Heritability and Genome-Wide Association Analyses of Serum Uric Acid in Middle and Old-Aged Chinese Twins

Abstract

Serum uric acid (SUA), as the end product of purine metabolism, has proven emerging roles in human disorders. Here based on a sample of 379 middle and old-aged Chinese twin pairs, we aimed to explore the magnitude of genetic impact on SUA variation by performing sex-limitation twin modeling analyses and further detect specific genetic variants related to SUA by conducting a genome-wide association study. Monozygotic (MZ) twin correlation for SUA level (rMZ = 0.56) was larger than for dizygotic (DZ) twin correlation (rDZ = 0.39). The common effects sex-limitation model provided the best fit with additive genetic parameter (A) accounting for 46.3%, common or shared environmental parameter (C) accounting for 26.3% and unique/nonshared environmental parameter (E) accounting for 27.5% for females and 29.9, 33.1, and 37.0% for males, respectively. Although no SUA-related genetic variants reached genome-wide significance level, 25 SNPs were suggestive of association (P < 1 × 10^-5). Most of the SNPs were located in an intronic region and detected to have regulatory effects on gene transcription. The cell-type specific enhancer of skeletal muscle was detected which has been reported to implicate SUA. Two promising genetic regions on chromosome 17 around rs2253277 and chromosome 14 around rs11621523 were found. Gene-based analysis found 167 genes nominally associated with SUA level (P < 0.05), including PTGR2, ENTPD5, well-known SLC2A9, etc. Enrichment analysis identified one pathway of transmembrane transport of small molecules and 20 GO gene sets involving in ion transport, transmembrane transporter activity, hydrolase activity acting on acid anhydrides, etc. In conclusion, SUA shows moderate heritability in women and low heritability in men in the Chinese population and genetic variations are significantly involved in functional genes and regulatory domains that mediate SUA level. Our findings provide clues to further elucidate molecular physiology of SUA homeostasis and identify new diagnostic biomarkers and therapeutic targets for hyperuricemia and gout.

Keywords: Chinese twins; gene-based test; genome-wide association study; heritability; serum uric acid.

Figure 1

Quantile–quantile plot for quality control check and visualizing crude association for genome-wide association study of serum uric acid (SUA) level. The x-axis shows the −log10 of expected P-values of association from chi-square distribution and the y-axis shows the −log10 of P-values from the observed chi-square distribution. The black dots represent the observed data with top hit SNP being colored, and the red line is the expectation under the null hypothesis of no association. Gene at the best SNP is indicated.

Figure 2

Manhattan plot for genome-wide association study of serum uric acid (SUA) level. The x-axis shows the numbers of autosomes and the X chromosome, and the y-axis shows the −log10 of P-values for statistical significance. The dots represent the SNPs. None of the SNPs reached the genome-wide significance level (P < 5 × 10⁻⁸); however, 25 SNPs were suggestive of association (P < 1 × 10⁻⁵).

Figure 3

Regional association plot showing signal around chromosomal loci of 17q25.3 for genome-wide association study of serum uric acid (SUA) level. The strongest association was detected with rs2253277 in TMC6/TNRC6C-AS1 genes.

Figure 4

Regional association plot showing signal around chromosomal loci of 14q24.3 for genome-wide association study of serum uric acid (SUA) level. The strongest association was detected with rs11621523 in PTGR2 gene.