05728nas a2201213 4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520227000293653001002563653000902573653002202582653001002604653002802614653002102642653004002663653001102703653003402714653001302748653001602761653002102777653001102798653000902809653001602818653001502834653001402849653003602863653001702899653003402916653003102950100002702981700002203008700002103030700001903051700002103070700002203091700002303113700002203136700002303158700001903181700002303200700002003223700002203243700002203265700002203287700001903309700002403328700002003352700001803372700001803390700002303408700002103431700001903452700002603471700002203497700002403519700001803543700002003561700001503581700002703596700002703623700001703650700002303667700002103690700001803711700002103729700001703750700002003767700002003787700002303807700003003830700002303860700002303883700002103906700002503927700002603952700001703978700002203995700001804017700002104035700001904056700002404075700002804099700002204127700002004149700002004169700002004189700002004209700002304229700002204252700002204274700002104296700002404317700002204341700002804363700002404391700002004415700001904435700002404454856003604478 2009 eng d a1538-359800aGenetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.0 aGenetic variants associated with cardiac structure and function c2009 Jul 08 a168-780 v3023 a
CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.
OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.
DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.
MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.
RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).
CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
10aAdult10aAged10aAged, 80 and over10aAorta10aCardiovascular Diseases10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHeart Ventricles10aHumans10aMale10aMiddle Aged10aOrgan Size10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aVentricular Dysfunction, Left10aVentricular Function, Left1 aVasan, Ramachandran, S1 aGlazer, Nicole, L1 aFelix, Janine, F1 aLieb, Wolfgang1 aWild, Philipp, S1 aFelix, Stephan, B1 aWatzinger, Norbert1 aLarson, Martin, G1 aSmith, Nicholas, L1 aDehghan, Abbas1 aGrosshennig, Anika1 aSchillert, Arne1 aTeumer, Alexander1 aSchmidt, Reinhold1 aKathiresan, Sekar1 aLumley, Thomas1 aAulchenko, Yurii, S1 aKönig, Inke, R1 aZeller, Tanja1 aHomuth, Georg1 aStruchalin, Maksim1 aAragam, Jayashri1 aBis, Joshua, C1 aRivadeneira, Fernando1 aErdmann, Jeanette1 aSchnabel, Renate, B1 aDörr, Marcus1 aZweiker, Robert1 aLind, Lars1 aRodeheffer, Richard, J1 aGreiser, Karin, Halina1 aLevy, Daniel1 aHaritunians, Talin1 aDeckers, Jaap, W1 aStritzke, Jan1 aLackner, Karl, J1 aVölker, Uwe1 aIngelsson, Erik1 aKullo, Iftikhar1 aHaerting, Johannes1 aO'Donnell, Christopher, J1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aZiegler, Andreas1 aReffelmann, Thorsten1 aRedfield, Margaret, M1 aWerdan, Karl1 aMitchell, Gary, F1 aRice, Kenneth1 aArnett, Donna, K1 aHofman, Albert1 aGottdiener, John, S1 aUitterlinden, André, G1 aMeitinger, Thomas1 aBlettner, Maria1 aFriedrich, Nele1 aWang, Thomas, J1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aMunzel, Thomas, F1 aKroemer, Heyo, K1 aBenjamin, Emelia, J1 aRotter, Jerome, I1 aWitteman, Jacqueline, C1 aSchunkert, Heribert1 aSchmidt, Helena1 aVölzke, Henry1 aBlankenberg, Stefan uhttps://chs-nhlbi.org/node/110804239nas a2200781 4500008004100000022001400041245024400055210006900299260001300368300001100381490000600392520185900398653002202257653000902279653002202288653001902310653001902329653004002348653001102388653003402399653001802433653001102451653001402462653000902476653001602485653003602501653000902537653003302546100002302579700002102602700002402623700002302647700002202670700002002692700002502712700001902737700001902756700002302775700001902798700002602817700001902843700002102862700002102883700002402904700002302928700001802951700002102969700001802990700002303008700002403031700002303055700002003078700002103098700001903119700002303138700001803161700003003179700002803209700002203237700002403259700001703283700002303300700002003323700003003343700002103373700002703394856003603421 2010 eng d a1942-326800aAssociation of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.0 aAssociation of genomewide variation with the risk of incident he c2010 Jun a256-660 v33 aBACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.
METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.
CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.
10aAfrican Americans10aAged10aAged, 80 and over10aCohort Studies10aEndopeptidases10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHeart Failure10aHumans10aIncidence10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk10aUbiquitin-Specific Proteases1 aSmith, Nicholas, L1 aFelix, Janine, F1 aMorrison, Alanna, C1 aDemissie, Serkalem1 aGlazer, Nicole, L1 aLoehr, Laura, R1 aCupples, Adrienne, L1 aDehghan, Abbas1 aLumley, Thomas1 aRosamond, Wayne, D1 aLieb, Wolfgang1 aRivadeneira, Fernando1 aBis, Joshua, C1 aFolsom, Aaron, R1 aBenjamin, Emelia1 aAulchenko, Yurii, S1 aHaritunians, Talin1 aCouper, David1 aMurabito, Joanne1 aWang, Ying, A1 aStricker, Bruno, H1 aGottdiener, John, S1 aChang, Patricia, P1 aWang, Thomas, J1 aRice, Kenneth, M1 aHofman, Albert1 aHeckbert, Susan, R1 aFox, Ervin, R1 aO'Donnell, Christopher, J1 aUitterlinden, André, G1 aRotter, Jerome, I1 aWillerson, James, T1 aLevy, Daniel1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aWitteman, Jacqueline, C M1 aBoerwinkle, Eric1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/119704080nas a2200757 4500008004100000022001400041245019100055210006900246260001300315300001100328490000600339520181900345653002202164653000902186653002202195653001502217653001902232653004002251653001102291653003402302653001302336653001802349653001102367653001202378653000902390653003802399653002202437653001602459653003602475653001702511100002402528700002102552700002502573700002202598700002002620700001902640700002302659700001902682700002302701700002402724700001802748700002302766700002102789700002602810700002402836700001902860700001802879700002302897700003002920700002102950700002302971700001902994700001703013700002203030700001803052700002803070700002003098700002003118700002403138700002303162700002103185700003003206700002703236700002303263856003603286 2010 eng d a1942-326800aGenomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium.0 aGenomic variation associated with mortality among adults of Euro c2010 Jun a248-550 v33 aBACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.
METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.
CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.
10aAfrican Americans10aAged10aAged, 80 and over10aChemokines10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Failure10aHumans10aIntrons10aMale10aMARVEL Domain-Containing Proteins10aMembrane Proteins10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aMorrison, Alanna, C1 aFelix, Janine, F1 aCupples, Adrienne, L1 aGlazer, Nicole, L1 aLoehr, Laura, R1 aDehghan, Abbas1 aDemissie, Serkalem1 aBis, Joshua, C1 aRosamond, Wayne, D1 aAulchenko, Yurii, S1 aWang, Ying, A1 aHaritunians, Talin1 aFolsom, Aaron, R1 aRivadeneira, Fernando1 aBenjamin, Emelia, J1 aLumley, Thomas1 aCouper, David1 aStricker, Bruno, H1 aO'Donnell, Christopher, J1 aRice, Kenneth, M1 aChang, Patricia, P1 aHofman, Albert1 aLevy, Daniel1 aRotter, Jerome, I1 aFox, Ervin, R1 aUitterlinden, André, G1 aWang, Thomas, J1 aPsaty, Bruce, M1 aWillerson, James, T1 aDuijn, Cornelia, M1 aBoerwinkle, Eric1 aWitteman, Jacqueline, C M1 aVasan, Ramachandran, S1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/118705378nas a2201249 4500008004100000022001400041245010600055210006900161260001600230300001100246490000800257520186000265653000902125653001102134653002902145653003402174653001102208653000902219653001602228653002602244653003602270653004302306653002502349653003202374653001202406653001902418100001902437700002202456700002002478700001902498700002102517700002002538700002602558700002302584700002202607700001602629700001802645700001902663700001602682700002002698700002602718700002102744700002102765700001502786700002002801700002002821700002302841700002202864700002402886700001902910700001802929700002002947700001702967700001902984700002303003700001903026700002103045700002203066700001903088700001903107700001903126700001803145700001903163700002203182700002203204700001703226700002003243700002003263700001903283700002603302700002203328700001903350700002403369700002003393700002203413700001903435700002203454700002003476700002103496700002603517700002003543700002203563700002603585700001903611700002803630700002503658700002003683700001803703700002503721700002403746700001803770700002003788700002503808700002403833700001703857700002003874700002303894700002503917700001903942700002603961700002003987700001704007700002404024700002104048700002304069856003604092 2012 eng d a1535-497000aGenome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.0 aGenomewide association studies identify CHRNA53 and HTR4 in the c2012 Oct 01 a622-320 v1863 aRATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.
MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
10aAged10aFemale10aForced Expiratory Volume10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPulmonary Disease, Chronic Obstructive10aReceptors, Nicotinic10aReceptors, Serotonin, 5-HT410aSmoking10aVital Capacity1 aWilk, Jemma, B1 aShrine, Nick, R G1 aLoehr, Laura, R1 aZhao, Jing Hua1 aManichaikul, Ani1 aLopez, Lorna, M1 aSmith, Albert, Vernon1 aHeckbert, Susan, R1 aSmolonska, Joanna1 aTang, Wenbo1 aLoth, Daan, W1 aCurjuric, Ivan1 aHui, Jennie1 aCho, Michael, H1 aLatourelle, Jeanne, C1 aHenry, Amanda, P1 aAldrich, Melinda1 aBakke, Per1 aBeaty, Terri, H1 aBentley, Amy, R1 aBorecki, Ingrid, B1 aBrusselle, Guy, G1 aBurkart, Kristin, M1 aChen, Ting-Hsu1 aCouper, David1 aCrapo, James, D1 aDavies, Gail1 aDupuis, Josée1 aFranceschini, Nora1 aGulsvik, Amund1 aHancock, Dana, B1 aHarris, Tamara, B1 aHofman, Albert1 aImboden, Medea1 aJames, Alan, L1 aKhaw, Kay-Tee1 aLahousse, Lies1 aLauner, Lenore, J1 aLitonjua, Augusto1 aLiu, Yongmei1 aLohman, Kurt, K1 aLomas, David, A1 aLumley, Thomas1 aMarciante, Kristin, D1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorrison, Alanna, C1 aMusk, Arthur, W1 aMyers, Richard, H1 aNorth, Kari, E1 aPostma, Dirkje, S1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRivadeneira, Fernando1 aRochat, Thierry1 aRotter, Jerome, I1 aArtigas, Maria, Soler1 aStarr, John, M1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aWijmenga, Cisca1 aZanen, Pieter1 aProvince, Michael, A1 aSilverman, Edwin, K1 aDeary, Ian, J1 aPalmer, Lyle, J1 aCassano, Patricia, A1 aGudnason, Vilmundur1 aBarr, Graham1 aLoos, Ruth, J F1 aStrachan, David, P1 aLondon, Stephanie, J1 aBoezen, Marike1 aProbst-Hensch, Nicole1 aGharib, Sina, A1 aHall, Ian, P1 aO'Connor, George, T1 aTobin, Martin, D1 aStricker, Bruno, H uhttps://chs-nhlbi.org/node/609204012nas a2200793 4500008004100000022001400041245009500055210006900150260001300219300001000232490000700242520174500249653005001994653000902044653001502053653001202068653002502080653002702105653001602132653001102148653003802159653002202197653001302219653001102232653000902243653003602252653001702288100002402305700002602329700002502355700002202380700002202402700002202424700002402446700001902470700001902489700001802508700001502526700001202541700002002553700001702573700002502590700002002615700002902635700002402664700002502688700002802713700001902741700001902760700002302779700002202802700002202824700001802846700002202864700002202886700001902908700001902927700003002946700002602976700002303002700002303025700002203048700002203070700002103092700002603113700001903139700002403158856003603182 2014 eng d a1556-387100aCommon variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest.0 aCommon variation in fatty acid metabolic genes and risk of incid c2014 Mar a471-70 v113 aBACKGROUND: There is limited information on genetic factors associated with sudden cardiac arrest (SCA).
OBJECTIVE: To assess the association of common variation in genes in fatty acid pathways with SCA risk.
METHODS: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases.
RESULTS: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (95% confidence interval -21% to -5%) in the discovery phase and 9% lower SCA risk (95% confidence interval -16% to -1%) in the replication phase.
CONCLUSIONS: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.
10a1-Acylglycerophosphocholine O-Acyltransferase10aAged10aAlgorithms10aAlleles10aCase-Control Studies10aDeath, Sudden, Cardiac10aFatty Acids10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenotype10aHumans10aMale10aPolymorphism, Single Nucleotide10aRisk Factors1 aLemaitre, Rozenn, N1 aJohnson, Catherine, O1 aHesselson, Stephanie1 aSotoodehnia, Nona1 aSotoodhenia, Nona1 aMcKnight, Barbara1 aSitlani, Colleen, M1 aRea, Thomas, D1 aKing, Irena, B1 aKwok, Pui-Yan1 aMak, Angel1 aLi, Guo1 aBrody, Jennifer1 aLarson, Eric1 aMozaffarian, Dariush1 aPsaty, Bruce, M1 aHuertas-Vazquez, Adriana1 aTardif, Jean-Claude1 aAlbert, Christine, M1 aLyytikäinen, Leo-Pekka1 aArking, Dan, E1 aKääb, Stefan1 aHuikuri, Heikki, V1 aKrijthe, Bouwe, P1 aEijgelsheim, Mark1 aWang, Ying, A1 aReinier, Kyndaron1 aLehtimäki, Terho1 aPulit, Sara, L1 aBrugada, Ramon1 aMüller-Nurasyid, Martina1 aNewton-Cheh, Chris, H1 aKarhunen, Pekka, J1 aStricker, Bruno, H1 aGoyette, Philippe1 aRotter, Jerome, I1 aChugh, Sumeet, S1 aChakravarti, Aravinda1 aJouven, Xavier1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/632510059nas a2203157 4500008004100000022001400041245012200055210006900177260001300246300001100259490000700270520116100277653001001438653000901448653002501457653002201482653002701504653002401531653001101555653003801566653003401604653001301638653002101651653001101672653002101683653000901704653001601713653001501729653003601744100001901780700001901799700001601818700001501834700002401849700002401873700002201897700002501919700002001944700001801964700002301982700001902005700002802024700002502052700002202077700001902099700002302118700001802141700003002159700002502189700001902214700002602233700001902259700001802278700002502296700002102321700001902342700001902361700002802380700002102408700001802429700002202447700002202469700001702491700001802508700002002526700002102546700002302567700002302590700001802613700002302631700002002654700002502674700002302699700002302722700002602745700001802771700002202789700002502811700002302836700002502859700002102884700002202905700002202927700002302949700001902972700001902991700001703010700002003027700002003047700002103067700002503088700001803113700002303131700002203154700002403176700002003200700001803220700002203238700003903260700001703299700002103316700002203337700002303359700002003382700002203402700001803424700001903442700002003461700001903481700001803500700002003518700001603538700002803554700002103582700001803603700002303621700002003644700002103664700002203685700003003707700001703737700001703754700002203771700002103793700002403814700002103838700002403859700002203883700001603905700002203921700002203943700002103965700001903986700001904005700001904024700001804043700002404061700001904085700002304104700002204127700002004149700001904169700002204188700002204210700002004232700002004252700001804272700002204290700002604312700002304338700001704361700003104378700002704409700001804436700002404454700001804478700002304496700002004519700002704539700002404566700003004590700001704620700002004637700002004657700001904677700002104696700002404717700002404741700002504765700002304790700002604813700002604839700002704865700002604892700001604918700002204934700002004956700001904976700002504995700001805020700002705038700002405065700001805089700002905107700002805136700002005164700002205184700002105206700001905227700001705246700002805263700003005291700002205321700002005343700001905363700002505382700002305407700002105430700001705451700002405468700001705492700002605509700001705535700002005552700002405572700001905596700001505615700002205630700002805652700001905680700002005699700001805719700002305737700002205760700001905782700001905801700001705820700002605837700002405863700002305887700002405910700002005934700002205954700002405976700002506000700002306025700002006048700002006068700002106088700002106109700001606130700001806146700002606164700002606190700002506216700002406241700001806265700001706283700002306300700002406323700002406347700002006371700002006391700002206411700001806433700002406451700002306475700002106498700002106519700002306540700002106563700001706584700002306601700001906624700002606643700002506669700001806694700002506712700002906737710002006766710002206786710001406808710002206822710002106844856003606865 2014 eng d a1546-171800aGenetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.0 aGenetic association study of QT interval highlights role for cal c2014 Aug a826-360 v463 aThe QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
