 of the 30 urate loci (Table). The percent variance explained by the 30 lead SNPs was calculated to be 4.83%, with the additional SNPs explaining a further 0.81% of variance (total 5.64%).

Conclusion: The independent effects provide evidence for multiple etiological variants at the serum urate loci in Europeans, emphasizing the complex genetic control of serum urate levels. These results are an important initial step in fine-mapping the causal variants. For example, one of the independent effects at SLC2A9 (rs3775948) was the lead SNP in a urate GWAS in East Asian individuals,³ indicating both shared and unique genetic effects between East Asians and Europeans. The use of multiple ancestral groups will be important in fine-mapping.

1. Köttgen et al. Nat Genet 2013;45:145.
2. Yang et al. Am J Hum Genet 2011;88:76
3. Okada et al. Nat Genet 2012;44:904

 

Lead SNP (locus), P	Additional SNP(s)	Residual P1
rs1260326 (GCKR), 1×10-24	rs11891554, rs17709034	3×10-3
rs12498742 (SLC2A9), <1x10-700	rs3775948, rs11724112, rs10939614,  rs9990701, rs13115661	9×10-16
rs2231142 (ABCG2), 1×10-134	rs2622629, rs2725256, rs3109823, rs4693211	1×10-4
rs17632159 (TMEM171), 4×10-11	rs575416	>0.05
rs675209(RREB1), 1×10-23	rs501510	1×10-3
rs1165151 (SLC17A1), 7×10-70	rs12182983, rs6923367	8×10-5
rs2941484 (HNF4G), 4×10-17	rs2941478	>0.01
rs10821905 (A1CF), 7×10-17	rs10761587	4×10-3
rs1171614 (SLC16A9), 2×10-28	rs1171606, rs1171620	7×10-5
rs2078267 (SLC22A11), 9×10-38.rs3782099 (NRXN2), 4×10-11	rs3782099, rs10897518, rs480617	9×10-3
rs642803 (OVOL1), 3×10-13	rs12289836	1×10-3
rs3741414 (INHBC), 2×10-25	rs1106766	3×10-3
rs1394125 (UBE2Q2), 3×10-13	rs1976748	2×10-3
rs7193778 (NFAT5), 8×10-10	rs732021	>0.05

¹P corresponds to the strongest associated SNP after the final round of conditioning at each locus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/conditional-analysis-of-30-serum-urate-loci-identifies-25-additional-independent-effects/