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

Patrick Sulem; Daniel F Gudbjartsson; G Bragi Walters; Hafdis T Helgadottir; Agnar Helgason; Sigurjon A Gudjonsson; Carlo Zanon; Soren Besenbacher; Gyda Bjornsdottir; Olafur T Magnusson; Gisli Magnusson; Eirikur Hjartarson; Jona Saemundsdottir; Arnaldur Gylfason; Adalbjorg Jonasdottir; Hilma Holm; Ari Karason; Thorunn Rafnar; Hreinn Stefansson; Ole A Andreassen; Jesper H Pedersen; Allan I Pack; Marieke C H de Visser; Lambertus A Kiemeney; Arni J Geirsson; Gudmundur I Eyjolfsson; Isleifur Olafsson; Augustine Kong; Gisli Masson; Helgi Jonsson; Unnur Thorsteinsdottir; Ingileif Jonsdottir; Kari Stefansson

doi:10.1038/ng.972

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

Patrick Sulem
, Daniel F Gudbjartsson
, G Bragi Walters
, Hafdis T Helgadottir
, Agnar Helgason
, Sigurjon A Gudjonsson
, Carlo Zanon
, Soren Besenbacher
, Gyda Bjornsdottir
, Olafur T Magnusson
, Gisli Magnusson
, Eirikur Hjartarson
, Jona Saemundsdottir
, Arnaldur Gylfason
, Adalbjorg Jonasdottir
, Hilma Holm
, Ari Karason
, Thorunn Rafnar
, Hreinn Stefansson
, Ole A Andreassen

Jesper H Pedersen, Allan I Pack, Marieke C H de Visser, Lambertus A Kiemeney, Arni J Geirsson, Gudmundur I Eyjolfsson, Isleifur Olafsson, Augustine Kong, Gisli Masson, Helgi Jonsson, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Kari Stefansson

133 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	43
Udgave nummer	11
Sider (fra-til)	1127-30
Antal sider	4
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.972
Status	Udgivet - 2011

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10.1038/ng.972

Citationsformater

Sulem, P., Gudbjartsson, D. F., Walters, G. B., Helgadottir, H. T., Helgason, A., Gudjonsson, S. A., Zanon, C., Besenbacher, S., Bjornsdottir, G., Magnusson, O. T., Magnusson, G., Hjartarson, E., Saemundsdottir, J., Gylfason, A., Jonasdottir, A., Holm, H., Karason, A., Rafnar, T., Stefansson, H., ... Stefansson, K. (2011). Identification of low-frequency variants associated with gout and serum uric acid levels. Nature Genetics, 43(11), 1127-30. https://doi.org/10.1038/ng.972

Sulem, P, Gudbjartsson, DF, Walters, GB, Helgadottir, HT, Helgason, A, Gudjonsson, SA, Zanon, C, Besenbacher, S, Bjornsdottir, G, Magnusson, OT, Magnusson, G, Hjartarson, E, Saemundsdottir, J, Gylfason, A, Jonasdottir, A, Holm, H, Karason, A, Rafnar, T, Stefansson, H, Andreassen, OA, Pedersen, JH, Pack, AI, de Visser, MCH, Kiemeney, LA, Geirsson, AJ, Eyjolfsson, GI, Olafsson, I, Kong, A, Masson, G, Jonsson, H, Thorsteinsdottir, U, Jonsdottir, I & Stefansson, K 2011, 'Identification of low-frequency variants associated with gout and serum uric acid levels', Nature Genetics, bind 43, nr. 11, s. 1127-30. https://doi.org/10.1038/ng.972

@article{9f33eda5b7544641af9acd1e08220034,

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 {\texttimes} 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 {\texttimes} 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 {\texttimes} 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.",

keywords = "Gout, Humans, Iceland, Mutation, Missense, Polymorphism, Single Nucleotide, Uric Acid",

author = "Patrick Sulem and Gudbjartsson, \{Daniel F\} and Walters, \{G Bragi\} and Helgadottir, \{Hafdis T\} and Agnar Helgason and Gudjonsson, \{Sigurjon A\} and Carlo Zanon and Soren Besenbacher and Gyda Bjornsdottir and Magnusson, \{Olafur T\} and Gisli Magnusson and Eirikur Hjartarson and Jona Saemundsdottir and Arnaldur Gylfason and Adalbjorg Jonasdottir and Hilma Holm and Ari Karason and Thorunn Rafnar and Hreinn Stefansson and Andreassen, \{Ole A\} and Pedersen, \{Jesper H\} and Pack, \{Allan I\} and \{de Visser\}, \{Marieke C H\} and Kiemeney, \{Lambertus A\} and Geirsson, \{Arni J\} and Eyjolfsson, \{Gudmundur I\} and Isleifur Olafsson and Augustine Kong and Gisli Masson and Helgi Jonsson and Unnur Thorsteinsdottir and Ingileif Jonsdottir and Kari Stefansson",

year = "2011",

doi = "10.1038/ng.972",

language = "English",

volume = "43",

pages = "1127--30",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "11",

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T1 - Identification of low-frequency variants associated with gout and serum uric acid levels

AU - Sulem, Patrick

AU - Gudbjartsson, Daniel F

AU - Walters, G Bragi

AU - Helgadottir, Hafdis T

AU - Helgason, Agnar

AU - Gudjonsson, Sigurjon A

AU - Zanon, Carlo

AU - Besenbacher, Soren

AU - Bjornsdottir, Gyda

AU - Magnusson, Olafur T

AU - Magnusson, Gisli

AU - Hjartarson, Eirikur

AU - Saemundsdottir, Jona

AU - Gylfason, Arnaldur

AU - Jonasdottir, Adalbjorg

AU - Holm, Hilma

AU - Karason, Ari

AU - Rafnar, Thorunn

AU - Stefansson, Hreinn

AU - Andreassen, Ole A

AU - Pedersen, Jesper H

AU - Pack, Allan I

AU - de Visser, Marieke C H

AU - Kiemeney, Lambertus A

AU - Geirsson, Arni J

AU - Eyjolfsson, Gudmundur I

AU - Olafsson, Isleifur

AU - Kong, Augustine

AU - Masson, Gisli

AU - Jonsson, Helgi

AU - Thorsteinsdottir, Unnur

AU - Jonsdottir, Ingileif

AU - Stefansson, Kari

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Gout

KW - Humans

KW - Iceland

KW - Mutation, Missense

KW - Polymorphism, Single Nucleotide

KW - Uric Acid

U2 - 10.1038/ng.972

DO - 10.1038/ng.972

M3 - Journal article

C2 - 21983786

SN - 1061-4036

VL - 43

SP - 1127

EP - 1130

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

Abstract

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