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Background  Hyperuricemia is associated with multiple diseases, including gout, cardiovascular disease, and renal disease. Serum urate is highly heritable, yet association studies of single nucleotide polymorphisms (SNPs) and serum uric acid explain a small fraction of the heritability. Whether copy number polymorphisms (CNPs) contribute to uric acid levels is unknown.    Results  We assessed copy number on a genome-wide scale among 8,411 individuals of European ancestry (EA) who participated in the Atherosclerosis Risk in Communities (ARIC) study. CNPs upstream of the urate transporter  SLC2A9  on chromosome 4p16.1 are associated with uric acid (χ    2  df    2    =  3545   ,  p =3.19×10 -23 ). Effect sizes, expressed as the percentage change in uric acid per deleted copy, are most pronounced among women ( 3.97 4.93 5.87  [  2.5 50 97.5  denoting percentiles],  p =4.57×10 -23 ) and independent of previously reported SNPs in  SLC2A9  as assessed by SNP and CNP regression models and the phasing SNP and CNP haplotypes (χ    2  df    2    =  3190  ,    p  =  7.23  ×  1    0    -  08). Our finding is replicated in the Framingham Heart Study (FHS), where the effect size estimated from 4,089 women is comparable to ARIC in direction and magnitude ( 1.41 4.70 7.88 ,  p =5.46×10 -03 ).    Conclusions  This is the first study to characterize CNPs in ARIC and the first genome-wide analysis of CNPs and uric acid. Our findings suggests a novel, non-coding regulatory mechanism for  SLC2A9 -mediated modulation of serum uric acid, and detail a bioinformatic approach for assessing the contribution of CNPs to heritable traits in large population-based studies where technical sources of variation are substantial.

Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations