6533b862fe1ef96bd12c6ce1

RESEARCH PRODUCT

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Peter KovacsAlan F. WrightStephen TurnerMichèle M. SaleSiim SõberJanoš TerzićElin OrgRichard S. CooperAlena StančákováJerome I. RotterW. H. Linda KaoAlbert HofmanAndrew B. SingletonFlorian KronenbergJianjun LiuNicole L. GlazerChristopher W. KnouffJennifer L. Bragg-greshamJuha KarjalainenLi Ching ChangBenjamin J. WrightJacqueline C.m. WittemanMartin G. LarsonKlaus StarkRichard J. RodehefferSharon L.r. KardiaDouglas M. RuderferSheila UliviMadhumathi RaoAndrew A. HicksEva BrandViviane NicaudStephen G. BallAnna KöttgenAnna KöttgenGermaine C. VerwoertAnders HamstenNick ShrineUwe VölkerStefan KloiberStephen HancockEmelia J. BenjaminBok Ghee HanKenneth RiceMark WoodwardVeronique VitartKarl AndersenNicholas J. WarehamRobert RobertsMaja BarbalićDavid CouperYukinori OkadaAndré G. UitterlindenSekar KathiresanLeo-pekka LyytikäinenPankaj AroraTatijana ZemunikDavid S. SiscovickSimonetta GuarreraDawn M. WaterworthTatjana StojakovicBraxton D. MitchellBraxton D. MitchellDevin AbsherCarmen A. PeraltaMika KivimäkiXueling SimNorihiro KatoPhilippe FroguelPhilippe FroguelPhilippe FroguelKeith L. KeeneDonna K. ArnettNaoyuki KamataniTazeen H. JafarIdris GuessousIdris GuessousIdris GuessousGunnar JacobsMichael M. HoffmannKari StefanssonKari StefanssonChristian HengstenbergTomonori OkamuraInga ProkopenkoChristina WillenborgPeter S. BraundRainer RettigFrancesco U.s. Mattace-rasoVikal TripathyF. Gerald R. FowkesLaura R. LoehrLaura R. LoehrHarry CampbellMargherita CavalieriOlle MelanderHao MeiI. Mateo LeachNicholette D. PalmerEva AlbrechtNaoharu IwaiStefan Martin BrandToshiko TanakaJackie A. CooperOmri GottesmanManuela UdaAngelo ScuteriAroon D. HingoraniCristiano FavaYusuke NakamuraJiang HeMin Jin GoSerge HercbergWendy L. McardlePhilipp S. WildFlorian ErnstPaul MitchellWolfgang KoenigCaroline S. FoxCaroline S. FoxS. J.cathy FannJanine F. FelixAnna F. DominiczakMike A. NallsErik IngelssonMario A. MorkenSusana EyheramendyChristopher Newton-chehIgor RudanD. G. VinayChristopher P. NelsonErvin R. FoxXiuqing GuoJing Hua ZhaoRick Twee-hee OngMargaret M. RedfieldOscar H. FrancoYongmei LiuFulvio RicceriMark A. HlatkyBernhard PaulweberMingyao LiThemistocles L. AssimesKarl WinklerInês BarrosoSylvia E. RosasM WalkerRichard W MorrisBo HedbladHakon HakonarsonSonny DandonaPeter H WhincupMartin AdamMartin AdamVilmundur GudnasonDaniel AckermannQiong YangCuno S. P. M. UiterwaalPaul M. RidkerGeorge Davey SmithLi ChenC. SinningTerri L. YoungJer-yuarn WuJer-yuarn WuWalter PalmasWill LongstrethJoe DevaneyPavel HametXiaofeng ZhuFredrik NybergWilfried RennerAnuj GoelL. Adrienne CupplesL. Adrienne CupplesNish ChaturvediIftikhar J. KulloNicholas D. HastieAude Saint-pierrePanos DeloukasSmita R. KulkarniEric BoerwinkleWolfram GoesslingGian Andri ThunGian Andri ThunEric J.g. SijbrandsShih-jen HwangCarole ProustHirotsugu UeshimaKristian HveemPierre MenetonJoshua C. DennyOlivier DevuystKerri L. WigginsMing-huei ChenRobert W. LawrenceRobert L. WilenskyAndre FrankeNicole SoranzoSimon HeathMargot HaunKarlhans EndlichDavid AltshulerHarald GrallertLaurence TiretLuigi FerrucciCaroline HaywardSudha SeshadriBénédicte StengelLynne E. WagenknechtJohn AttiaJohn AttiaAndreas ZieglerRenate B. SchnabelStefan SchreiberSantosh DahgamKurt LohmanChristian M. ShafferBarbara LudwigKatalin SusztakChien-hsiun ChenChien-hsiun ChenMichele K EvansPaolo VineisGuo LiThomas J. WangMeena KumariHeather M. StringhamBruce M. PsatyNorman KloppHalit OngenBen A. OostraStefan CoassinPetra BruseWei-min ChenUnnur ThorsteinsdottirUnnur ThorsteinsdottirCharles N. RotimiRobert J. CarrollMuredach P. ReillyNiek VerweijDena