title: 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.
authors: deCODE genetics, Reykjavik, Iceland. patrick.sulem@decode.is
authors: Patrick
authors: P
authors: Sulem
authors: Daniel F
authors: DF
authors: Gudbjartsson
authors: G Bragi
authors: GB
authors: Walters
authors: Hafdis T
authors: HT
authors: Helgadottir
authors: Agnar
authors: A
authors: Helgason
authors: Sigurjon A
authors: SA
authors: Gudjonsson
authors: Carlo
authors: C
authors: Zanon
authors: Soren
authors: S
authors: Besenbacher
authors: Gyda
authors: G
authors: Bjornsdottir
authors: Olafur T
authors: OT
authors: Magnusson
authors: Gisli
authors: G
authors: Magnusson
authors: Eirikur
authors: E
authors: Hjartarson
authors: Jona
authors: J
authors: Saemundsdottir
authors: Arnaldur
authors: A
authors: Gylfason
authors: Adalbjorg
authors: A
authors: Jonasdottir
authors: Hilma
authors: H
authors: Holm
authors: Ari
authors: A
authors: Karason
authors: Thorunn
authors: T
authors: Rafnar
authors: Hreinn
authors: H
authors: Stefansson
authors: Ole A
authors: OA
authors: Andreassen
authors: Jesper H
authors: JH
authors: Pedersen
authors: Allan I
authors: AI
authors: Pack
authors: Marieke C H
authors: MC
authors: de Visser
authors: Lambertus A
authors: LA
authors: Kiemeney
authors: Arni J
authors: AJ
authors: Geirsson
authors: Gudmundur I
authors: GI
authors: Eyjolfsson
authors: Isleifur
authors: I
authors: Olafsson
authors: Augustine
authors: A
authors: Kong
authors: Gisli
authors: G
authors: Masson
authors: Helgi
authors: H
authors: Jonsson
authors: Unnur
authors: U
authors: Thorsteinsdottir
authors: Ingileif
authors: I
authors: Jonsdottir
authors: Kari
authors: K
authors: Stefansson
mesh_terms: D006073:Gout / Q000235:genetics*; D006801:Humans; D007055:Iceland; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D014527:Uric Acid / Q000097:blood*
chemical_list: D014527:Uric Acid