10aAdult10aAged10aArrhythmias, Cardiac10aCalcium Signaling10aDeath, Sudden, Cardiac10aElectrocardiography10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHeart Ventricles10aHumans10aLong QT Syndrome10aMale10aMiddle Aged10aMyocardium10aPolymorphism, Single Nucleotide1 aArking, Dan, E1 aPulit, Sara, L1 aCrotti, Lia1 aHarst, Pim1 aMunroe, Patricia, B1 aKoopmann, Tamara, T1 aSotoodehnia, Nona1 aRossin, Elizabeth, J1 aMorley, Michael1 aWang, Xinchen1 aJohnson, Andrew, D1 aLundby, Alicia1 aGudbjartsson, Daniel, F1 aNoseworthy, Peter, A1 aEijgelsheim, Mark1 aBradford, Yuki1 aTarasov, Kirill, V1 aDörr, Marcus1 aMüller-Nurasyid, Martina1 aLahtinen, Annukka, M1 aNolte, Ilja, M1 aSmith, Albert, Vernon1 aBis, Joshua, C1 aIsaacs, Aaron1 aNewhouse, Stephen, J1 aEvans, Daniel, S1 aPost, Wendy, S1 aWaggott, Daryl1 aLyytikäinen, Leo-Pekka1 aHicks, Andrew, A1 aEisele, Lewin1 aEllinghaus, David1 aHayward, Caroline1 aNavarro, Pau1 aUlivi, Sheila1 aTanaka, Toshiko1 aTester, David, J1 aChatel, Stéphanie1 aGustafsson, Stefan1 aKumari, Meena1 aMorris, Richard, W1 aNaluai, Åsa, T1 aPadmanabhan, Sandosh1 aKluttig, Alexander1 aStrohmer, Bernhard1 aPanayiotou, Andrie, G1 aTorres, Maria1 aKnoflach, Michael1 aHubacek, Jaroslav, A1 aSlowikowski, Kamil1 aRaychaudhuri, Soumya1 aKumar, Runjun, D1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShuldiner, Alan, R1 aAlonso, Alvaro1 aBader, Joel, S1 aEhret, Georg1 aHuang, Hailiang1 aKao, Linda, W H1 aStrait, James, B1 aMacfarlane, Peter, W1 aBrown, Morris1 aCaulfield, Mark, J1 aSamani, Nilesh, J1 aKronenberg, Florian1 aWilleit, Johann1 aSmith, Gustav1 aGreiser, Karin, H1 aSchwabedissen, Henriette, Meyer Zu1 aWerdan, Karl1 aCarella, Massimo1 aZelante, Leopoldo1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aKolcic, Ivana1 aPolasek, Ozren1 aWright, Alan, F1 aGriffin, Maura1 aDaly, Mark, J1 aArnar, David, O1 aHolm, Hilma1 aThorsteinsdottir, Unnur1 aDenny, Joshua, C1 aRoden, Dan, M1 aZuvich, Rebecca, L1 aEmilsson, Valur1 aPlump, Andrew, S1 aLarson, Martin, G1 aO'Donnell, Christopher, J1 aYin, Xiaoyan1 aBobbo, Marco1 aD'Adamo, Adamo, P1 aIorio, Annamaria1 aSinagra, Gianfranco1 aCarracedo, Angel1 aCummings, Steven, R1 aNalls, Michael, A1 aJula, Antti1 aKontula, Kimmo, K1 aMarjamaa, Annukka1 aOikarinen, Lasse1 aPerola, Markus1 aPorthan, Kimmo1 aErbel, Raimund1 aHoffmann, Per1 aJöckel, Karl-Heinz1 aKälsch, Hagen1 aNöthen, Markus, M1 aHoed, Marcel, den1 aLoos, Ruth, J F1 aThelle, Dag, S1 aGieger, Christian1 aMeitinger, Thomas1 aPerz, Siegfried1 aPeters, Annette1 aPrucha, Hanna1 aSinner, Moritz, F1 aWaldenberger, Melanie1 ade Boer, Rudolf, A1 aFranke, Lude1 avan der Vleuten, Pieter, A1 aBeckmann, Britt, Maria1 aMartens, Eimo1 aBardai, Abdennasser1 aHofman, Nynke1 aWilde, Arthur, A M1 aBehr, Elijah, R1 aDalageorgou, Chrysoula1 aGiudicessi, John, R1 aMedeiros-Domingo, Argelia1 aBarc, Julien1 aKyndt, Florence1 aProbst, Vincent1 aGhidoni, Alice1 aInsolia, Roberto1 aHamilton, Robert, M1 aScherer, Stephen, W1 aBrandimarto, Jeffrey1 aMargulies, Kenneth1 aMoravec, Christine, E1 aM, Fabiola, del Greco1 aFuchsberger, Christian1 aO'Connell, Jeffrey, R1 aLee, Wai, K1 aWatt, Graham, C M1 aCampbell, Harry1 aWild, Sarah, H1 aMokhtari, Nour, E El1 aFrey, Norbert1 aAsselbergs, Folkert, W1 aLeach, Irene, Mateo1 aNavis, Gerjan1 avan den Berg, Maarten, P1 avan Veldhuisen, Dirk, J1 aKellis, Manolis1 aKrijthe, Bouwe, P1 aFranco, Oscar, H1 aHofman, Albert1 aKors, Jan, A1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aKedenko, Lyudmyla1 aLamina, Claudia1 aOostra, Ben, A1 aAbecasis, Goncalo, R1 aLakatta, Edward, G1 aMulas, Antonella1 aOrrù, Marco1 aSchlessinger, David1 aUda, Manuela1 aMarkus, Marcello, R P1 aVölker, Uwe1 aSnieder, Harold1 aSpector, Timothy, D1 aArnlöv, Johan1 aLind, Lars1 aSundström, Johan1 aSyvänen, Ann-Christine1 aKivimaki, Mika1 aKähönen, Mika1 aMononen, Nina1 aRaitakari, Olli, T1 aViikari, Jorma, S1 aAdamkova, Vera1 aKiechl, Stefan1 aBrion, Maria1 aNicolaides, Andrew, N1 aPaulweber, Bernhard1 aHaerting, Johannes1 aDominiczak, Anna, F1 aNyberg, Fredrik1 aWhincup, Peter, H1 aHingorani, Aroon, D1 aSchott, Jean-Jacques1 aBezzina, Connie, R1 aIngelsson, Erik1 aFerrucci, Luigi1 aGasparini, Paolo1 aWilson, James, F1 aRudan, Igor1 aFranke, Andre1 aMühleisen, Thomas, W1 aPramstaller, Peter, P1 aLehtimäki, Terho, J1 aPaterson, Andrew, D1 aParsa, Afshin1 aLiu, Yongmei1 aDuijn, Cornelia, M1 aSiscovick, David, S1 aGudnason, Vilmundur1 aJamshidi, Yalda1 aSalomaa, Veikko1 aFelix, Stephan, B1 aSanna, Serena1 aRitchie, Marylyn, D1 aStricker, Bruno, H1 aStefansson, Kari1 aBoyer, Laurie, A1 aCappola, Thomas, P1 aOlsen, Jesper, V1 aLage, Kasper1 aSchwartz, Peter, J1 aKääb, Stefan1 aChakravarti, Aravinda1 aAckerman, Michael, J1 aPfeufer, Arne1 ade Bakker, Paul, I W1 aNewton-Cheh, Christopher1 aCARe Consortium1 aCOGENT Consortium1 aDCCT/EDIC1 aeMERGE Consortium1 aHRGEN Consortium uhttps://chs-nhlbi.org/node/654407147nas a2202257 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2014 eng d a1546-171800aGenome-wide association analysis identifies six new loci associated with forced vital capacity.0 aGenomewide association analysis identifies six new loci associat c2014 Jul a669-770 v463 aForced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
10aCohort Studies10aDatabases, Genetic10aFollow-Up Studies10aForced Expiratory Volume10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLung Diseases10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aPrognosis10aQuantitative Trait Loci10aRespiratory Function Tests10aSpirometry10aVital Capacity1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aWain, Louise, V1 aFranceschini, Nora1 aKoch, Beate1 aPottinger, Tess, D1 aSmith, Albert, Vernon1 aDuan, Qing1 aOldmeadow, Chris1 aLee, Mi, Kyeong1 aStrachan, David, P1 aJames, Alan, L1 aHuffman, Jennifer, E1 aVitart, Veronique1 aRamasamy, Adaikalavan1 aWareham, Nicholas, J1 aKaprio, Jaakko1 aWang, Xin-Qun1 aTrochet, Holly1 aKähönen, Mika1 aFlexeder, Claudia1 aAlbrecht, Eva1 aLopez, Lorna, M1 ade Jong, Kim1 aThyagarajan, Bharat1 aAlves, Alexessander, Couto1 aEnroth, Stefan1 aOmenaas, Ernst1 aJoshi, Peter, K1 aFall, Tove1 aViñuela, Ana1 aLauner, Lenore, J1 aLoehr, Laura, R1 aFornage, Myriam1 aLi, Guo1 aWilk, Jemma, B1 aTang, Wenbo1 aManichaikul, Ani1 aLahousse, Lies1 aHarris, Tamara, B1 aNorth, Kari, E1 aRudnicka, Alicja, R1 aHui, Jennie1 aGu, Xiangjun1 aLumley, Thomas1 aWright, Alan, F1 aHastie, Nicholas, D1 aCampbell, Susan1 aKumar, Rajesh1 aPin, Isabelle1 aScott, Robert, A1 aPietiläinen, Kirsi, H1 aSurakka, Ida1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aSchulz, Holger1 aHeinrich, Joachim1 aDavies, Gail1 aVonk, Judith, M1 aWojczynski, Mary1 aPouta, Anneli1 aJohansson, Asa1 aWild, Sarah, H1 aIngelsson, Erik1 aRivadeneira, Fernando1 aVölzke, Henry1 aHysi, Pirro, G1 aEiriksdottir, Gudny1 aMorrison, Alanna, C1 aRotter, Jerome, I1 aGao, Wei1 aPostma, Dirkje, S1 aWhite, Wendy, B1 aRich, Stephen, S1 aHofman, Albert1 aAspelund, Thor1 aCouper, David1 aSmith, Lewis, J1 aPsaty, Bruce, M1 aLohman, Kurt1 aBurchard, Esteban, G1 aUitterlinden, André, G1 aGarcia, Melissa1 aJoubert, Bonnie, R1 aMcArdle, Wendy, L1 aMusk, Bill1 aHansel, Nadia1 aHeckbert, Susan, R1 aZgaga, Lina1 avan Meurs, Joyce, B J1 aNavarro, Pau1 aRudan, Igor1 aOh, Yeon-Mok1 aRedline, Susan1 aJarvis, Deborah, L1 aZhao, Jing Hua1 aRantanen, Taina1 aO'Connor, George, T1 aRipatti, Samuli1 aScott, Rodney, J1 aKarrasch, Stefan1 aGrallert, Harald1 aGaddis, Nathan, C1 aStarr, John, M1 