04063nas a2201069 4500008004100000022001400041245007500055210006900130260001300199300001000212490000700222520107100229653001501300653001001315653000901325653002401334653002501358653001901383653001101402653003401413653001101447653001201458653000901470653002701479653001601506653003601522653005901558653001601617100002401633700002401657700002201681700001801703700001901721700001901740700002201759700002501781700002101806700002201827700001501849700001901864700002301883700002301906700002401929700002401953700002101977700002601998700002202024700002502046700001302071700002002084700002202104700002202126700002302148700002102171700002202192700002202214700001802236700001602254700002002270700002002290700001602310700001902326700002002345700002902365700001202394700002402406700002002430700002002450700002702470700002302497700002102520700002602541700001902567700002802586700001702614700002102631700002102652700001902673700002602692700002402718700002002742700001802762700002202780700002202802700003002824700001802854700001902872700002402891700002302915700001902938856003602957 2010 eng d a1546-171800aCommon variants in KCNN3 are associated with lone atrial fibrillation.0 aCommon variants in KCNN3 are associated with lone atrial fibrill c2010 Mar a240-40 v423 a
Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.
10aAdolescent10aAdult10aAged10aAtrial Fibrillation10aCase-Control Studies10aCohort Studies10aFemale10aGenome-Wide Association Study10aHumans10aIntrons10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aSmall-Conductance Calcium-Activated Potassium Channels10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aGlazer, Nicole, L1 aPfeufer, Arne1 aAlonso, Alvaro1 aChung, Mina, K1 aSinner, Moritz, F1 ade Bakker, Paul, I W1 aMueller, Martina1 aLubitz, Steven, A1 aFox, Ervin1 aDarbar, Dawood1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aSchnabel, Renate, B1 aSoliman, Elsayed, Z1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aBeckmann, Britt-M1 avan Noord, Charlotte1 aWang, Ke1 aEhret, Georg, B1 aRotter, Jerome, I1 aHazen, Stanley, L1 aSteinbeck, Gerhard1 aSmith, Albert, V1 aLauner, Lenore, J1 aHarris, Tamara, B1 aMakino, Seiko1 aNelis, Mari1 aMilan, David, J1 aPerz, Siegfried1 aEsko, Tõnu1 aKöttgen, Anna1 aMoebus, Susanne1 aNewton-Cheh, Christopher1 aLi, Man1 aMöhlenkamp, Stefan1 aWang, Thomas, J1 aKao, Linda, W H1 aVasan, Ramachandran, S1 aNöthen, Markus, M1 aMacRae, Calum, A1 aStricker, Bruno, H Ch1 aHofman, Albert1 aUitterlinden, André, G1 aLevy, Daniel1 aBoerwinkle, Eric1 aMetspalu, Andres1 aTopol, Eric, J1 aChakravarti, Aravinda1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aRoden, Dan, M1 aMeitinger, Thomas1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aBarnard, John1 aArking, Dan, E1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aKääb, Stefan uhttps://chs-nhlbi.org/node/117004917nas a2201453 4500008004100000022001400041245008200055210006900137260001600206300001000222490000700232520088500239653001501124653001001139653000901149653002201158653003701180653002401217653001001241653002101251653004001272653001101312653001701323653003801340653003401378653001101412653001101423653002001434653000901454653001601463653003601479653001701515653001601532100002401548700002401572700002501596700002201621700002401643700002101667700001901688700003001707700002201737700002201759700001901781700001901800700001801819700001901837700002201856700001801878700001801896700002201914700001701936700002001953700002301973700002301996700002202019700002102041700002602062700002202088700001702110700002202127700002202149700002302171700002202194700002202216700002302238700002202261700001902283700001702302700001902319700002002338700001902358700002102377700001702398700002402415700002402439700001202463700002602475700001902501700002002520700001902540700002002559700001702579700002302596700002302619700002202642700001402664700002202678700001702700700002102717700001802738700001902756700002002775700002102795700002102816700002002837700002202857700002002879700002202899700003002921700002002951700002202971700001802993700002803011700002603039700002203065700002203087700002003109700001703129700002303146700001903169700002203188700002603210700002203236700001903258700001903277700001803296700002303314700002303337700002403360700002403384700001903408856003603427 