Common and rare variants associated with kidney stones and biochemical traits.
Kidney stone disease is a complex disorder with a strong genetic component. We conducted a genome-wide association study of 28.3 million sequence variants detected through whole-genome sequencing of 2,636 Icelanders that were imputed into 5,419 kidney stone cases, including 2,172 cases with a history of recurrent kidney stones, and 279,870 controls. We identify sequence variants associating with kidney stones at ALPL (rs1256328[T], odds ratio (OR)=1.21, P=5.8 × 10(-10)) and a suggestive association at CASR (rs7627468[A], OR=1.16, P=2.0 × 10(-8)). Focusing our analysis on coding sequence variants in 63 genes with preferential kidney expression we identify two rare missense variants SLC34A1 p.Tyr489Cys (OR=2.38, P=2.8 × 10(-5)) and TRPV5 p.Leu530Arg (OR=3.62, P=4.1 × 10(-5)) associating with recurrent kidney stones. We also observe associations of the identified kidney stone variants with biochemical traits in a large population set, indicating potential biological mechanism.
deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland.
Asmundur
A
Oddsson
deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland.
Patrick
P
Sulem
1] deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik 101, Iceland.
Hannes
H
Helgason
1] Children's Medical Center, Landspitali-The National University Hospital of Iceland, Reykjavik 101, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland [3] The Rare Kidney Stone Consortium, Mayo Clinic, Rochester, Minnesota, USA.
Vidar O
VO
Edvardsson
deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland.
Gudmar
G
Thorleifsson
deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland.
Gardar
G
Sveinbjörnsson
deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland.
Eik
E
Haraldsdottir
Icelandic Medical Center (Laeknasetrid), Laboratory in Mjodd (RAM), Reykjavik 109, Iceland.
Gudmundur I
GI
Eyjolfsson
Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, 600, Iceland.
Olof
O
Sigurdardottir
Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik 101, Iceland.
Isleifur
I
Olafsson
deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland.
Gisli
G
Masson
deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland.
Hilma
H
Holm
1] deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik 101, Iceland.
Daniel F
DF
Gudbjartsson
1] deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
Unnur
U
Thorsteinsdottir
Division of Nephrology, Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik Iceland.
Olafur S
OS
Indridason
1] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland [2] The Rare Kidney Stone Consortium, Mayo Clinic, Rochester, Minnesota, USA [3] Division of Nephrology, Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik Iceland.
Runolfur
R
Palsson
1] deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
Kari
K
Stefansson
D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D007669:Kidney Calculi / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D040641:Quantitative Trait Loci