aWijmenga, Cisca1 aMinster, Ryan, L1 aLederer, David, J1 aPekkanen, Juha1 aGyllensten, Ulf1 aCampbell, Harry1 aMorris, Andrew, P1 aGläser, Sven1 aHammond, Christopher, J1 aBurkart, Kristin, M1 aBeilby, John1 aKritchevsky, Stephen, B1 aGudnason, Vilmundur1 aHancock, Dana, B1 aWilliams, Dale1 aPolasek, Ozren1 aZemunik, Tatijana1 aKolcic, Ivana1 aPetrini, Marcy, F1 aWjst, Matthias1 aKim, Woo, Jin1 aPorteous, David, J1 aScotland, Generation1 aSmith, Blair, H1 aViljanen, Anne1 aHeliövaara, Markku1 aAttia, John, R1 aSayers, Ian1 aHampel, Regina1 aGieger, Christian1 aDeary, Ian, J1 aBoezen, Marike1 aNewman, Anne1 aJarvelin, Marjo-Riitta1 aWilson, James, F1 aLind, Lars1 aStricker, Bruno, H1 aTeumer, Alexander1 aSpector, Timothy, D1 aMelén, Erik1 aPeters, Marjolein, J1 aLange, Leslie, A1 aBarr, Graham1 aBracke, Ken, R1 aVerhamme, Fien, M1 aSung, Joohon1 aHiemstra, Pieter, S1 aCassano, Patricia, A1 aSood, Akshay1 aHayward, Caroline1 aDupuis, Josée1 aHall, Ian, P1 aBrusselle, Guy, G1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/658205294nas a2201225 4500008004100000022001400041245011300055210006900168260000900237300001200246490000600258520192600264653001002190653003202200653001102232653003102243653001702274653003402291653001102325653002502336653000902361653001602370100001602386700002102402700001802423700002602441700002302467700001702490700002002507700002102527700002002548700002402568700002302592700002202615700002102637700002202658700002402680700002302704700001802727700002402745700002302769700001702792700002202809700002102831700001902852700001702871700001802888700001902906700001502925700001902940700002302959700001302982700001802995700001703013700002103030700002203051700001903073700001903092700002003111700001603131700002103147700001603168700002803184700001803212700001903230700001203249700001503261700002203276700001703298700001703315700001903332700002203351700001903373700002203392700002403414700001503438700001903453700002003472700002903492700002003521700002603541700002203567700001903589700002003608700001703628700001903645700002303664700002203687700002803709700001903737700001903756700002003775700002103795700001903816700001903835700002303854700002303877700002503900700002003925700002103945700002403966700001703990700002504007856003604032 2014 eng d a1932-620300aLarge-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.0 aLargescale genomewide association studies and metaanalyses of lo c2014 ae1007760 v93 aBACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
10aAdult10aChromosomes, Human, Pair 1110aFemale10aGene Expression Regulation10aGenetic Loci10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aMale10aRespiration1 aTang, Wenbo1 aKowgier, Matthew1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aJoubert, Bonnie, R1 aHodge, Emily1 aGharib, Sina, A1 aSmith, Albert, V1 aRuczinski, Ingo1 aGudnason, Vilmundur1 aMathias, Rasika, A1 aHarris, Tamara, B1 aHansel, Nadia, N1 aLauner, Lenore, J1 aBarnes, Kathleen, C1 aHansen, Joyanna, G1 aAlbrecht, Eva1 aAldrich, Melinda, C1 aAllerhand, Michael1 aBarr, Graham1 aBrusselle, Guy, G1 aCouper, David, J1 aCurjuric, Ivan1 aDavies, Gail1 aDeary, Ian, J1 aDupuis, Josée1 aFall, Tove1 aFoy, Millennia1 aFranceschini, Nora1 aGao, Wei1 aGläser, Sven1 aGu, Xiangjun1 aHancock, Dana, B1 aHeinrich, Joachim1 aHofman, Albert1 aImboden, Medea1 aIngelsson, Erik1 aJames, Alan1 aKarrasch, Stefan1 aKoch, Beate1 aKritchevsky, Stephen, B1 aKumar, Ashish1 aLahousse, Lies1 aLi, Guo1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLohman, Kurt1 aLumley, Thomas1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMusk, Bill1 aNorth, Kari, E1 aPalmer, Lyle, J1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchulz, Holger1 aSmith, Lewis, J1 aSood, Akshay1 aStarr, John, M1 aStrachan, David, P1 aTeumer, Alexander1 aUitterlinden, André, G1 aVölzke, Henry1 aVoorman, Arend1 aWain, Louise, V1 aWells, Martin, T1 aWilk, Jemma, B1 aWilliams, Dale1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aLondon, Stephanie, J1 aFornage, Myriam1 aTobin, Martin, D1 aO'Connor, George, T1 aHall, Ian, P1 aCassano, Patricia, A uhttps://chs-nhlbi.org/node/660404953nas a2201105 4500008004100000022001400041245009300055210006900148260001500217300001200232490000700244520183400251653001002085653000902095653002202104653003702126653002402163653002302187653003102210653001102241653004002252653001102292653002002303653003802323653002502361653001102386653001002397653000902407653001602416653003602432653002602468100002202494700002402516700001902540700001902559700002002578700001202598700002202610700002302632700001802655700002202673700001802695700001902713700002102732700003002753700001902783700002202802700001902824700002302843700001702866700002402883700001402907700002102921700002202942700001902964700001902983700001903002700002203021700001903043700002203062700002503084700002203109700002203131700002203153700002003175700002003195700001903215700002203234700002603256700002303282700002203305700002003327700002003347700002403367700002303391700002803414700002603442700001703468700001903485700002403504700002203528700002403550700002203574700002003596700001603616700002503632700002303657700002203680700002303702700001903725700001903744700002403763700002403787856003603811 2014 eng d a1558-359700aNovel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.0 aNovel genetic markers associate with atrial fibrillation risk in c2014 Apr 1 a1200-100 v633 aOBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factors1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aLin, Honghuang1 aArking, Dan, E1 aTrompet, Stella1 aLi, Guo1 aKrijthe, Bouwe, P1 aChasman, Daniel, I1 aBarnard, John1 aKleber, Marcus, E1 aDörr, Marcus1 aOzaki, Kouichi1 aSmith, Albert, V1 aMüller-Nurasyid, Martina1 aWalter, Stefan1 aAgarwal, Sunil, K1 aBis, Joshua, C1 aBrody, Jennifer, A1 aChen, Lin, Y1 aEverett, Brendan, M1 aFord, Ian1 aFranco, Oscar, H1 aHarris, Tamara, B1 aHofman, Albert1 aKääb, Stefan1 aMahida, Saagar1 aKathiresan, Sekar1 aKubo, Michiaki1 aLauner, Lenore, J1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aMcKnight, Barbara1 aMcManus, David, D1 aPeters, Annette1 aPsaty, Bruce, M1 aRose, Lynda, M1 aRotter, Jerome, I1 aSilbernagel, Guenther1 aSmith, Jonathan, D1 aSotoodehnia, Nona1 aStott, David, J1 aTaylor, Kent, D1 aTomaschitz, Andreas1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aMurabito, Joanne, M1 aSinner, Moritz, F1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aMärz, Winfried1 aChung, Mina1 aAlbert, Christine, M1 aStricker, Bruno, H1 aTanaka, Toshihiro1 aHeckbert, Susan, R1 aJukema, Wouter1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/682004872nas a2201453 4500008004100000022001400041245010900055210006900164260001600233300000900249490000600258520072200264653002100986653003401007653001101041653005101052653002101103653003601124100001801160700002001178700002501198700002301223700001601246700002101262700002301283700001701306700002501323700002401348700002201372700002201394700001901416700001701435700002001452700001201472700002101484700002101505700002801526700002301554700002501577700002001602700002401622700001401646700002601660700002001686700001901706700002401725700001701749700001801766700001901784700002201803700001801825700002201843700001901865700002601884700002101910700002501931700002401956700001801980700002501998700002202023700002102045700001702066700002402083700001602107700001602123700001902139700002202158700001602180700001902196700001902215700001802234700002302252700001902275700002102294700001802315700002102333700002002354700003002374700002702404700001602431700002202447700001802469700001602487700001702503700002302520700001602543700002202559700002102581700002602602700002002628700002502648700002802673700002402701700002302725700002202748700001902770700002302789700002302812700002202835700002002857700002302877700002802900700001902928700002602947700002002973700002102993700002003014700002403034700001703058700002103075700002803096700002203124700002203146700002003168700002303188700002403211700002203235700001903257700002203276700001903298700002303317710004203340856003603382 2014 eng d a2041-172300aPharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.0 aPharmacogenetic metaanalysis of genomewide association studies o c2014 Oct 28 a50680 v53 aStatins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