2012 eng d a1546-171800aMeta-analysis identifies six new susceptibility loci for atrial fibrillation.0 aMetaanalysis identifies six new susceptibility loci for atrial f c2012 Apr 29 a670-50 v443 aAtrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChild10aChild, Preschool10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aAlbert, Christine, M1 aGlazer, Nicole, L1 aRitchie, Marylyn, D1 aSmith, Albert, V1 aArking, Dan, E1 aMüller-Nurasyid, Martina1 aKrijthe, Bouwe, P1 aLubitz, Steven, A1 aBis, Joshua, C1 aChung, Mina, K1 aDörr, Marcus1 aOzaki, Kouichi1 aRoberts, Jason, D1 aSmith, Gustav1 aPfeufer, Arne1 aSinner, Moritz, F1 aLohman, Kurt1 aDing, Jingzhong1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aRienstra, Michiel1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aMagnani, Jared, W1 aWakili, Reza1 aClauss, Sebastian1 aRotter, Jerome, I1 aSteinbeck, Gerhard1 aLauner, Lenore, J1 aDavies, Robert, W1 aBorkovich, Matthew1 aHarris, Tamara, B1 aLin, Honghuang1 aVölker, Uwe1 aVölzke, Henry1 aMilan, David, J1 aHofman, Albert1 aBoerwinkle, Eric1 aChen, Lin, Y1 aSoliman, Elsayed, Z1 aVoight, Benjamin, F1 aLi, Guo1 aChakravarti, Aravinda1 aKubo, Michiaki1 aTedrow, Usha, B1 aRose, Lynda, M1 aRidker, Paul, M1 aConen, David1 aTsunoda, Tatsuhiko1 aFurukawa, Tetsushi1 aSotoodehnia, Nona1 aXu, Siyan1 aKamatani, Naoyuki1 aLevy, Daniel1 aNakamura, Yusuke1 aParvez, Babar1 aMahida, Saagar1 aFurie, Karen, L1 aRosand, Jonathan1 aMuhammad, Raafia1 aPsaty, Bruce, M1 aMeitinger, Thomas1 aPerz, Siegfried1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aKao, Linda, W H1 aKathiresan, Sekar1 aRoden, Dan, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aMcKnight, Barbara1 aSjögren, Marketa1 aNewman, Anne, B1 aLiu, Yongmei1 aGollob, Michael, H1 aMelander, Olle1 aTanaka, Toshihiro1 aStricker, Bruno, H Ch1 aFelix, Stephan, B1 aAlonso, Alvaro1 aDarbar, Dawood1 aBarnard, John1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aGudnason, Vilmundur1 aKääb, Stefan uhttps://chs-nhlbi.org/node/138310059nas a2203157 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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/654409668nas a2203061 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2017 eng d a1546-171800aExome-wide association study of plasma lipids in >300,000 individuals.0 aExomewide association study of plasma lipids in 300000 individua c2017 Dec a1758-17660 v493 aWe screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
10aCoronary Artery Disease10aDiabetes Mellitus, Type 210aExome10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenetic Variation10aGenotype10aHumans10aLipids10aMacular Degeneration10aPhenotype10aRisk Factors1 aLiu, Dajiang, J1 aPeloso, Gina, M1 aYu, Haojie1 aButterworth, Adam, S1 aWang, Xiao1 aMahajan, Anubha1 aSaleheen, Danish1 aEmdin, Connor1 aAlam, Dewan1 aAlves, Alexessander, Couto1 aAmouyel, Philippe1 aDi Angelantonio, Emanuele1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aAuer, Paul, L1 aBaber, Usman1 aBallantyne, Christie, M1 aBang, Lia, E1 aBenn, Marianne1 aBis, Joshua, C1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrandslund, Ivan1 aBrown, Morris1 aBusonero, Fabio1 aCaulfield, Mark, J1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Eugene1 aChen, Yii-Der Ida1 aChowdhury, Raj1 aChristensen, Cramer1 aChu, Audrey, Y1 aConnell, John, M1 aCucca, Francesco1 aCupples, Adrienne, L1 aDamrauer, Scott, M1 aDavies, Gail1 aDeary, Ian, J1 aDedoussis, George1 aDenny, Joshua, C1 aDominiczak, Anna1 aDubé, Marie-Pierre1 aEbeling, Tapani1 aEiriksdottir, Gudny1 aEsko, Tõnu1 aFarmaki, Aliki-Eleni1 aFeitosa, Mary, F1 aFerrario, Marco1 aFerrieres, Jean1 