An X chromosome-wide meta-analysis based on Japanese cohorts revealed that non-autosomal variations are associated with serum urate

Abstract

DEAR EDITOR, we have recently identified 36 genomic loci influencing serum urate (SU) levels via a genome-wide meta-analysis using 121,745 Japanese individuals [1]; however, non-autosomal data have hitherto been excluded in genome-wide association study (GWAS) quality-control procedures. The same limitation was applied to a transancestry GWAS of SU in 457,690 individuals, the largest currently published genetic study on SU [2]. Other previous GWASs [3] have focussed exclusively on the associations between genetic variants in the autosomes and SU. The largely unknown role of the X chromosome in SU levels, in spite of it constituting 5% of the human nuclear genome, prompted us to conduct an X chromosome-wide meta-analysis. We herein report our results, which reveal a novel locus that influences SU. Our findings may provide insights into gender differences in the homeostasis of urate, the circulating form of uric acid. To investigate the contribution of genetic variations in the X chromosome to SU levels, we conducted an X chromosome-wide meta-analysis for SU using enlarged data sets encompassing 142,121 Japanese subjects based on three Japanese cohorts: the Japan Multiinstitutional Collaborative Cohort Study, the Kita-Nagoya Genomic Epidemiology Study and the BioBank Japan Project. Details of these cohorts and analysis methods are described in the Supplementary Methods, available at Rheumatology online. Via our meta-analysis for SU, we successfully identified 12 single nucleotide polymorphisms (SNPs) at the Xq28 locus that satisfied a genome-wide significance threshold of a1⁄45.0 10 8 (Fig. 1A, supplementary Table S1, available at Rheumatology online). Strong linkage disequilibrium among these 12 SNPs was observed in the Japanese population. We first identified a novel non-autosomal locus that is associated with SU. A regional association plot for this locus is shown in Fig. 1B, where the lead SNP (rs3020789) with the lowest P-value was in an intergenic region between LOC105373383 and dual specificity phosphatase 9 (DUSP9). The results of sex-stratified analyses with the lead SNP both in each cohort and the meta-analysis are summarized in supplementary Table S2, available at Rheumatology online. In the meta-analysis, the rs3020789 showed a genome-wide significant association and a nominally significant association for the male group (b1⁄4 –0.020; P1⁄42.12 10 ) and female group (b1⁄4 –0.012; P1⁄4 0.024). To enhance understanding of the functional annotation of the newly identified locus (Xq28) in the context of SU, we then performed further analyses using publicly available data in the Genotype-Tissue Expression database (GTEx). We found that among the 12 SNPs associated with SU at the locus, 10 SNPs harbour variants that Rheumatology key message