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Identification of low-frequency variants associated with gout and serum uric acid levels

Abstract

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10−16, at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10−21). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10−16). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.

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Figure 1: Overview of the chromosome 1 centromeric and chromosome 19q13 loci.
Figure 2: Effects on gout and serum uric acid levels of newly discovered and previously reported sequence variants stratified by sex.

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Accessions

GenBank/EMBL/DDBJ

NCBI Reference Sequence

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Acknowledgements

This project was supported by a European Commission Framework 7 Programme grant (200800 TREAT-OA, Translational Research in Europa–Applied Technologies for Osteoarthritis).

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P.S., D.F.G., G.B.W., H.J., U.T., I.J. and K.S. wrote the manuscript. P.S., D.F.G., G.B.W., G.B., H.H., H.J., U.T., I.J. and K.S. designed the study. A. Karason, T.R., H.S., O.A.A., J.H.P., A.I.P., M.C.H.d.V., L.A.K., A.J.G., G.I.E., I.O., H.J. and I.J. recruited participants for the study and collected clinical or paraclinical information. P.S., D.F.G., G.B.W., A.H., S.B., A.G., A. Kong and G. Masson performed statistical analyses. S.A.G. and C.Z. performed bioinformatics analyses. O.T.M., G. Magnusson, E.H., J.S., A.J. and G. Masson generated, processed and managed data for the whole-genome sequencing project. H.T.H. performed genotype and sequence calling.

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Correspondence to Patrick Sulem or Kari Stefansson.

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Some of the authors employed by deCODE genetics own stock or stock options in the company.

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Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–3 (PDF 1051 kb)

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Sulem, P., Gudbjartsson, D., Walters, G. et al. Identification of low-frequency variants associated with gout and serum uric acid levels. Nat Genet 43, 1127–1130 (2011). https://doi.org/10.1038/ng.972

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