biostudies-literatureWang ZNICHD NIH HHSCancer Research UKBritish Heart FoundationVetenskapsrådetNIA NIH HHSNIEHS NIH HHSNHLBI NIH HHSNNF Center for Basic Metabolic ResearchKjell och Märta Beijers StiftelseNIDDK NIH HHSSteno Diabetes Center Copenhagen (SDCC)Medical Research CouncilNational Institute for Health Research (NIHR)NHGRI NIH HHSNINDS NIH HHSNCI NIH HHSWellcome TrustNovo Nordisk Fonden1332-1344https://www.ebi.ac.uk/biostudies/studies/S-EPMC9470530biostudies-literatureUnknown54(9)Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II_A muscle fibers, and possibly protection from exercise-induced muscle damage. FiNature geneticsGenome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.PMC9470530R01 HL149683R01 DK122503R01 NS105150BRC-1215-20010NNF13OC0005785RG/18/13/33946HDR-9004R01 NS100178MC_UU_00011CBMR - 008NNF17OC0030088P30 DK020572NNF14OC0010513CBMR - 001R01 DK1018552019-01417R01 HL151152MC_UU_00007/10R01 DK075787SP/16/4/32697R01 DK124097NNF18OC0052457R01 DK089256BRC-1215-2001CH/12/2/29428NNF19OC0055250NNF15SA0018346C18281/A19169R01 NS114045UM1 CA182876U01 DK062370R01 HG010297Grarup GroupNF-SI-0611-10170R01 HG009974RG/13/13/30194217065/Z/19/ZR01 HL143885SDCC 3.A Complications202802/Z/16/ZP30 ES007033NNF17OC0026848U01 CA164973U01 AG070959NNF18OC003389829019PhenomicsR01 HD057194Kilpeläinen GroupNNF20OC0059313R01 DK107786R01 HL142302R01 DK062370P30 DK020541R01 DK110113MC_UU_00006/4R01 HL105756MC_UU_00006/1Cupples LAKardia SLRMartin NGUitterlinden AGWichmann HEWilliams KFranco OHJames ANavis GLuan JVangipurapu JZhao JHDueker NDEnroth STonjes AHoed MDSonestedt EKoolhaas CMEsko TNolte IMWeir DRRaitakari OTHui JXu HBartz TMGordon SDLyytikainen LPLorentzon MSidney SBoezen HMMarchand LLScott RAMazzaferro ECollins FSJackson AUKerr KFZhao WMusk BLoos RJFPenninx BWJHTimpson NJMonroe KRHeard-Costa NLi ASmith AVRidker PMHeiss GFernandez-Rhodes LWong Qvan Rooij FJABrage Svan Dam RMVolker UHemerich DKuusisto JMilaneschi YFohner AEBis JCBoehnke MZillikens MCFaul JDJohansson AVollenweider PAlizadeh BZWijmenga CTurman CVidal PMPeters AOrho-Melander MKrook ARots MWilson JFFeenstra BMedland SEProkopenko IAhluwalia TSGieger CKiemeney LAWillemsen GKahonen MAmeur AMeyre Dvan Duijn CMSarzynski MAJarvelin MRLagou VKilpelainen TOSamani NJLiu CTBeilby JLifelines Cohort StudyFornage MHall LMSchraut KEFeitosa MFMetzendorf CIllig TMangino MLind PAvan Schoor NJohnson WCStringham HMPedersen OMetspalu AKasbohm ESnieder HMoore THansen TRobiou-du-Pont SZhang XLauner LJThorand BHypponen EReedik MRichmond RCVolzke HHartman CAGudnason VBielak LFBruinenberg MTai ESStrom MChasman DIThomis MAIPacolet AOldehinkel AJFox CHayward CMelbye MRotimi CNTremblay APare GPerusse LNelson CPMagnusson PKEJorgensen AMSorensen TIABaumeister SEVoortman TCornelis MCChong MSwertz MRyan KJago RLaakso MBalkhiyarova ZFranke LKim BDorajoo RBlangero JGraff MSchulz CAKoh WPTanaka TPedersen NLBouchard CWareham NJSmith JAYuan JMReiner APHuikari VBoomsma DIHillis DAJung TScott LJGrarup NSiggeirsdottir KTeumer APers THKarlsson REmmerich ADeldicque LKaakinen MABraund PSCole JWKolcic IHaller TYoung KLOhlsson CChu AYHolzapfel Cvan der Velde NZonderman ABFerrucci LSpector TDHevener ALWang ZPillon NJJoshi PKBroos SBerry DWaeber GPark TEvans MKGyllensten Uvan Vliet-Ostaptchouk JVVanmunster MBrody JAZierath JRPeyser PAPool RGarland TBalslev-Harder MNKutalik ZLinneberg ADorr Mvan der Most PJMoscati APolasek OEkelund Ude Geus EJCBentley ARKraft PPPower CWolffenbuttel BHRHorta BLBandinelli STeo KKRivera NVLehtimaki Tvan der Harst PGalesloot TERudan IHartwig FPLangenberg CSim XSmith GDNorth KEfalseGenome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II_A muscle fibers, and possibly protection from exercise-induced muscle damage. Fi2022-01-01T00:00:00Z2022 Sep2026-05-27T11:49:51.703Z2024-11-14T17:52:40.619ZS-EPMC94705303607117210.1038/s41588-022-01165-1