6533b852fe1ef96bd12ab974

RESEARCH PRODUCT

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Symen LigthartAhmad VaezUrmo VõsaMaria G. StathopoulouPaul S. De VriesBram P. PrinsPeter J. Van Der MostToshiko TanakaElnaz NaderiLynda M. RoseYing WuRobert KarlssonMaja BarbalicHonghuang LinRené PoolGu ZhuAurélien MacéCarlo SidoreStella TrompetMassimo ManginoMaria Sabater-llealJohn P. KempAli AbbasiTim KacprowskiNiek VerweijAlbert V. SmithTao HuangCarola MarziMary F. FeitosaKurt K. LohmanMarcus E. KleberYuri MilaneschiChristian MuellerMahmudul HuqEfthymia VlachopoulouLeo-pekka LyytikäinenChristopher OldmeadowJoris DeelenMarkus PerolaJing Hua ZhaoBjarke FeenstraMarzyeh AminiJari LahtiKatharina E. SchrautMyriam FornageBhoom SuktitipatWei-min ChenXiaohui LiTeresa NutileGiovanni MalerbaJian’an LuanTom BakNicholas J. SchorkFabiola Del Greco MElisabeth ThieringAnubha MahajanRiccardo E. MarioniEvelin MihailovJoel ErikssonAyse Bilge OzelWeihua ZhangMaria NethanderYu-ching ChengStella AslibekyanWei AngIlaria GandinLoïc YengoLaura PortasCharles KooperbergEdith HoferKumar B. RajanClaudia SchurmannWouter Den HollanderTarunveer S. AhluwaliaJing ZhaoHarmen H.m. DraismaIan FordNicholas J. TimpsonAlexander TeumerHongyan HuangSimone WahlYongmei LiuJie HuangHae-won UhFrank GellerPeter K. JoshiLisa R. YanekElisabetta TrabettiBenjamin LehneDiego VozziMarie VerbanckGinevra BiinoYasaman SabaIngrid MeulenbeltJeff R. O’connellMarkku LaaksoFranco GiulianiniPatrik K.e. MagnussonChristie M. BallantyneJouke Jan HottengaGrant W. MontgomeryFernando RivadineiraRico RueediMaristella SteriKarl-heinz HerzigDavid J. StottCristina MenniMattias FrånbergBeate St PourcainStephan B. FelixTune H. PersStephan J.l. BakkerPeter KraftAnnette PetersDhananjay VaidyaGraciela DelgadoJohannes H. SmitVera GroßmannJuha SinisaloIlkka SeppäläStephen R. WilliamsElizabeth G. HollidayMatthijs MoedClaudia LangenbergKatri RäikkönenJingzhong DingHarry CampbellMichele M. SaleYii-der I. ChenAlan L. JamesDaniela RuggieroNicole SoranzoCatharina A. HartmanErin N. SmithGerald S. BerensonChristian FuchsbergerDena HernandezCarla M.t. TieslerVilmantas GiedraitisDavid LiewaldKrista FischerDan MellströmAnders LarssonYunmei WangWilliam R. ScottMatthias LorentzonJohn BeilbyKathleen A. RyanCraig E. PennellDragana VuckovicBeverly BalkauMaria Pina ConcasReinhold SchmidtCarlos F. Mendes De LeonErwin P. BottingerMargreet KloppenburgLavinia PaternosterMichael BoehnkeA.w. MuskGonneke WillemsenDavid M. EvansPamela A.f. MaddenMika KähönenZoltán KutalikMagdalena ZoledziewskaVille KarhunenStephen B. KritchevskyNaveed SattarGenevieve LachanceRobert ClarkeTamara B. HarrisOlli T. RaitakariJohn R. AttiaDiana Van HeemstEero KajantieRossella SoriceGiovanni GambaroRobert A. ScottAndrew A. HicksLuigi FerrucciMarie StandlCecilia M. LindgrenJohn M. StarrMagnus KarlssonLars LindJun Z. LiJohn C. ChambersTrevor A. MoriEco J.c.n. De GeusAndrew C. HeathNicholas G. MartinJuha AuvinenBrendan M. BuckleyAnton J.m. De CraenMelanie WaldenbergerKonstantin StrauchThomas MeitingerRodney J. ScottMark McevoyMarian BeekmanCristina BombieriPaul M. RidkerKaren L. MohlkeNancy L. PedersenAlanna C. MorrisonDorret I. BoomsmaJohn B. WhitfieldDavid P. StrachanAlbert HofmanPeter VollenweiderFrancesco CuccaMarjo-riitta JarvelinJ. Wouter JukemaTim D. SpectorAnders HamstenTanja ZellerAndré G. UitterlindenMatthias NauckVilmundur GudnasonLu QiHarald GrallertIngrid B. BoreckiJerome I. RotterWinfried MärzPhilipp S. WildMarja-liisa LokkiMichael BoyleVeikko SalomaaMads MelbyeJohan G. ErikssonJames F. WilsonBrenda W.j.h. PenninxDiane M. BeckerBradford B. WorrallGreg GibsonRonald M. KraussMarina CiulloGianluigi ZazaNicholas J. WarehamAlbertine J. OldehinkelLyle J. PalmerSarah S. MurrayPeter P. PramstallerStefania BandinelliJoachim HeinrichErik IngelssonIan J. DearyReedik MägiLiesbeth VandenputPim Van Der HarstKarl C. DeschJaspal S. KoonerClaes OhlssonCaroline HaywardTerho LehtimäkiAlan R. ShuldinerDonna K. ArnettLawrence J. BeilinAntonietta RobinoPhilippe FroguelMario PirastuTine JessWolfgang KoenigRuth J.f. LoosDenis A. EvansHelena SchmidtGeorge Davey SmithP. Eline SlagboomGudny EiriksdottirAndrew P. MorrisBruce M. PsatyRussell P. TracyIlja M. NolteEric BoerwinkleSophie Visvikis-siestAlex P. ReinerMyron GrossJoshua C. BisLude FrankeOscar H. FrancoEmelia J. BenjaminDaniel I. ChasmanJosée DupuisHarold SniederAbbas DehghanBehrooz Z. AlizadehBehrooz Z. AlizadehH. Marike BoezenLude FrankePim Van Der HarstGerjan NavisMarianne RotsHarold SniederMorris SwertzBruce H.r. WolffenbuttelCisca WijmengaEmelia J. BenjaminDaniel I. ChasmanAbbas DehghanTarunveer Singh AhluwaliaJames MeigsRussell TracyBehrooz Z. AlizadehSymen LigthartJosh BisGudny EiriksdottirNathan PankratzMyron GrossAlex RainerHarold SniederJames G. WilsonBruce M. PsatyJosee DupuisBram PrinsUrmo VasoMaria G. StathopoulouLude FrankeTerho LehtimakiWolfgang KoenigYalda JamshidiSophie SiestAli AbbasiAndre G. UitterlindenMohammadreza AbdollahiRenate SchnabelUrsula M. SchickIlja M. NolteAldi KrajaYi-hsiang HsuDaniel S. TyleeAlyson ZwickerRudolf UherGeorge Davey SmithAlanna C. MorrisonAndrew A. HicksCornelia M. Van DuijnCavin Ward-cavinessEric BoerwinkleJ. RotterKen RiceLeslie LangeMarkus PerolaEco De GeusAndrew P. MorrisKari Matti MakelaDavid StaceyJohan ErikssonTim M. FraylingEline P. Slagboom