G. HernandezAmy J. SwiftBarbara KolleritsHyung Lae KimCristian PattaroIvana KolcicRonit KatzJohn M. C. ConnellDan E. ArkingAlbert W. DreisbachPeter VollenweiderC. S. JanipalliJian'an LuanErkki VartiainenJames T. WillersonJames T. WillersonJohn R. ThompsonDaniela TonioloLyle J. PalmerAlexander TeumerSerkalem Demissie-banjawSerkalem Demissie-banjawStella TrompetJames E. HixsonSue Shaw-hawkinsRossella SoriceBernhard R. WinkelmannJohn DaneshAnthony J. BalmforthToshio OgiharaJyotika K. FernandesUlf GyllenstenVille AaltoÅSa JohanssonAndres MetspaluJohn F. PedenDiana KuhMedea ImbodenMedea ImbodenAntonio LupoSu Chi LimSu Chi LimYoung-jin KimGiovanni MalerbaYurii S. AulchenkoSatoshi UmemuraIoanna TzoulakiAlan B. WederHelena SchmidtGerjan NavisSusan R. HeckbertHans J. RupprechtEdward G. LakattaChristian GiegerNajaf AminPaul MuntnerLenore J. LaunerIvana PersicoHugh WatkinsIan FordK. Radha ManiSylvia StrackeSylvia StrackeJohanna KuusistoJohn ChalmersMuhammad IslamLars LindStefan R. BornsteinMarjo-riitta JärvelinJ. H. YoungReiner BiffarSanthi K. GaneshKazuhiko YamamotoAnnette PetersLinda S. AdairTõnu EskoTõnu EskoRebecca HardyOlga JarinovaAntonietta RobinoRuth McphersonBenjamin F. VoightAnne U. JacksonGang ShiStefania BandinelliPeter J. Van Der MostJohn S. GottdienerYing A. WangMariza De AndradeJoshua C. BisLeslie J. RaffelMan LiJemma C. HopewellBernhard O. BöhmAaron R. FolsomNoël P. BurttS. SidneyDiana ZelenikaYuri MilaneschiPilar GalanIris M. HeidBernhard K. KrämerJean-michel GaspozLynda M. RoseMassimiliano CoccaJaap W. DeckersMartin FarrallKent D. TaylorAlbert V. SmithCandace GuiducciAlan R. ShuldinerAlan R. ShuldinerShiro MaedaLiming QuMarilyn C. CornelisXiaoling WangDaniel ShrinerJutta PalmenYingchang LuHeyo K. KroemerPio D'adamoStephan J. L. BakkerTamara B. HarrisMyriam RheinbergerTetsuro MikiAudrey Y. ChuRamachandran S. VasanFuu Jen TsaiJan A StaessenDaniel I. ChasmanJan StritzkeJasmin DiversMeredith C. FosterJeanette M. StaffordMaksim StruchalinArne SchillertJacques S. BeckmannMark E. CooperJean-charles LambertMario PirastuKatja ButterbachCarl G. P. PlatouYan V. SunMarcus FischerMaciej TomaszewskiKarl WerdanPeng ChenDaniel J. RaderThomas MünzelLowell F. SatlerTom R. GauntBrenda W.j.h. PenninxWilliam H. MatthaiJohn WhitfieldRita P.s. MiddelbergMargus ViigimaaToshihiro TanakaIda Yii Der ChenMorris J. BrownValur EmilssonJ. ViikariWolfgang LiebStephen E. EpsteinHarald DobnigAravinda ChakravartiPatrick Linsel-nitschkeStefan PilzAngela DoeringSarah H. WildPatricia B. MunroeMegan E. RudockNicole Probst-henschNicole Probst-henschDanish SaleheenDiederick E. GrobbeeAnke TönjesNarisu NarisuAnnika RosengrenMasato IsonoCatherine HelmerCatherine HelmerM. J.kranthi KumarAlanna C. MorrisonKay-tee KhawTanja ZellerJeffrey R. O'connellChristian MüllerGeorg HomuthGiriraj R. ChandakPankaj SharmaMarcus DörrVeikko SalomaaPaul F. O'reillyDavid HadleyHermann BrennerPaolo GaspariniNanette R. LeeBamidele O. TayoRobert ClarkeHenri WallaschofskiMarketa SjögrenAbbas DehghanMelanie WaldenbergerNeil RischVasyl PihurJessica D. FaulFrançois CambienChristian FuchsbergerNicholas G. MartinNicholas G. MartinJohn C. ChambersZouhair AherrahrouKarl J. LacknerLeif GroopMatthias OldenWiek H. Van GilstMathias GorskiYvonne T. Van Der SchouwPatrick DiemertChristoph BickelYik Ying TeoYik Ying TeoGiorgio PistisRuth J. F. LoosGudrun VeldreThorsten ReffelmannLude FrankeKaren L. MohlkeStefan BlankenbergMassimo ManginoIan N. M. DayAtsushi TakahashiAlan B ZondermanHua TangReijo LaaksonenHolly KramerGary C. CurhanAdrienne TinTalin HarituniansLoic YengoLoic YengoLoic YengoPhilip HowardArnika Kathleen WagnerAnna Maria CorsiYen Pei C. ChangKarin Halina GreiserJeanette ErdmannSolveig