Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

CC BYZoltán KutalikMassimo ManginoPhilippe FroguelChing-Ti LiuHeikki A. KoistinenNancy L. Heard-CostaJan A. StaessenCecilia M. LindgrenClaes OhlssonL. Adrienne CupplesBruna GiganteXuan DengMorris A. SwertzStephan J. L. BakkerRobert LubenMarkus JuonalaGemma CadbyStefania BandinelliNese DirekDaniele BragaLyle J. PalmerCornelia M. van DuijnJana V. van Vliet-OstaptchoukRichard N. BergmanNajaf AminDamiano BaldassarreHenrik VestergaardJennifer A. SmithCristina MenniAlbert V. SmithSerena SannaKristin L. YoungJohanne Marie JustesenMarie-Claude VohlCharlotta PisingerTerho LehtimäkiPim van der HarstMette HollenstedMary F. FeitosaIgor RudanAndrew WongMarie LohKirsti KvaløyClaude BouchardOzren PolasekJohn BeilbyPedro Marques-VidalRuth J. F. LoosGöran HallmansOlli T. RaitakariMeena KumariJacek CzajkowskiMassimo ManginoDavid P. StrachanCinzia SartiAlena StančákováIlja M. NolteWinfried MärzLouis PérusseJie HuangUzma AfzalHeikki A. KoistinenNancy L. Heard-CostaJan A. StaessenDaniele CusiAndrew P. MorrisYun Ju SungElise LimBamidele O. TayoGeorg HomuthHenning TiemeierRobert A. ScottL. Adrienne CupplesLars LindDena G. HernandezM. Carola ZillikensIris M. HeidSteve BuyskeJohn-Olov JanssonGerard PasterkampHeather M. StringhamDavid J. HunterGonçalo R. AbecasisAnja Ludolph-DonislawskiRainer RauramaaAnton J. M. de CraenPirjo KomulainenLlilda BarataJoel ErikssonDan MellströmJohanna KuusistoSven BergmannYii-Der Ida ChenNicola GloriosoTanguy CorreMagnus KarlssonAlan JamesMark A. SarzynskiPau NavarroDorothée ThuillierJessica TyrrellJohn D. EicherThorkild I. A. SørensenMarkku LaaksoMichael BoehnkeJing Hua ZhaoLu QiMelanie WaldenbergerJennifer BraggAndrew C. HeathLucia A. HindorffNese DirekMathias GorskiGudny EiriksdottirJaspal S. KoonerPenny Gordon-LarsenKristian HveemJonathan MarchiniTreva RiceCarsten A. BögerEric BoerwinkleJouke-Jan HottengaTerrence ForresterShafqat AhmadAndres MetspaluTuomo RankinenMatthias OldenJaakko TuomilehtoHenrik VestergaardTraci M. BartzJacqueline M. VinkCaroline S. FoxAni ManichaikulChristopher A. HaimanHarry CampbellJames F. WilsonAnna ErikssonNina Hutri-KähönenHarold SniederGraciela E. DelgadoPatricia A. PeyserGitta H. LubkeErik IngelssonJudith M. VonkDorret I. BoomsmaGrant W. MontgomeryArthur W. MuskTõnu EskoKen K. OngMomoko HorikoshiP. Eline SlagboomReiner BiffarVirginia FisherGert J. de BorstQibin QiTimothy M. FraylingLynne J. HockingWei ZhaoRichard S. CooperLinda S. AdairTanja B. GrammerAlbertine J. OldehinkelLeena KinnunenDavid SchlessingerTamara B. HarrisAudrey Y. ChuMarie LohAlan F. WrightDaniel I. ChasmanNiha ZubairGenovefa KolovouAmélie BonnefondNanette R. LeeAnders HamstenCatharina A. HartmanOzren PolasekClaudia SchurmannJonathan MartenBeverley BalkauJohn BeilbyLoic Le MarchandRuth J. F. Loos2025-06-142025-06-142017-04-262041-172310.1038/ncomms1497710.17863/cam.1074910.17615/55b7-9477https://ror.circle-u.eu/handle/123456789/413376AbstractFew genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.OPENNetherlands Twin Register (NTR)Epidemiology201668RG/10/12/28456Arthritis Research UK (ARUK)Body Mass IndexLSHG-CT-2006-018947name=General Biochemistry,Genetics and Molecular BiologyIMPUTATION284167POPULATIONAdiposity018996230374HEALTH-F2-2008-201865-GEFOSgenetics [Smoking]ASSOCIATION1600 Chemistryname=General Physics and Astronomy305739Science & Technology - Other Topicsddc:500Waist CircumferenceRG2008/014/dk/atira/pure/subjectarea/asjc/1600/1600European Research Councilgenetics [Adiposity]H Social Sciences (General)018947330G0601966ScienceQuantitative Trait Loci610ta3111ArticleLSHM-CT-2006-037697*SP/04/002IMI/115006GeneticSDG 3 - Good Health and Well-beingGWAS, obesity, smoking616HEALTH-2011-294713-EPLOREHumansPolymorphismScience & Technologygenetics [Quantitative Trait Loci]QLG2-CT-2002-01254323195:SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERCEpistasis, Geneticta3121R1BBMRI-LPC-313010HEALTH-2011.2.4.2-2-EU-MASCARAgenetics researchMC_U106179471General BiochemistryEpistasis/dk/atira/pure/subjectarea/asjc/3100/3100Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all)British Heart FoundationobesityMedicin och hälsovetenskapRG2008/08General Physics and AstronomyR Medicine (General)methods [Genome-Wide Association Study]HEALTH-F4-2007-201550-HYPERGENESMedical and Health SciencesGenome-wide association studiesLSHG-CT-2006-01947Public health care science, environmental and occupational healthG0000934genetics [Obesity]Genetics researchBody Fat Distribution3100 Physics and Astronomygenetics [Genetic Predisposition to Disease]OXIDATIVE STRESSMETABOLIC SYNDROMELSHM-CT-2004-005272/dk/atira/pure/subjectarea/asjc/1300/1300QSmoking223004Public Health, Global Health, Social Medicine and EpidemiologySingle NucleotideGeneral medicine, internal medicine and other clinical medicineMultidisciplinary SciencesDEFICIENCYADDICTIONPhenotypeHEALTH-F2-2013-601456Adult1300 BiochemistryHEALTH-F7-305507 HOMAGEGeneral Biochemistry,Genetics and Molecular Biologygenetics [Waist Circumference]Genetics and Molecular BiologyQH426 GeneticsHEALTH-F4-2007-201413Polymorphism, Single NucleotideMD MultidisciplinaryJournal ArticleGenetic Predisposition to DiseaseObesityEuropean CommissionNational Institute for Health Research (NIHR)EMC ONWAR-01-58-02VITAMIN-CWaist-Hip RatioQLG1-CT-2002-00896G0701863General ChemistryGENE279143HEALTH-2011-278913Medical Research Council (MRC)Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologiMICELSHM-CT-2007-037273MC_UU_12019/1genome-wide association studiesCancer Research UKG0700931name=General ChemistryDevelopmental PsychopathologyGenome-Wide Association StudyGenome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traitspublication0303 health sciences03 medical and health sciences3. Good health2. Zero hungerdoi_dedup___PMC541404428443625https://repository.ubn.ru.nl/handle/2066/1693781871.1/e0fc5e12-575e-440d-95ef-db800338568e11370/f493b788-93e0-44b2-946d-9a3221db126411250/24999741887/11451520.500.14243/3403782066/1693782434/49147611388/20179910138/19693320.500.11820/895d835a-cfd1-469f-848d-21d74fc708b92164/922710044/1/486702440/10574610871/27945