Kraja, Aldi TAldi TKrajaLiu, ChunyuChunyuLiuFetterman, Jessica LJessica LFettermanGraff, MariaelisaMariaelisaGraffHave, Christian TheilChristian TheilHaveGu, CharlesCharlesGuYanek, Lisa RLisa RYanekFeitosa, Mary FMary FFeitosaArking, Dan EDan EArkingChasman, Daniel IDaniel IChasmanYoung, KristinKristinYoungLigthart, SymenSymenLigthartHill, W DavidW DavidHillWeiss, StefanStefanWeissLuan, Jian'anJian'anLuanGiulianini, FrancoFrancoGiulianiniLi-Gao, RuifangRuifangLi-GaoHartwig, Fernando PFernando PHartwigLin, Shiow JShiow JLinWang, LihuaLihuaWangRichardson, Tom GTom GRichardsonYao, JieJieYaoFernandez, Eliana PEliana PFernandezGhanbari, MohsenMohsenGhanbariWojczynski, Mary KMary KWojczynskiLee, Wen-JaneWen-JaneLeeArgos, MariaMariaArgosArmasu, Sebastian MSebastian MArmasuBarve, Ruteja ARuteja ABarveRyan, Kathleen AKathleen ARyanAn, PingPingAnBaranski, Thomas JThomas JBaranskiBielinski, Suzette JSuzette JBielinskiBowden, Donald WDonald WBowdenBroeckel, UlrichUlrichBroeckelChristensen, KaareKaareChristensenChu, Audrey YAudrey YChuCorley, JanieJanieCorleyCox, Simon RSimon RCoxUitterlinden, Andre GAndre GUitterlindenRivadeneira, FernandoFernandoRivadeneiraCropp, Cheryl DCheryl DCroppDaw, E WarwickE WarwickDawvan Heemst, DianaDianavan Heemstde Las Fuentes, LisaLisade Las FuentesGao, HeHeGaoTzoulaki, IoannaIoannaTzoulakiAhluwalia, Tarunveer STarunveer SAhluwaliade Mutsert, RenéeRenéede MutsertEmery, Leslie SLeslie SEmeryErzurumluoglu, A MesutA MesutErzurumluogluPerry, James AJames APerryFu, MaoMaoFuForouhi, Nita GNita GForouhiGu, ZhenglongZhenglongGuHai, YangYangHaiHarris, Sarah ESarah EHarrisHemani, GibranGibranHemaniHunt, Steven CSteven CHuntIrvin, Marguerite RMarguerite RIrvinJonsson, Anna EAnna EJonssonJustice, Anne EAnne EJusticeKerrison, Nicola DNicola DKerrisonLarson, Nicholas BNicholas BLarsonLin, Keng-HungKeng-HungLinLove-Gregory, Latisha DLatisha DLove-GregoryMathias, Rasika ARasika AMathiasLee, Joseph HJoseph HLeeNauck, MatthiasMatthiasNauckNoordam, RaymondRaymondNoordamOng, Ken KKen KOngPankow, JamesJamesPankowPatki, AmitAmitPatkiPattie, AlisonAlisonPattiePetersmann, AstridAstridPetersmannQi, QibinQibinQiRibel-Madsen, RasmusRasmusRibel-MadsenRohde, RebeccaRebeccaRohdeSandow, KevinKevinSandowSchnurr, Theresia MTheresia MSchnurrSofer, TamarTamarSoferStarr, John MJohn MStarrTaylor, Adele MAdele MTaylorTeumer, AlexanderAlexanderTeumerTimpson, Nicholas JNicholas JTimpsonde Haan, Hugoline GHugoline Gde HaanWang, YujieYujieWangWeeke, Peter EPeter EWeekeWilliams, ChristineChristineWilliamsWu, HongshengHongshengWuYang, WeiWeiYangZeng, DonglinDonglinZengWitte, Daniel RDaniel RWitteWeir, Bruce SBruce SWeirWareham, Nicholas JNicholas JWarehamVestergaard, HenrikHenrikVestergaardTurner, Stephen TStephen TTurnerTorp-Pedersen, ChristianChristianTorp-PedersenStergiakouli, EvieEvieStergiakouliSheu, Wayne Huey-HerngWayne Huey-HerngSheuRosendaal, Frits RFrits RRosendaalIkram, M ArfanM ArfanIkramFranco Duran, Oscar HoracioOscar HoracioFranco DuranRidker, Paul MPaul MRidkerPerls, Thomas TThomas TPerlsPedersen, OlufOlufPedersenNohr, Ellen AEllen ANohrNewman, Anne BAnne BNewmanLinneberg, AllanAllanLinnebergLangenberg, ClaudiaClaudiaLangenbergKilpeläinen, Tuomas OTuomas OKilpeläinenKardia, Sharon L RSharon L RKardiaJørgensen, Marit EMarit EJørgensenJørgensen, TorbenTorbenJørgensenSørensen, Thorkild I AThorkild I ASørensenHomuth, GeorgGeorgHomuthHansen, TorbenTorbenHansenGoodarzi, Mark OMark OGoodarziDeary, Ian JIan JDearyChristensen, CramerCramerChristensenChen, Yii-Der IdaYii-Der IdaChenChakravarti, AravindaAravindaChakravartiBrandslund, IvanIvanBrandslundBonnelykke, KlausKlausBonnelykkeTaylor, Kent DKent DTaylorWilson, James GJames GWilsonRodriguez, SantiagoSantiagoRodriguezDavies, GailGailDaviesHorta, Bernardo LBernardo LHortaThyagarajan, BharatBharatThyagarajanRao, D CD CRaoGrarup, NielsNielsGrarupDavila-Roman, Victor GVictor GDavila-RomanHudson, GavinGavinHudsonGuo, XiuqingXiuqingGuoArnett, Donna KDonna KArnettHayward, CarolineCarolineHaywardVaidya, DhananjayDhananjayVaidyaMook-Kanamori, Dennis ODennis OMook-KanamoriTiwari, Hemant KHemant KTiwariLevy, DanielDanielLevyLoos, Ruth J FRuth J FLoosDehghan, AbbasAbbasDehghanElliott, PaulPaulElliottMalik, Afshan NAfshan NMalikScott, Robert ARobert AScottBecker, Diane MDiane MBeckerde Andrade, MarizaMarizade AndradeProvince, Michael AMichael AProvinceMeigs, James BJames BMeigsRotter, Jerome IJerome IRotterNorth, Kari EKari ENorth2024-10-072024-10-072019-01-03https://boris-portal.unibe.ch/handle/20.500.12422/61999Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.enBMI HOMA-B HOMA-IR HbA1c MT-nDNA candidate genes glucose insulin mitochondria mtDNA waist-to-hip ratio600 - Technology::610 - Medicine & health300 - Social sciences, sociology & anthropology::360 - Social problems & social servicesarticle10.7892/boris.1231293059537310.1016/j.ajhg.2018.12.001