GretarsdottirSanjay KinraAlex ParkerBelen PonteMarina CiulloMichael PreussTin AungTin AungNicholas L. SmithMichiaki KuboRichard N. BergmanAlan S. GoPatricia P. ChangGudmundur ThorgeirssonChrista MeisingerGonçalo R. AbecasisMaria BlettnerJaana LaitinenDaniel TaliunCarlos IribarrenPaavo ZittingThomas LumleyAndreas MeinitzerWayne D. RosamondDaehee KangJohanne TremblayStephan B. FelixColin A. MckenzieYuan-tsong ChenLyudmyla KedenkoMladen BobanFadi J CharcharAdebowale AdeyemoBrendan M. BuckleyJennifer A. SmithReinhold SchmidtJaspal S. KoonerGavin LucasPaul ElliottDorairajan PrabhakaranTune H. PersTune H. PersTunde SalakoTerrence ForresterPaul BurtonJeffrey R. GulcherKelly A. VolcikRichard M. MyersAndreas TomaschitzH.-erich WichmannJie YaoGiuseppe MatulloCarsten A. BögerHenry VölzkeDaniela RuggieroFederico MurgiaYoshikuni KitaAugustine KongGiovanni GambaroCinzia SalaPeter P. PramstallerJames ScottMaris LaanLaura J. ScottAlistair S. HallSanaz SedaghatJames F. WilsonJoanne M. MurabitoYi-an KoHonghuang LinMark SeielstadLeena PeltonenSven BergmannThomas MeitingerMatthias NauckMaría Soler ArtigasThomas IlligNanette I. SteinleSamer S. NajjarChristina LoleyDebbie A LawlorSteven C. HuntYali LiWeihua ZhangJie Jin WangDaniele CusiMarco OrrùStephen P. FortmannMelissa GarciaBarry I. FreedmanJoseph M. LindsayJuan P. CasasTomohiro KatsuyaGrant W. MontgomeryHubert ScharnaglKhanh-dung H. NguyenSteven M. SchwartzAfshin ParsaElizabeth G. HollidayMurielle BochudKiran MusunuruKiran MusunuruBruno H. StrickerLori L. BonnycastleIlja M. NolteTimothy M. FraylingStefan EnrothMichiel L. BotsMark J. CaulfieldLaura PortasVincent ChourakiCarl D. LangefeldEran HalperinEran HalperinShufeng ChenPhilippa J. TalmudTerho LehtimäkiSteve E. HumphriesGudmar ThorleifssonAnika GrosshennigNorbert WatzingerFumihiko TakeuchiPim Van Der HarstTakayoshi OhkuboNabila Bouatia-najiNabila Bouatia-najiErwin P. BottingerRoberto ElosuaAndrew WongVladan MijatovicMaija K. GarnaasRobert ZweikerJoel N. HirschhornJoel N. HirschhornWinfried MärzNilesh J. SamaniInke R. KönigFrank B. HuMarcus E. KleberFrancis S. CollinsElena RochtchinaEwa Zukowska-szczechowskaYong LiAyse DemirkanGina HiltonG. EhretThomas H. MosleyMarkus PerolaAlexandre F.r. StewartJosef CoreshOlli T. RaitakariFeng ZhangMark LathropMichael MarmotYanbin DongChristopher J. O'donnellKristin D. MarcianteAsif RasheedMary F. FeitosaMary Susan BurnettRory CollinsJ. Wouter JukemaNele FriedrichAida Karina DieffenbachYing WuYoon Shin ChoAaron IsaacsHaidong ZhuMarie MetzgerMyriam AlexanderTanja B. GrammerTatiana KuznetsovaDabeeru C. RaoJayashri AragamAugusto D. PichardJaakko TuomilehtoLouise V. WainElizabeth J. AtkinsonTim D. SpectorReedik MägiTiit NikopensiusKenneth M. KentGuangju ZhaiAndrew D. JohnsonMenno PruijmDavid P. StrachanMartin D. TobinJoban SehmiJanja NahrstedtE. Shyong TaiThor AspelundJürgen GrässlerHilma HolmMatthew DenniffJoshua W. KnowlesTien Yin WongTien Yin WongTien Yin WongErika SalviJames F. MeschiaDongfeng GuRon WaksmanStacey GabrielJudith A. Hoffman BoltonMichael BoehnkeJohannes HaertingDarina CzamaraHeribert SchunkertHeribert SchunkertThomas QuertermousPeter M. NilssonJong-young LeeYasuharu TabaraChittaranjan S. YajnikDaniel LevyJohn BeilbyFernando RivadeneiraClaire PerretGudny EiriksdottirJingzhong DingGeorge A. WellsHarold SniederAyo P. DoumateyDag S. ThelleAnja MedackN. Charlotte Onland-moretMichael StumvollDavid EllinghausIngrid B. BoreckiTatsuhiko TsunodaIan H. De BoerM. Arfan IkramAndrew M. TaylorJohannes H. SmitGary F. MitchellAnna-liisa HartikainenMarkku LaaksoMark McevoyAndrew S. PlumpToby JohnsonCornelia M. Van DuijnOzren PolasekWilmar IglVincent MooserRodney J. ScottMika KähönenPeter Schwarz

