title: Common variants in Mendelian kidney disease genes and their association with renal function.
abstract: Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
authors.affiliation: Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Afshin
authors.initials: A
authors.lastname: Parsa
authors.forename: Christian
authors.initials: C
authors.lastname: Fuchsberger
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
authors.forename: Conall M
authors.initials: CM
authors.lastname: O'Seaghdha
authors.forename: Cristian
authors.initials: C
authors.lastname: Pattaro
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Karlhans
authors.initials: K
authors.lastname: Endlich
authors.forename: Matthias
authors.initials: M
authors.lastname: Olden
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chen
authors.forename: Adrienne
authors.initials: A
authors.lastname: Tin
authors.forename: Young J
authors.initials: YJ
authors.lastname: Kim
authors.forename: Daniel
authors.initials: D
authors.lastname: Taliun
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.forename: Mary
authors.initials: M
authors.lastname: Feitosa
authors.forename: Mathias
authors.initials: M
authors.lastname: Gorski
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Claudia
authors.initials: C
authors.lastname: Hundertmark
authors.forename: Meredith C
authors.initials: MC
authors.lastname: Foster
authors.forename: Nicole
authors.initials: N
authors.lastname: Glazer
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.forename: Madhumathi
authors.initials: M
authors.lastname: Rao
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.forename: Maksim
authors.initials: M
authors.lastname: Struchalin
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Atkinson
authors.forename: Kurt
authors.initials: K
authors.lastname: Lohman
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Cornelis
authors.forename: Asa
authors.initials: A
authors.lastname: Johansson
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.forename: Vincent
authors.initials: V
authors.lastname: Couraki
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Holliday
authors.forename: Rossella
authors.initials: R
authors.lastname: Sorice
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Kutalik
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.forename: Harshal
authors.initials: H
authors.lastname: Deshmukh
authors.forename: Sheila
authors.initials: S
authors.lastname: Ulivi
authors.forename: Audrey Y
authors.initials: AY
authors.lastname: Chu
authors.forename: Federico
authors.initials: F
authors.lastname: Murgia
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.forename: Medea
authors.initials: M
authors.lastname: Imboden
authors.forename: Barbara
authors.initials: B
authors.lastname: Kollerits
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pistis
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.forename: Thor
authors.initials: T
authors.lastname: Aspelund
authors.forename: Gudny
authors.initials: G
authors.lastname: Eiriksdottir
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Helena
authors.initials: H
authors.lastname: Schmidt
authors.forename: Edith
authors.initials: E
authors.lastname: Hofer
authors.forename: Frank
authors.initials: F
authors.lastname: Hu
authors.forename: Ayse
authors.initials: A
authors.lastname: Demirkan
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Ding
authors.forename: Jeanette S
authors.initials: JS
authors.lastname: Andrews
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: Franco
authors.initials: F
authors.lastname: Giulianini
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Angela
authors.initials: A
authors.lastname: Döring
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Lina
authors.initials: L
authors.lastname: Zgaga
authors.forename: Tatijana
authors.initials: T
authors.lastname: Zemunik
authors.forename: Mladen
authors.initials: M
authors.lastname: Boban
authors.forename: Cosetta
authors.initials: C
authors.lastname: Minelli
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.forename: Wilmar
authors.initials: W
authors.lastname: Igl
authors.forename: Ghazal
authors.initials: G
authors.lastname: Zaboli
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Wild
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.forename: Ute
authors.initials: U
authors.lastname: Nöthlings
authors.forename: Gunnar
authors.initials: G
authors.lastname: Jacobs
authors.forename: Reiner
authors.initials: R
authors.lastname: Biffar
authors.forename: Florian
authors.initials: F
authors.lastname: Ernst
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stracke
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: Ozren
authors.initials: O
authors.lastname: Polasek
authors.forename: Nick
authors.initials: N
authors.lastname: Hastie
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.forename: Catherine
authors.initials: C
authors.lastname: Helmer
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Stengel
authors.forename: Daniela
authors.initials: D
authors.lastname: Ruggiero
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Jorma
authors.initials: J
authors.lastname: Viikari
authors.forename: Tiit