aFord, Ian1 aFornage, Myriam1 aFranks, Paul, W1 aFrayling, Timothy, M1 aFrikke-Schmidt, Ruth1 aFritsche, Lars, G1 aFrossard, Philippe1 aFuster, Valentin1 aGanesh, Santhi, K1 aGao, Wei1 aGarcia, Melissa, E1 aGieger, Christian1 aGiulianini, Franco1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGrarup, Niels1 aGroop, Leif1 aGrove, Megan, L1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHirschhorn, Joel, N1 aHolmen, Oddgeir, L1 aHuffman, Jennifer1 aHuo, Yong1 aHveem, Kristian1 aJabeen, Sehrish1 aJackson, Anne, U1 aJakobsdottir, Johanna1 aJarvelin, Marjo-Riitta1 aJensen, Gorm, B1 aJørgensen, Marit, E1 aJukema, Wouter1 aJustesen, Johanne, M1 aKamstrup, Pia, R1 aKanoni, Stavroula1 aKarpe, Fredrik1 aKee, Frank1 aKhera, Amit, V1 aKlarin, Derek1 aKoistinen, Heikki, A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo1 aLangenberg, Claudia1 aLangsted, Anne1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLiewald, David, C M1 aLin, Li, An1 aLinneberg, Allan1 aLoos, Ruth, J F1 aLu, Yingchang1 aLu, Xiangfeng1 aMägi, Reedik1 aMälarstig, Anders1 aManichaikul, Ani1 aManning, Alisa, K1 aMäntyselkä, Pekka1 aMarouli, Eirini1 aMasca, Nicholas, G D1 aMaschio, Andrea1 aMeigs, James, B1 aMelander, Olle1 aMetspalu, Andres1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMulas, Antonella1 aMüller-Nurasyid, Martina1 aMunroe, Patricia, B1 aNeville, Matt, J1 aNielsen, Jonas, B1 aNielsen, Sune, F1 aNordestgaard, Børge, G1 aOrdovas, Jose, M1 aMehran, Roxana1 aO'Donnell, Christoper, J1 aOrho-Melander, Marju1 aMolony, Cliona, M1 aMuntendam, Pieter1 aPadmanabhan, Sandosh1 aPalmer, Colin, N A1 aPasko, Dorota1 aPatel, Aniruddh, P1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPisinger, Charlotta1 aPistis, Giorgio1 aPolasek, Ozren1 aPoulter, Neil1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRasheed, Asif1 aRauramaa, Rainer1 aReilly, Dermot, F1 aReiner, Alex, P1 aRenstrom, Frida1 aRich, Stephen, S1 aRidker, Paul, M1 aRioux, John, D1 aRobertson, Neil, R1 aRoden, Dan, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSanna, Serena1 aSattar, Naveed1 aSchmidt, Ellen, M1 aScott, Robert, A1 aSever, Peter1 aSevilla, Raquel, S1 aShaffer, Christian, M1 aSim, Xueling1 aSivapalaratnam, Suthesh1 aSmall, Kerrin, S1 aSmith, Albert, V1 aSmith, Blair, H1 aSomayajula, Sangeetha1 aSoutham, Lorraine1 aSpector, Timothy, D1 aSpeliotes, Elizabeth, K1 aStarr, John, M1 aStirrups, Kathleen, E1 aStitziel, Nathan1 aStrauch, Konstantin1 aStringham, Heather, M1 aSurendran, Praveen1 aTada, Hayato1 aTall, Alan, R1 aTang, Hua1 aTardif, Jean-Claude1 aTaylor, Kent, D1 aTrompet, Stella1 aTsao, Philip, S1 aTuomilehto, Jaakko1 aTybjaerg-Hansen, Anne1 avan Zuydam, Natalie, R1 aVarbo, Anette1 aVarga, Tibor, V1 aVirtamo, Jarmo1 aWaldenberger, Melanie1 aWang, Nan1 aWareham, Nick, J1 aWarren, Helen, R1 aWeeke, Peter, E1 aWeinstock, Joshua1 aWessel, Jennifer1 aWilson, James, G1 aWilson, Peter, W F1 aXu, Ming1 aYaghootkar, Hanieh1 aYoung, Robin1 aZeggini, Eleftheria1 aZhang, He1 aZheng, Neil, S1 aZhang, Weihua1 aZhang, Yan1 aZhou, Wei1 aZhou, Yanhua1 aZoledziewska, Magdalena1 aHowson, Joanna, M M1 aDanesh, John1 aMcCarthy, Mark, I1 aCowan, Chad, A1 aAbecasis, Goncalo1 aDeloukas, Panos1 aMusunuru, Kiran1 aWiller, Cristen, J1 aKathiresan, Sekar1 aCharge Diabetes Working Group1 aEPIC-InterAct Consortium1 aEPIC-CVD Consortium1 aGOLD Consortium1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/757304213nas 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/759506999nas a2202113 