subject

0301 basic medicineNephrologyGenetics and Molecular Biology (all)estimated glomerular filtration rateestimated glomerular filtration rate chronic kidney disease genetic determinantsGeneral Physics and AstronomyKidney developmentGenome-wide association studyBiochemistrySettore MED/14 - NEFROLOGIARenal InsufficiencyChronicGeneticsAGEN Consortiumddc:616education.field_of_studyKidneyStage renal-diseaseMultidisciplinaryGenome-wide associationCHARGe-Heart Failure GroupGene Expression Regulation; Genome-Wide Association Study; Genotype; Humans; Renal Insufficiency Chronic; Genetic Predisposition to Disease; Biochemistry Genetics and Molecular Biology (all); Chemistry (all); Physics and Astronomy (all)QChemistry (all)MetaanalysisGene Expression Regulation; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Renal Insufficiency Chronic/geneticsBiological sciencesSerum creatininemedicine.anatomical_structureEfficientRonyons -- FisiologiaHypertensionICBP ConsortiumTransmembrane transporter activitygenetic association loci kidney functionCARDIOGRAMHumanmedicine.medical_specialtyGenotypeSciencePopulationRenal functionECHOGen ConsortiumReplicationBiologyEnvironmentResearch SupportGeneral Biochemistry Genetics and Molecular BiologyN.I.H.genetic determinants03 medical and health sciencesPhysics and Astronomy (all)GENOME-WIDE ASSOCIATION ; FALSE DISCOVERY RATES ; STAGE RENAL-DISEASE ; SERUM CREATININE ; METAANALYSIS ; VARIANTS ; INDIVIDUALS ; POPULATION ; RISK ; HYPERTENSIONKidney functionResearch Support N.I.H. ExtramuralInternal medicineMD MultidisciplinarymedicineGeneticsJournal ArticleHumanseGFRcrea; eGFRcysGenetic Predisposition to Diseaseddc:610GenetikRenal Insufficiency ChronicMortalityeducationddc:613Biochemistry Genetics and Molecular Biology (all)urogenital systemIndividualsExtramuralGeneral Chemistryta3121medicine.diseaseR1030104 developmental biologyGene Expression RegulationBiochemistry Genetics and Molecular Biology (all); Chemistry (all); Physics and Astronomy (all)570 Life sciences; biologyGenèticachronic kidney diseaseKidney diseaseGenome-Wide Association StudyMeta-Analysis

description

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

yearjournalcountryeditionlanguage
2016-01-21
10.1038/ncomms10023https://doi.org/10.1038/ncomms10023