10aCholesterol, LDL10aGenome-Wide Association Study10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aPharmacogenetics10aPolymorphism, Single Nucleotide1 aPostmus, Iris1 aTrompet, Stella1 aDeshmukh, Harshal, A1 aBarnes, Michael, R1 aLi, Xiaohui1 aWarren, Helen, R1 aChasman, Daniel, I1 aZhou, Kaixin1 aArsenault, Benoit, J1 aDonnelly, Louise, A1 aWiggins, Kerri, L1 aAvery, Christy, L1 aGriffin, Paula1 aFeng, QiPing1 aTaylor, Kent, D1 aLi, Guo1 aEvans, Daniel, S1 aSmith, Albert, V1 ade Keyser, Catherine, E1 aJohnson, Andrew, D1 ade Craen, Anton, J M1 aStott, David, J1 aBuckley, Brendan, M1 aFord, Ian1 aWestendorp, Rudi, G J1 aSlagboom, Eline1 aSattar, Naveed1 aMunroe, Patricia, B1 aSever, Peter1 aPoulter, Neil1 aStanton, Alice1 aShields, Denis, C1 aO'Brien, Eoin1 aShaw-Hawkins, Sue1 aChen, Y-D, Ida1 aNickerson, Deborah, A1 aSmith, Joshua, D1 aDubé, Marie, Pierre1 aBoekholdt, Matthijs1 aHovingh, Kees1 aKastelein, John, J P1 aMcKeigue, Paul, M1 aBetteridge, John1 aNeil, Andrew1 aDurrington, Paul, N1 aDoney, Alex1 aCarr, Fiona1 aMorris, Andrew1 aMcCarthy, Mark, I1 aGroop, Leif1 aAhlqvist, Emma1 aBis, Joshua, C1 aRice, Kenneth1 aSmith, Nicholas, L1 aLumley, Thomas1 aWhitsel, Eric, A1 aStürmer, Til1 aBoerwinkle, Eric1 aNgwa, Julius, S1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWei, Wei-Qi1 aWilke, Russell, A1 aLiu, Ching-Ti1 aSun, Fangui1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aPost, Wendy1 aSotoodehnia, Nona1 aArnold, Alice, M1 aStafford, Jeanette, M1 aDing, Jingzhong1 aHerrington, David, M1 aKritchevsky, Stephen, B1 aEiriksdottir, Gudny1 aLauner, Leonore, J1 aHarris, Tamara, B1 aChu, Audrey, Y1 aGiulianini, Franco1 aMacFadyen, Jean, G1 aBarratt, Bryan, J1 aNyberg, Fredrik1 aStricker, Bruno, H1 aUitterlinden, André, G1 aHofman, Albert1 aRivadeneira, Fernando1 aEmilsson, Valur1 aFranco, Oscar, H1 aRidker, Paul, M1 aGudnason, Vilmundur1 aLiu, Yongmei1 aDenny, Joshua, C1 aBallantyne, Christie, M1 aRotter, Jerome, I1 aCupples, Adrienne1 aPsaty, Bruce, M1 aPalmer, Colin, N A1 aTardif, Jean-Claude1 aColhoun, Helen, M1 aHitman, Graham1 aKrauss, Ronald, M1 aJukema, Wouter1 aCaulfield, Mark, J1 aWelcome Trust Case Control Consortium uhttps://chs-nhlbi.org/node/659105255nas a2200949 4500008004100000022001400041245015700055210006900212260000900281300001300290490000700303520251800310653002202828653000902850653002802859653002802887653004002915653001102955653003402966653001103000653001703011653001403028653000903042653001603051653003603067653002203103100001903125700002103144700001603165700002203181700002603203700001603229700002103245700002303266700001603289700002003305700002203325700002203347700002103369700002303390700002303413700002003436700002203456700002303478700002103501700002203522700002003544700002103564700002203585700001803607700002003625700002503645700002203670700002303692700001703715700002103732700002303753700002403776700002003800700002103820700002203841700002503863700002803888700002203916700001403938700001903952700001903971700002003990700002604010700002404036700002704060700001904087700002404106700002204130700001604152700001904168700002304187700002104210700002004231700001804251856003604269 2015 eng d a1932-620300aDrug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.0 aDrugGene Interactions of Antihypertensive Medications and Risk o c2015 ae01404960 v103 aBACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).
RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.
10aAfrican Americans10aAged10aAntihypertensive Agents10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aHypertension10aIncidence10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTreatment Outcome1 aBis, Joshua, C1 aSitlani, Colleen1 aIrvin, Ryan1 aAvery, Christy, L1 aSmith, Albert, Vernon1 aSun, Fangui1 aEvans, Daniel, S1 aMusani, Solomon, K1 aLi, Xiaohui1 aTrompet, Stella1 aKrijthe, Bouwe, P1 aHarris, Tamara, B1 aQuibrera, Miguel1 aBrody, Jennifer, A1 aDemissie, Serkalem1 aDavis, Barry, R1 aWiggins, Kerri, L1 aTranah, Gregory, J1 aLange, Leslie, A1 aSotoodehnia, Nona1 aStott, David, J1 aFranco, Oscar, H1 aLauner, Lenore, J1 aStürmer, Til1 aTaylor, Kent, D1 aCupples, Adrienne, L1 aEckfeldt, John, H1 aSmith, Nicholas, L1 aLiu, Yongmei1 aWilson, James, G1 aHeckbert, Susan, R1 aBuckley, Brendan, M1 aIkram, Arfan, M1 aBoerwinkle, Eric1 aChen, Yii-Der Ida1 ade Craen, Anton, J M1 aUitterlinden, André, G1 aRotter, Jerome, I1 aFord, Ian1 aHofman, Albert1 aSattar, Naveed1 aSlagboom, Eline1 aWestendorp, Rudi, G J1 aGudnason, Vilmundur1 aVasan, Ramachandran, S1 aLumley, Thomas1 aCummings, Steven, R1 aTaylor, Herman, A1 aPost, Wendy1 aJukema, Wouter1 aStricker, Bruno, H1 aWhitsel, Eric, A1 aPsaty, Bruce, M1 aArnett, Donna uhttps://chs-nhlbi.org/node/687507420nas a2202053 4500008004100000022001400041245005000055210004800105260001600153300001200169490000700181520170000188100001501888700002401903700001801927700001801945700001701963700002401980700001802004700002402022700002202046700002202068700002202090700002102112700002202133700002802155700001902183700002002202700001902222700001802241700002002259700003002279700002102309700001802330700002202348700002202370700002602392700001802418700001902436700002202455700002502477700002302502700001602525700002502541700002502566700001902591700001802610700001902628700001702647700002402664700002002688700002102708700002602729700001702755700002502772700002502797700002602822700002402848700002002872700001402892700002202906700002202928700001702950700002102967700002302988700002103011700002403032700001903056700002003075700002003095700002103115700002003136700002003156700001803176700002503194700002203219700001703241700002303258700001703281700002203298700001703320700001903337700002503356700001503381700002203396700002103418700002003439700001903459700001603478700001803494700001903512700001903531700002103550700001903571700002403590700002303614700001803637700002003655700002003675700002003695700001803715700002503733700002603758700001903784700002303803700002503826700001703851700002503868700002203893700002303915700002403938700002403962700002203986700002504008700002404033700002204057700002304079700002404102700002404126700002004150700003204170700002104202700002404223700002004247700002304267700001704290700002804307700002804335700002304363700001904386700002204405700002304427700002204450700001704472700002604489700003204515700002104547700002004568700002804588700001504616700002304631700002404654700002004678700002004698700001604718700002104734700002704755700002804782700002304810700002004833700001904853700001804872700002204890700002104912700002504933700001904958700002104977700001904998700001905017700002405036700002205060700002305082700002305105700002905128700002105157700002205178700002005200700001605220700002905236700001805265700002205283700002505305856003605330 2016 eng d a1558-359700a52 Genetic Loci Influencing Myocardial Mass.0 a52 Genetic Loci Influencing Myocardial Mass c2016 Sep 27 a1435-480 v683 aBACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.
OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.
METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.
RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.
CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
1 aHarst, Pim1 avan Setten, Jessica1 aVerweij, Niek1 aVogler, Georg1 aFranke, Lude1 aMaurano, Matthew, T1 aWang, Xinchen1 aLeach, Irene, Mateo1 aEijgelsheim, Mark1 aSotoodehnia, Nona1 aHayward, Caroline1 aSorice, Rossella1 aMeirelles, Osorio1 aLyytikäinen, Leo-Pekka1 aPolasek, Ozren1 aTanaka, Toshiko1 aArking, Dan, E1 aUlivi, Sheila1 aTrompet, Stella1 aMüller-Nurasyid, Martina1 aSmith, Albert, V1 aDörr, Marcus1 aKerr, Kathleen, F1 aMagnani, Jared, W1 aM, Fabiola, del Greco1 aZhang, Weihua1 aNolte, Ilja, M1 aSilva, Claudia, T1 aPadmanabhan, Sandosh1 aTragante, Vinicius1 aEsko, Tõnu1 aAbecasis, Goncalo, R1 aAdriaens, Michiel, E1 aAndersen, Karl1 aBarnett, Phil1 aBis, Joshua, C1 aBodmer, Rolf1 aBuckley, Brendan, M1 aCampbell, Harry1 aCannon, Megan, V1 aChakravarti, Aravinda1 aChen, Lin, Y1 aDelitala, Alessandro1 aDevereux, Richard, B1 aDoevendans, Pieter, A1 aDominiczak, Anna, F1 aFerrucci, Luigi1 aFord, Ian1 aGieger, Christian1 aHarris, Tamara, B1 aHaugen, Eric1 aHeinig, Matthias1 aHernandez, Dena, G1 aHillege, Hans, L1 aHirschhorn, Joel, N1 aHofman, Albert1 aHubner, Norbert1 aHwang, Shih-Jen1 aIorio, Annamaria1 aKähönen, Mika1 aKellis, Manolis1 aKolcic, Ivana1 aKooner, Ishminder, K1 aKooner, Jaspal, S1 aKors, Jan, A1 aLakatta, Edward, G1 aLage, Kasper1 aLauner, Lenore, J1 aLevy, Daniel1 aLundby, Alicia1 aMacfarlane, Peter, W1 aMay, Dalit1 aMeitinger, Thomas1 aMetspalu, Andres1 aNappo, Stefania1 aNaitza, Silvia1 aNeph, Shane1 aNord, Alex, S1 aNutile, Teresa1 aOkin, Peter, M1 aOlsen, Jesper, V1 aOostra, Ben, A1 aPenninger, Josef, M1 aPennacchio, Len, A1 aPers, Tune, H1 aPerz, Siegfried1 aPeters, Annette1 aPinto, Yigal, M1 aPfeufer, Arne1 aPilia, Maria, Grazia1 aPramstaller, Peter, P1 aPrins, Bram, P1 aRaitakari, Olli, T1 aRaychaudhuri, Soumya1 aRice, Ken, M1 aRossin, Elizabeth, J1 aRotter, Jerome, I1 aSchafer, Sebastian1 aSchlessinger, David1 aSchmidt, Carsten, O1 aSehmi, Jobanpreet1 aSilljé, Herman, H W1 aSinagra, Gianfranco1 aSinner, Moritz, F1 aSlowikowski, Kamil1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aSpiering, Wilko1 aStamatoyannopoulos, John, A1 aStolk, Ronald, P1 aStrauch, Konstantin1 aTan, Sian-Tsung1 aTarasov, Kirill, V1 aTrinh, Bosco1 aUitterlinden, André, G1 avan den Boogaard, Malou1 aDuijn, Cornelia, M1 aGilst, Wiek, H1 aViikari, Jorma, S1 aVisscher, Peter, M1 aVitart, Veronique1 aVölker, Uwe1 aWaldenberger, Melanie1 aWeichenberger, Christian, X1 aWestra, Harm-Jan1 aWijmenga, Cisca1 aWolffenbuttel, Bruce, H1 aYang, Jian1 aBezzina, Connie, R1 aMunroe, Patricia, B1 aSnieder, Harold1 aWright, Alan, F1 aRudan, Igor1 aBoyer, Laurie, A1 aAsselbergs, Folkert, W1 avan Veldhuisen, Dirk, J1 aStricker, Bruno, H1 aPsaty, Bruce, M1 aCiullo, Marina1 aSanna, Serena1 aLehtimäki, Terho1 aWilson, James, F1 aBandinelli, Stefania1 aAlonso, Alvaro1 aGasparini, Paolo1 aJukema, Wouter1 aKääb, Stefan1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aHeckbert, Susan, R1 ade Boer, Rudolf, A1 aNewton-Cheh, Christopher1 aHicks, Andrew, A1 aChambers, John, C1 aJamshidi, Yalda1 aVisel, Axel1 aChristoffels, Vincent, M1 aIsaacs, Aaron1 aSamani, Nilesh, J1 ade Bakker, Paul, I W uhttps://chs-nhlbi.org/node/726204724nas a2201189 4500008004100000022001400041245009300055210006900148260001300217300001200230490000700242520135800249100001801607700002101625700002001646700002501666700002201691700001901713700002301732700002801755700002501783700002101808700001701829700001601846700002201862700002101884700001601905700002001921700002101941700002301962700002201985700002102007700002402028700002102052700002402073700001902097700002502116700002402141700002102165700002502186700002402211700002402235700001402259700001702273700002202290700002302312700001902335700001802354700002502372700002302397700001802420700001702438700001902455700002202474700002402496700001702520700002602537700002002563700001802583700003002601700001602631700001802647700002702665700001802692700002102710700002602731700001902757700001702776700002202793700002202815700002002837700002302857700002102880700002202901700001902923700002002942700002302962700001802985700002803003700001603031700002603047700002103073700002203094700002203116700002803138700002203166700002503188700002103213700002403234700001903258700002303277700002003300700002003320700002603340700002203366700002403388700002303412700001903435700002203454700002203476856003603498 2016 eng d a1468-624400aMeta-analysis of genome-wide association studies of HDL cholesterol response to statins.0 aMetaanalysis of genomewide association studies of HDL cholestero c2016 Dec a835-8450 v533 aBACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.
METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.
CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
1 aPostmus, Iris1 aWarren, Helen, R1 aTrompet, Stella1 aArsenault, Benoit, J1 aAvery, Christy, L1 aBis, Joshua, C1 aChasman, Daniel, I1 ade Keyser, Catherine, E1 aDeshmukh, Harshal, A1 aEvans, Daniel, S1 aFeng, QiPing1 aLi, Xiaohui1 aSmit, Roelof, A J1 aSmith, Albert, V1 aSun, Fangui1 aTaylor, Kent, D1 aArnold, Alice, M1 aBarnes, Michael, R1 aBarratt, Bryan, J1 aBetteridge, John1 aBoekholdt, Matthijs1 aBoerwinkle, Eric1 aBuckley, Brendan, M1 aChen, Y-D, Ida1 ade Craen, Anton, J M1 aCummings, Steven, R1 aDenny, Joshua, C1 aDubé, Marie, Pierre1 aDurrington, Paul, N1 aEiriksdottir, Gudny1 aFord, Ian1 aGuo, Xiuqing1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHofman, Albert1 aHovingh, Kees1 aKastelein, John, J P1 aLauner, Leonore, J1 aLiu, Ching-Ti1 aLiu, Yongmei1 aLumley, Thomas1 aMcKeigue, Paul, M1 aMunroe, Patricia, B1 aNeil, Andrew1 aNickerson, Deborah, A1 aNyberg, Fredrik1 aO'Brien, Eoin1 aO'Donnell, Christopher, J1 aPost, Wendy1 aPoulter, Neil1 aVasan, Ramachandran, S1 aRice, Kenneth1 aRich, Stephen, S1 aRivadeneira, Fernando1 aSattar, Naveed1 aSever, Peter1 aShaw-Hawkins, Sue1 aShields, Denis, C1 aSlagboom, Eline1 aSmith, Nicholas, L1 aSmith, Joshua, D1 aSotoodehnia, Nona1 aStanton, Alice1 aStott, David, J1 aStricker, Bruno, H1 aStürmer, Til1 aUitterlinden, André, G1 aWei, Wei-Qi1 aWestendorp, Rudi, G J1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aWilke, Russell, A1 aBallantyne, Christie, M1 aColhoun, Helen, M1 aCupples, Adrienne, L1 aFranco, Oscar, H1 aGudnason, Vilmundur1 aHitman, Graham1 aPalmer, Colin, N A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aStafford, Jeanette, M1 aStein, Charles, M1 aTardif, Jean-Claude1 aCaulfield, Mark, J1 aJukema, Wouter1 aRotter, Jerome, I1 aKrauss, Ronald, M uhttps://chs-nhlbi.org/node/735806088nas a2201561 4500008004100000022001400041245007200055210006900127260001600196520173100212100002801943700002101971700002401992700001802016700002002034700002202054700002502076700001602101700001802117700001802135700001802153700002002171700002002191700001502211700002302226700003002249700001902279700001302298700002102311700002802332700002002360700002402380700002002404700001902424700001802443700002102461700002102482700002102503700001702524700002202541700001902563700001902582700002002601700002502621700002302646700002202669700002402691700002102715700002402736700002202760700002202782700001702804700002302821700001902844700002202863700002302885700001902908700002002927700002002947700002402967700001802991700002203009700001203031700001303043700002103056700001503077700002503092700002103117700002203138700002103160700002203181700002703203700001703230700002503247700002003272700002303292700001803315700002003333700001503353700002303368700002603391700002203417700001603439700001903455700001703474700002203491700002403513700002403537700002203561700002603583700002003609700002103629700002403650700002103674700001803695700002403713700001703737700002603754700001603780700002803796700001903824700001903843700002103862700002003883700002303903700002403926700001903950700002703969700002203996700002204018700002404040700001804064700002204082700001904104700002204123700002304145700002304168700001804191700002904209700002004238700001904258700002204277700001804299700002404317700002204341700001904363700002404382700001504406700002204421700002304443700002404466856003604490 2017 eng d a1460-208300aDiscovery of novel heart rate-associated loci using the Exome Chip.0 aDiscovery of novel heart rateassociated loci using the Exome Chi c2017 Apr 033 aBackground Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
1 avan den Berg, Marten, E1 aWarren, Helen, R1 aCabrera, Claudia, P1 aVerweij, Niek1 aMifsud, Borbala1 aHaessler, Jeffrey1 aBihlmeyer, Nathan, A1 aFu, Yi-Ping1 aWeiss, Stefan1 aLin, Henry, J1 aGrarup, Niels1 aLi-Gao, Ruifang1 aPistis, Giorgio1 aShah, Nabi1 aBrody, Jennifer, A1 aMüller-Nurasyid, Martina1 aLin, Honghuang1 aMei, Hao1 aSmith, Albert, V1 aLyytikäinen, Leo-Pekka1 aHall, Leanne, M1 avan Setten, Jessica1 aTrompet, Stella1 aPrins, Bram, P1 aIsaacs, Aaron1 aRadmanesh, Farid1 aMarten, Jonathan1 aEntwistle, Aiman1 aKors, Jan, A1 aSilva, Claudia, T1 aAlonso, Alvaro1 aBis, Joshua, C1 ade Boer, Rudolf1 ade Haan, Hugoline, G1 ade Mutsert, Renée1 aDedoussis, George1 aDominiczak, Anna, F1 aDoney, Alex, S F1 aEllinor, Patrick, T1 aEppinga, Ruben, N1 aFelix, Stephan, B1 aGuo, Xiuqing1 aHagemeijer, Yanick1 aHansen, Torben1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHuang, Paul, L1 aHwang, Shih-Jen1 aKähönen, Mika1 aKanters, Jørgen, K1 aKolcic, Ivana1 aLauner, Lenore, J1 aLi, Man1 aYao, Jie1 aLinneberg, Allan1 aLiu, Simin1 aMacfarlane, Peter, W1 aMangino, Massimo1 aMorris, Andrew, D1 aMulas, Antonella1 aMurray, Alison, D1 aNelson, Christopher, P1 aOrrù, Marco1 aPadmanabhan, Sandosh1 aPeters, Annette1 aPorteous, David, J1 aPoulter, Neil1 aPsaty, Bruce, M1 aQi, Lihong1 aRaitakari, Olli, T1 aRivadeneira, Fernando1 aRoselli, Carolina1 aRudan, Igor1 aSattar, Naveed1 aSever, Peter1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStanton, Alice, V1 aStirrups, Kathleen, E1 aTaylor, Kent, D1 aTobin, Martin, D1 aUitterlinden, Andre1 aVaartjes, Ilonca1 aHoes, Arno, W1 avan der Meer, Peter1 aVölker, Uwe1 aWaldenberger, Melanie1 aXie, Zhijun1 aZoledziewska, Magdalena1 aTinker, Andrew1 aPolasek, Ozren1 aRosand, Jonathan1 aJamshidi, Yalda1 aDuijn, Cornelia, M1 aZeggini, Eleftheria1 aJukema, Wouter1 aAsselbergs, Folkert, W1 aSamani, Nilesh, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aWilson, James1 aLubitz, Steven, A1 aKääb, Stefan1 aSotoodehnia, Nona1 aCaulfield, Mark, J1 aPalmer, Colin, N A1 aSanna, Serena1 aMook-Kanamori, Dennis, O1 aDeloukas, Panos1 aPedersen, Oluf1 aRotter, Jerome, I1 aDörr, Marcus1 aO'Donnell, Chris, J1 aHayward, Caroline1 aArking, Dan, E1 aKooperberg, Charles1 aHarst, Pim1 aEijgelsheim, Mark1 aStricker, Bruno, H1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/736304297nas a2200889 4500008004100000022001400041245007400055210006900129260001300198490000700211520176700218653002501985653001502010653001502025653002402040653001702064653003402081653001302115653001602128653001102144653004002155653004002195653002602235100003002261700002202291700001702313700001802330700001802348700001902366700002602385700002202411700002202433700001502455700002202470700001902492700002202511700001802533700003002551700002302581700001902604700002002623700002202643700001702665700002202682700002302704700002202727700002102749700002302770700002602793700001702819700002602836700002002862700002202882700002402904700002402928700002002952700001902972700002402991700002203015700002003037700002403057700001903081700002003100700002203120700002203142700001803164700001203182700001903194700002403213700001903237700002103256700002303277700002403300700002303324700002403347856003603371 2017 eng d a1942-326800aFifteen Genetic Loci Associated With the Electrocardiographic P Wave.0 aFifteen Genetic Loci Associated With the Electrocardiographic P c2017 Aug0 v103 aBACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.
METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.
CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.
