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 FeenstraBehrooz Z. AlizadehH. Marike BoezenLude FrankePim van der HarstGerjan NavisMarianne RotsHarold SniederMorris SwertzBruce H.R. WolffenbuttelCisca WijmengaMarzyeh AminiEmelia BenjaminDaniel I. ChasmanAbbas DehghanTarunveer Singh AhluwaliaJames MeigsRussell TracyJosh BisGudny EiriksdottirNathan PankratzMyron GrossAlex RainerJames G. WilsonBruce M. PsatyJosee DupuisBram PrinsUrmo VasoMaria StathopoulouTerho LehtimakiWolfgang KoenigYalda JamshidiSophie SiestAndre G. UitterlindenMohammadreza AbdollahiRenate SchnabelUrsula M. SchickIlja M. NolteAldi KrajaYi Hsiang HsuDaniel S. TyleeAlyson ZwickerRudolf UherGeorge Davey-SmithAlanna C. MorrisonAndrew HicksCornelia M. van DuijnCavin Ward-CavinessEric BoerwinkleJ. RotterKen RiceLeslie LangeMarkus PerolaEco de GeusAndrew P. MorrisAmsterdam Public HealthFimlab Laboratoriot OyDeutsches Zentrum für Herz-Kreislauf-Forschung e. V.National Institute for Health and WelfareInstitut dInvestigació Biomèdica Sant Pau (IIB Sant Pau)Université de LorraineMax Planck Institute for Biology of AgeingHunter Medical Research Institute, AustraliaIcelandic Heart AssociationHaskoli IslandsUniversity of TartuHarvard School of Public HealthErasmus University Medical CenterUniversity of CambridgeUniversity of QueenslandSwiss Institute of BioinformaticsWake Forest University Health SciencesUniversity of Cambridge, School of Clinical MedicineStatens Serum InstitutThe University of North Carolina at Chapel HillQIMR Berghofer Medical Research InstituteHelmholtz Center Munich German Research Center for Environmental HealthWashington University School of Medicine in St. LouisInstitut Universitaire de Médecine Sociale et Préventive LausanneErnst-Moritz-Arndt-Universität GreifswaldConsiglio Nazionale delle RicercheIsfahan University of Medical SciencesNational Institute on AgingUniversity of Newcastle, Faculty of Health and MedicineBrigham and Women's HospitalLeiden University Medical Center - LUMCUniversitätsklinikum Schleswig-Holstein Campus LübeckPeking UniversityUniversity of Bristol, Faculty of Medicine and DentistryUniversity of Texas School of Public HealthKarolinska InstitutetKing's College LondonTampereen YliopistoVrije Universiteit AmsterdamSveučilište u SplituBoston University School of MedicineUniversity of Groningen, University Medical Center GroningenGuy's and St Thomas' NHS Foundation TrustWellcome Sanger InstituteUniversitätsklinikum Hamburg-Eppendorf und Medizinische FakultätHelsingin YliopistoUniversitätsklinikum MannheimUniversité de Lausanne (UNIL)German Center for Diabetes Research (DZD)German Center for Cardiovascular Research, Partner Site RheinMain2019-08-232019-08-232018-11-01American Journal of Human Genetics. Vol.103, No.5 (2018), 691-70615376605000292972-s2.0-85055557317https://repository.li.mahidol.ac.th/handle/20.500.14594/45025© 2018 American Society of Human Genetics 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1016/j.ajhg.2018.09.009