subject

0301 basic medicineMaleNetherlands Twin Register (NTR)Bipolar DisorderLD SCORE REGRESSION[SDV]Life Sciences [q-bio]Genome-wide association study[SDV.GEN] Life Sciences [q-bio]/GeneticsBody Mass Indexinflammatory disorder80 and overWIDE ASSOCIATIONEPIDEMIOLOGYta318International HapMap ProjectChildGenetics (clinical)2. Zero hungerGeneticsGenetics & HeredityAged 80 and over[SDV.MHEP] Life Sciences [q-bio]/Human health and pathologyC-reactive proteingenome-wide association studyinflammationMendelian randomizationinflammatory disordersDEPICTcoronary artery diseaseschizophreniasystem biologysystem biologyDEPICTMendelian Randomization Analysis11 Medical And Health SciencesMiddle AgedC-reactive protein; coronary artery disease; DEPICT; genome-wide association study; inflammation; inflammatory disorders; Mendelian randomization; schizophrenia; system biology; Adolescent; Adult; Aged; Aged 80 and over; Biomarkers; Bipolar Disorder; Body Mass Index; C-Reactive Protein; Child; Female; Genetic Loci; Genome-Wide Association Study; Humans; Inflammation; Liver; Male; Mendelian Randomization Analysis; Metabolic Networks and Pathways; Middle Aged; Schizophrenia; Young Adult3. Good health[SDV] Life Sciences [q-bio]LiverMedical geneticsBiomarker (medicine)/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_beingFemaleinflammatory disordersLife Sciences & BiomedicineMetabolic Networks and Pathwayscoronary artery diseaseHumanAdultmedicine.medical_specialtyAdolescentCHARGE Inflammation Working GroupC-reactive protein ; DEPICT ; Mendelian randomization ; coronary artery disease ; genome-wide association study ; inflammation ; inflammatory disorders ; schizophrenia ; system biologyBiologyIMMUNITYta3111ArticleC-reactive protein03 medical and health sciencesYoung AdultSDG 3 - Good Health and Well-beingMendelian randomizationGeneticsmedicine/dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_Mendelian randomizationHumansCORONARY-HEART-DISEASEMendelian Randomization Analysi1000 Genomes ProjectMETAANALYSISGenetic associationAged[SDV.GEN]Life Sciences [q-bio]/GeneticsScience & Technologygenome-wide association studyta1184Metabolic Networks and PathwayBiomarkerINSTRUMENTS06 Biological SciencesMendelian Randomization Analysisschizophrenia030104 developmental biologyGenetic LociinflammationC-reactive protein; DEPICT; Mendelian randomization; coronary artery disease; genome-wide association study; inflammation; inflammatory disorders; schizophrenia; system biology[SDV.MHEP]Life Sciences [q-bio]/Human health and pathologyBiomarkersLifeLines Cohort Study

description

International audience; C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.Copyright © 2018 American Society of Human Genetics. All rights reserved.

yearjournalcountryeditionlanguage
2018-11-01
10.1016/j.ajhg.2018.09.009https://hdl.handle.net/1887/86903