title: Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.
abstract: In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Christian
authors.initials: C
authors.lastname: Fuchsberger
authors.forename: Cristian
authors.initials: C
authors.lastname: Pattaro
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Böger
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: Daniel
authors.initials: D
authors.lastname: Taliun
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Gao
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: Conall M
authors.initials: CM
authors.lastname: O'Seaghdha
authors.forename: Nicole
authors.initials: N
authors.lastname: Glazer
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
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: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.forename: Hinco J
authors.initials: HJ
authors.lastname: Gierman
authors.forename: Mary F
authors.initials: MF
authors.lastname: Feitosa
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: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
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: Stefan
authors.initials: S
authors.lastname: Coassin
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: Margherita
authors.initials: M
authors.lastname: Cavalieri
authors.forename: Madhumathi
authors.initials: M
authors.lastname: Rao
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: Mariza
authors.initials: M
authors.lastname: de Andrade
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: Christa
authors.initials: C
authors.lastname: Meisinger
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
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: Shamika
authors.initials: S
authors.lastname: Ketkar
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: Stuart K
authors.initials: SK
authors.lastname: Kim
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: David S
authors.initials: DS
authors.lastname: Siscovick
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Ingrid B
authors.initials: IB
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: Afshin
authors.initials: A
authors.lastname: Parsa
authors.forename: Murielle
authors.initials: M
authors.lastname: Bochud
authors.forename: Iris M
authors.initials: IM
authors.lastname: Heid
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D005919:Glomerular Filtration Rate / Q000235:genetics / Q000502:physiology; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D026923:Amino Acid Transport Systems, Basic; D027282:Fusion Regulatory Protein 1, Heavy Chain; C504186:INHBC protein, human; D047908:Intracellular Signaling Peptides and Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D008565:Membrane Proteins; C435927:PLEKHA1 protein, human; C545989:SLC3A2 protein, human; C469951:SLC7A6 protein, human; D028322:Inhibin-beta Subunits