10aArrhythmias, Cardiac10aCaveolin 110aCaveolin 210aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHumans10aNAV1.5 Voltage-Gated Sodium Channel10aNAV1.8 Voltage-Gated Sodium Channel10aT-Box Domain Proteins1 aChristophersen, Ingrid, E1 aMagnani, Jared, W1 aYin, Xiaoyan1 aBarnard, John1 aWeng, Lu-Chen1 aArking, Dan, E1 aNiemeijer, Maartje, N1 aLubitz, Steven, A1 aAvery, Christy, L1 aDuan, Qing1 aFelix, Stephan, B1 aBis, Joshua, C1 aKerr, Kathleen, F1 aIsaacs, Aaron1 aMüller-Nurasyid, Martina1 aMüller, Christian1 aNorth, Kari, E1 aReiner, Alex, P1 aTinker, Lesley, F1 aKors, Jan, A1 aTeumer, Alexander1 aPetersmann, Astrid1 aSinner, Moritz, F1 aBůzková, Petra1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aVölker, Uwe1 aWaldenberger, Melanie1 aPeters, Annette1 aMeitinger, Thomas1 aLimacher, Marian, C1 aWilhelmsen, Kirk, C1 aPsaty, Bruce, M1 aHofman, Albert1 aUitterlinden, Andre1 aKrijthe, Bouwe, P1 aZhang, Zhu-Ming1 aSchnabel, Renate, B1 aKääb, Stefan1 aDuijn, Cornelia1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aDörr, Marcus1 aLi, Yun1 aChung, Mina, K1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aWhitsel, Eric, A1 aStricker, Bruno, H1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/755704213nas a2200973 4500008004100000022001400041245013200055210006900187260001600256300001000272490000600282520142300288100001801711700002401729700003001753700002601783700002701809700002001836700001801856700001901874700002801893700002201921700002401943700001801967700002201985700002002007700002202027700001802049700001802067700002302085700002202108700002602130700002202156700002202178700002402200700001902224700002102243700002302264700002102287700002402308700002602332700002302358700002002381700002202401700002002423700002002443700001702463700002502480700001902505700002202524700001302546700001702559700003002576700002402606700002302630700001802653700002202671700001402693700001802707700002102725700002802746700001702774700002202791700001902813700001902832700002402851700001902875700001702894700001802911700001902929700002302948700002402971700002202995700002003017700001803037700002203055700001503077700001903092700002303111700002203134700002503156700002203181856003603203 2017 eng d a2045-232200aGenetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.0 aGenetic Interactions with Age Sex Body Mass Index and Hypertensi c2017 Sep 12 a113030 v73 aIt is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
1 aWeng, Lu-Chen1 aLunetta, Kathryn, L1 aMüller-Nurasyid, Martina1 aSmith, Albert, Vernon1 aThériault, Sébastien1 aWeeke, Peter, E1 aBarnard, John1 aBis, Joshua, C1 aLyytikäinen, Leo-Pekka1 aKleber, Marcus, E1 aMartinsson, Andreas1 aLin, Henry, J1 aRienstra, Michiel1 aTrompet, Stella1 aKrijthe, Bouwe, P1 aDörr, Marcus1 aKlarin, Derek1 aChasman, Daniel, I1 aSinner, Moritz, F1 aWaldenberger, Melanie1 aLauner, Lenore, J1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aParé, Guillaume1 aTeixeira, Pedro, L1 aDenny, Joshua, C1 aShoemaker, Benjamin1 aVan Wagoner, David, R1 aSmith, Jonathan, D1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aKähönen, Mika1 aNikus, Kjell1 aDelgado, Graciela, E1 aMelander, Olle1 aEngström, Gunnar1 aYao, Jie1 aGuo, Xiuqing1 aChristophersen, Ingrid, E1 aEllinor, Patrick, T1 aGeelhoed, Bastiaan1 aVerweij, Niek1 aMacfarlane, Peter1 aFord, Ian1 aHeeringa, Jan1 aFranco, Oscar, H1 aUitterlinden, André, G1 aVölker, Uwe1 aTeumer, Alexander1 aRose, Lynda, M1 aKääb, Stefan1 aGudnason, Vilmundur1 aArking, Dan, E1 aConen, David1 aRoden, Dan, M1 aChung, Mina, K1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aLehtimäki, Terho1 aMärz, Winfried1 aSmith, Gustav1 aRotter, Jerome, I1 aHarst, Pim1 aJukema, Wouter1 aStricker, Bruno, H1 aFelix, Stephan, B1 aAlbert, Christine, M1 aLubitz, Steven, A uhttps://chs-nhlbi.org/node/759504391nas a2201129 4500008004100000022001400041245013100055210006900186260001300255300001200268490000700280520110800287100002001395700001701415700002301432700001801455700001701473700002501490700002001515700001701535700002501552700001901577700002501596700001901621700002301640700002301663700002001686700002201706700002001728700002301748700002101771700002001792700002301812700002001835700002001855700001801875700002001893700002201913700001601935700002401951700002101975700002401996700002002020700001602040700002002056700002602076700001902102700002402121700001902145700001802164700002002182700001702202700002002219700002402239700001902263700002402282700002402306700002102330700001802351700002102369700001702390700001902407700002502426700001502451700001902466700001902485700002202504700002302526700002802549700002802577700002402605700002602629700002302655700001602678700002002694700001802714700002102732700002502753700002102778700001802799700002402817700002302841700002202864700002002886700002102906700002402927700001902951700002002970710002702990710002603017710002803043710002903071710005403100710002803154710004303182856003603225 2017 eng d a1546-171800aGenetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.0 aGenetic loci associated with chronic obstructive pulmonary disea c2017 Mar a426-4320 v493 aChronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.
1 aHobbs, Brian, D1 ade Jong, Kim1 aLamontagne, Maxime1 aBossé, Yohan1 aShrine, Nick1 aArtigas, Maria Soler1 aWain, Louise, V1 aHall, Ian, P1 aJackson, Victoria, E1 aWyss, Annah, B1 aLondon, Stephanie, J1 aNorth, Kari, E1 aFranceschini, Nora1 aStrachan, David, P1 aBeaty, Terri, H1 aHokanson, John, E1 aCrapo, James, D1 aCastaldi, Peter, J1 aChase, Robert, P1 aBartz, Traci, M1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aGharib, Sina, A1 aZanen, Pieter1 aLammers, Jan, W1 aOudkerk, Matthijs1 aGroen, H, J1 aLocantore, Nicholas1 aTal-Singer, Ruth1 aRennard, Stephen, I1 aVestbo, Jørgen1 aTimens, Wim1 aParé, Peter, D1 aLatourelle, Jeanne, C1 aDupuis, Josée1 aO'Connor, George, T1 aWilk, Jemma, B1 aKim, Woo, Jin1 aLee, Mi, Kyeong1 aOh, Yeon-Mok1 aVonk, Judith, M1 ade Koning, Harry, J1 aLeng, Shuguang1 aBelinsky, Steven, A1 aTesfaigzi, Yohannes1 aManichaikul, Ani1 aWang, Xin-Qun1 aRich, Stephen, S1 aBarr, Graham1 aSparrow, David1 aLitonjua, Augusto, A1 aBakke, Per1 aGulsvik, Amund1 aLahousse, Lies1 aBrusselle, Guy, G1 aStricker, Bruno, H1 aUitterlinden, André, G1 aAmpleford, Elizabeth, J1 aBleecker, Eugene, R1 aWoodruff, Prescott, G1 aMeyers, Deborah, A1 aQiao, Dandi1 aLomas, David, A1 aYim, Jae-Joon1 aKim, Deog, Kyeom1 aHawrylkiewicz, Iwona1 aSliwinski, Pawel1 aHardin, Megan1 aFingerlin, Tasha, E1 aSchwartz, David, A1 aPostma, Dirkje, S1 aMacNee, William1 aTobin, Martin, D1 aSilverman, Edwin, K1 aBoezen, Marike1 aCho, Michael, H1 aCOPDGene Investigators1 aECLIPSE Investigators1 aLifeLines Investigators1 aSPIROMICS Research Group1 aInternational COPD Genetics Network Investigators1 aUK BiLEVE Investigators1 aInternational COPD Genetics Consortium uhttps://chs-nhlbi.org/node/734506994nas a2202101 4500008004100000022001400041245009900055210006900154260001600223300001000239490000600249520104500255100001901300700001901319700002301338700002201361700001701383700001601400700002801416700002201444700001901466700001801485700002201503700002701525700002201552700002301574700001901597700002001616700001801636700002201654700002301676700002201699700002001721700002801741700002801769700002201797700002001819700002701839700003001866700001901896700001701915700002201932700002201954700001801976700001701994700002102011700002702032700002202059700002302081700002202104700001902126700001702145700001802162700002002180700002202200700002502222700002102247700001802268700002102286700002002307700002302327700002202350700002702372700002102399700002102420700002402441700001902465700002102484700002002505700002102525700001902546700002502565700001902590700002602609700002602635700002102661700001902682700002402701700002002725700002602745700001902771700002102790700002002811700002402831700001702855700001802872700002402890700002102914700002202935700001302957700001202970700001902982700002403001700001803025700002503043700002203068700002003090700002203110700003903132700002103171700001803192700002203210700001903232700001803251700002003269700001703289700001903306700002403325700001703349700002003366700002003386700002003406700002303426700002703449700002203476700002103498700002203519700002303541700002403564700002203588700002103610700002203631700002303653700003203676700002403708700002203732700002003754700002803774700002403802700002003826700002203846700002503868700002203893700002803915700002403943700001803967700002603985700002404011700002304035700001704058700002004075700002304095700001804118700002204136700002304158700001504181700002104196700002004217700002704237700001904264700002004283700001904303700002404322700001504346700002204361700001504383700002804398700002404426700002904450700002004479700002504499700002204524700002204546700001904568700002204587700001704609700002304626700002204649700002604671700002704697700002704724700002304751700002104774700002204795700002004817700001904837856003604856 2017 eng d a2041-172300aGenetic loci associated with heart rate variability and their effects on cardiac disease risk.0 aGenetic loci associated with heart rate variability and their ef c2017 Jun 14 a158050 v83 aReduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries. CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results. Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery. BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING: For detailed information per study, see Acknowledgments. BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus. CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health. BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes. We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed. The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations. We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms. Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF. Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development. AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable. The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.