authors.initials: T
authors.lastname: Nikopensius
authors.forename: Michael
authors.initials: M
authors.lastname: Province
authors.forename: Helen
authors.initials: H
authors.lastname: Colhoun
authors.forename: Alex
authors.initials: A
authors.lastname: Doney
authors.forename: Antonietta
authors.initials: A
authors.lastname: Robino
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Krämer
authors.forename: Laura
authors.initials: L
authors.lastname: Portas
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Buckley
authors.forename: Martin
authors.initials: M
authors.lastname: Adam
authors.forename: Gian-Andri
authors.initials: GA
authors.lastname: Thun
authors.forename: Bernhard
authors.initials: B
authors.lastname: Paulweber
authors.forename: Margot
authors.initials: M
authors.lastname: Haun
authors.forename: Cinzia
authors.initials: C
authors.lastname: Sala
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.forename: Marina
authors.initials: M
authors.lastname: Ciullo
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.forename: Olli
authors.initials: O
authors.lastname: Raitakari
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.forename: Colin
authors.initials: C
authors.lastname: Palmer
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.forename: Mario
authors.initials: M
authors.lastname: Pirastu
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Probst-Hensch
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schmidt
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Ingrid
authors.initials: I
authors.lastname: Borecki
authors.forename: Sharon L R
authors.initials: SL
authors.lastname: Kardia
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Gary C
authors.initials: GC
authors.lastname: Curhan
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Rainer
authors.initials: R
authors.lastname: Rettig
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Witteman
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.forename: Murielle
authors.initials: M
authors.lastname: Bochud
authors.forename: Iris M
authors.initials: IM
authors.lastname: Heid
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: W Linda
authors.initials: WL
authors.lastname: Kao
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Böger
mesh_terms: D030541:Databases, Genetic; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007668:Kidney / Q000502:physiology*; D057182:Mendelian Randomization Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D051436:Renal Insufficiency, Chronic / Q000235:genetics*; D044465:White People / Q000235:genetics*
references.citation: Nat Genet. 2010 May;42(5):373-5
references.pmid: 20383145
references.citation: Adv Chronic Kidney Dis. 2005 Apr;12(2):155-69
references.pmid: 15822051
references.citation: Nat Genet. 2009 Jun;41(6):712-7
references.pmid: 19430482
references.citation: Kidney Int. 2003 Jan;63(1):225-32
references.pmid: 12472787
references.citation: Nat Genet. 2010 May;42(5):376-84
references.pmid: 20383146
references.citation: PLoS Genet. 2012;8(3):e1002584
references.pmid: 22479191
references.citation: J Intern Med. 2010 Jun;267(6):612-20
references.pmid: 20210838
references.citation: Kidney Int. 2007 Aug;72(3):247-59
references.pmid: 17568785
references.citation: BMC Med Genet. 2010 Mar 11;11:41
references.pmid: 20222955
references.citation: Lancet. 2010 Apr 10;375(9722):1287-95
references.pmid: 20382325
references.citation: Am J Hum Genet. 2007 Dec;81(6):1158-68
references.pmid: 17966093
references.citation: Semin Dial. 2007 May-Jun;20(3):229-36
references.pmid: 17555489
references.citation: PLoS Genet. 2011 Sep;7(9):e1002292
references.pmid: 21980298
references.citation: Diabetes Care. 2008 Jul;31(7):1337-42
references.pmid: 18436617
references.citation: Lancet. 2005 Jan 22-28;365(9456):331-40
references.pmid: 15664230
references.citation: JAMA. 2007 Nov 7;298(17):2038-47
references.pmid: 17986697
references.citation: JAMA. 2004 Feb 18;291(7):844-50
references.pmid: 14970063
references.citation: Arch Intern Med. 2005 Apr 25;165(8):923-8
references.pmid: 15851645
references.citation: Am J Kidney Dis. 1996 Feb;27(2):167-94
references.pmid: 8659491
references.citation: Lancet. 2010 Jun 12;375(9731):2073-81
references.pmid: 20483451
references.citation: Kidney Int. 1997 Jun;51(6):1908-19
references.pmid: 9186882
references.citation: J Am Soc Nephrol. 2011 Mar;22(3):555-70
references.pmid: 21355061
references.citation: BMC Med Genet. 2012 Sep 05;13:78
references.pmid: 22947327
references.citation: Nature. 2010 Aug 5;466(7307):707-13
references.pmid: 20686565
references.citation: Hum Mol Genet. 2012 Dec 15;21(24):5329-43
references.pmid: 22962313
references.citation: Bioinformatics. 2010 Sep 1;26(17):2190-1
references.pmid: 20616382
references.citation: Genet Epidemiol. 2010 Nov;34(7):739-46
references.pmid: 20878715
references.citation: N Engl J Med. 2006 Mar 30;354(13):1387-401
references.pmid: 16571882
references.citation: PLoS Genet. 2010 Jul 29;6(7):e1001039
references.pmid: 20686651
references.citation: Am J Nephrol. 2010;31(3):222-9
references.pmid: 20068286
references.citation: Hypertension. 2008 Jun;51(6):1658-64
references.pmid: 18443236