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

• Published in: Nature genetics Vol. 43; no. 11; pp. 1127 - 1130
• Main Authors: Sulem, Patrick, Stefansson, Kari, Gudbjartsson, Daniel F, Walters, G Bragi, Helgadottir, Hafdis T, Helgason, Agnar, Gudjonsson, Sigurjon A, Zanon, Carlo, Besenbacher, Soren, Bjornsdottir, Gyda, Magnusson, Olafur T, Magnusson, Gisli, Hjartarson, Eirikur, Saemundsdottir, Jona, Gylfason, Arnaldur, Jonasdottir, Adalbjorg, Holm, Hilma, Karason, Ari, Rafnar, Thorunn, Stefansson, Hreinn, Andreassen, Ole A, Pedersen, Jesper H, Pack, Allan I, de Visser, Marieke C H, Kiemeney, Lambertus A, Geirsson, Arni J, Eyjolfsson, Gudmundur I, Olafsson, Isleifur, Kong, Augustine, Masson, Gisli, Jonsson, Helgi, Thorsteinsdottir, Unnur, Jonsdottir, Ingileif
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2011; Nature Publishing Group
• Subjects: 631/208/726/649/2219; 692/699/1670/3/2765/1528; Agriculture; Amino acids; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Diseases of the osteoarticular system; DNA sequencing; Fundamental and applied biological sciences. Psychology; Gene Function; Genes; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genomics; Genotypes; Gout; Gout - genetics; Human; Human Genetics; Humans; Iceland; Inflammatory joint diseases; letter; Medical schools; Medical sciences; Mutation, Missense; Polymorphism, Single Nucleotide; Population genetics, reproduction patterns; Purines; Uric Acid - blood; Urine; Iceland; Gout; Diseases of the osteoarticular system; Metabolic diseases; Identification; Uric acid; Microcristalline arthropathy; Population genetics; Variant; Hyperuricemia; Frequency; Serum; Purine; Microcrystal
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.972

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.