biostudies-literature00420Horikoshi MNICHD NIH HHSBritish Heart FoundationMedical Research CouncilNHLBI NIH HHSNational Institute for Health Research (NIHR)Chief Scientist OfficeNNF Center for Basic Metabolic ResearchWellcome TrustNovo Nordisk FondenLundbeck Foundation248-252https://www.ebi.ac.uk/biostudies/studies/S-EPMC5164934biostudies-literatureUnknown538(7624)Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.NatureGenome-wide associations for birth weight and correlations with adult disease.PMC5164934NF-SI-0611-10219R163-2013-16235104150/Z/14/ZCZB/4/733Grarup GroupMC_UU_12013/3MC_UU_12015/1MC_UU_12013/1NNF14OC0012955MR/J012165/1NF-SI-0611-10099R01 HL122684MC_QA137853MC_PC_15018MR/N01104X/1G0601261Hansen GroupG9815508R16-2007-1691R01 HD056465RG/11/4/287341201677104150MC_U106179472MC_UU_12013/5MC_UU_12015/2MC_UU_12013/4P2C HD050924Pedersen GroupG0500070G1001799MC_PC_U127561128McCarthy MIRing SMUitterlinden AGAtalay MScholtens DMSanchez FRosendaal FRGaulton KJVaag AALuan JZhao JHMa RCWMahajan AGroves CJTonjes AZondervan KTMook-Kanamori DOEarly Growth Genetics (EGG) ConsortiumFrayling TMde Haan HGMelbye MBonnelykke KLoh PRSorensen TIGeller Fde Geus EJBennett AJRaitakari OTReynolds RMLyytikainen LPFelix JFStandl MGrant SFOng KKBonas-Guarch SHattersley ATNiinikoski HNewnham JPZeggini EScott RADavies EBustamante MSaw SMHolm JCPanoutsopoulou KFernandez-Tajes JFonvig CEDedoussis GVRueedi RKooijman MNCousminer DLVrijheid MLi-Gao RBorja JBPaternoster LTimpson NJWalker BRNyholt DRCHARGE Consortium Hematology Working GroupHofman AMcMahon GWareham NJTuke MAWiden EECarstensen LRobertson NRDay FRBoomsma DIHollegaard MVGanesh SKJaddoe VWBradfield JPRivadeneira FBisgaard HMentch FDVollenweider PGrarup NWang CANodzenski MSebert SBeilin LJMohlke KLLakka TAMedina-Gomez CKadarmideen HNvan Zuydam NRJoro RPennell CEEvans DMWilson JFTrier CTam WHStumvoll MPisinger CFeenstra BWood ARProkopenko IJones SEAhluwalia TSWang XTeo YYRahmioglu NJoshi PKWu YMurcia Mvan Beijsterveldt CEThiering EPitkanen NMarques-Vidal PWillemsen GHemani GKahonen MDiver LALindi Vvan Duijn CMEriksson JGJarvelin MRLagou VPahkala KHakonarson HLawlor DAvan Leeuwen EMDavey Smith GHorikoshi MTyrrell JFreathy RMWarrington NMAdair LSMercader JMHougaard DMKutalik ZYaghootkar HBeaumont RNSchraut KETorrents DTam CHTPower CVilor-Tejedor NViikari JSLowe WLKiess WKorner APerry JRMorris APHottenga JJLehtimaki TKovacs PPedersen OKreiner EHeinrich JStrachan DPTiesler CMRuth KSLangenberg CAppel EVRCampbell HHansen Tvan Rooij FJWillems SMWaage JNtalla IHave CTBoh ETHMacKenzie SMHypponen E42falseGenome-wide associations for birth weight and correlations with adult disease.Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.2016-01-01T00:00:00Z2016 Oct2024-11-20T08:21:42.07Z2019-03-27T02:31:47ZS-EPMC51649342768069410.1038/nature19806