4500008004100000022001400041245011100055210006900166260001300235300001200248490000700260520104100267100003001308700002201338700002201360700001701382700002301399700001801422700001901440700001901459700002101478700002501499700001801524700002201542700001501564700001801579700002501597700001801622700002001640700003001660700001801690700002301708700002601731700001801757700002001775700002201795700002301817700002301840700002201863700002801885700002101913700001801934700002801952700001701980700001901997700002602016700002702042700001302069700002102082700001802103700002202121700002202143700001802165700002202183700001502205700002102220700001902241700001602260700002302276700002302299700002002322700001602342700002502358700002102383700002302404700002602427700001802453700002302471700001902494700002302513700002602536700001902562700002002581700002002601700002002621700002202641700002202663700002202685700002402707700002502731700002202756700002002778700002602798700002002824700001902844700002102863700002002884700001802904700002302922700002002945700002002965700001502985700002103000700001803021700002403039700002303063700002503086700001903111700001503130700001903145700002203164700001403186700002003200700002203220700001703242700002203259700002503281700001203306700002103318700001803339700001903357700001803376700002903394700002003423700002103443700002503464700002003489700002203509700002703531700002303558700001703581700002503598700002003623700001803643700002103661700002203682700001903704700002903723700002303752700002503775700003203800700001903832700001903851700002203870700002403892700002803916700001903944700002103963700001703984700002404001700002204025700001804047700001704065700002104082700002004103700002404123700001904147700002004166700001904186700001704205700002104222700001504243700002304258700002204281700002304303700001904326700002204345700002204367700002004389700002204409700002304431700001904454700002204473700002404495700001904519700001804538700001904556700002304575700002304598700002404621700002204645700002404667700002204691700002404713710003804737710005304775710002104828856003604849 2017 eng d a1546-171800aLarge-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.0 aLargescale analyses of common and rare variants identify 12 new c2017 Jun a946-9520 v493 aAtrial 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.
1 aChristophersen, Ingrid, E1 aRienstra, Michiel1 aRoselli, Carolina1 aYin, Xiaoyan1 aGeelhoed, Bastiaan1 aBarnard, John1 aLin, Honghuang1 aArking, Dan, E1 aSmith, Albert, V1 aAlbert, Christine, M1 aChaffin, Mark1 aTucker, Nathan, R1 aLi, Molong1 aKlarin, Derek1 aBihlmeyer, Nathan, A1 aLow, Siew-Kee1 aWeeke, Peter, E1 aMüller-Nurasyid, Martina1 aSmith, Gustav1 aBrody, Jennifer, A1 aNiemeijer, Maartje, N1 aDörr, Marcus1 aTrompet, Stella1 aHuffman, Jennifer1 aGustafsson, Stefan1 aSchurmann, Claudia1 aKleber, Marcus, E1 aLyytikäinen, Leo-Pekka1 aSeppälä, Ilkka1 aMalik, Rainer1 aHorimoto, Andrea, R V R1 aPerez, Marco1 aSinisalo, Juha1 aAeschbacher, Stefanie1 aThériault, Sébastien1 aYao, Jie1 aRadmanesh, Farid1 aWeiss, Stefan1 aTeumer, Alexander1 aChoi, Seung, Hoan1 aWeng, Lu-Chen1 aClauss, Sebastian1 aDeo, Rajat1 aRader, Daniel, J1 aShah, Svati, H1 aSun, Albert1 aHopewell, Jemma, C1 aDebette, Stephanie1 aChauhan, Ganesh1 aYang, Qiong1 aWorrall, Bradford, B1 aParé, Guillaume1 aKamatani, Yoichiro1 aHagemeijer, Yanick, P1 aVerweij, Niek1 aSiland, Joylene, E1 aKubo, Michiaki1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aBis, Joshua, C1 aPerz, Siegfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aMagnani, Jared, W1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShoemaker, Benjamin1 aPadmanabhan, Sandosh1 aHaessler, Jeffrey1 aBartz, Traci, M1 aWaldenberger, Melanie1 aLichtner, Peter1 aArendt, Marina1 aKrieger, Jose, E1 aKähönen, Mika1 aRisch, Lorenz1 aMansur, Alfredo, J1 aPeters, Annette1 aSmith, Blair, H1 aLind, Lars1 aScott, Stuart, A1 aLu, Yingchang1 aBottinger, Erwin, B1 aHernesniemi, Jussi1 aLindgren, Cecilia, M1 aWong, Jorge, A1 aHuang, Jie1 aEskola, Markku1 aMorris, Andrew, P1 aFord, Ian1 aReiner, Alex, P1 aDelgado, Graciela1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aSandhu, Roopinder, K1 aLi, Man1 aBoerwinkle, Eric1 aEisele, Lewin1 aLannfelt, Lars1 aRost, Natalia1 aAnderson, Christopher, D1 aTaylor, Kent, D1 aCampbell, Archie1 aMagnusson, Patrik, K1 aPorteous, David1 aHocking, Lynne, J1 aVlachopoulou, Efthymia1 aPedersen, Nancy, L1 aNikus, Kjell1 aOrho-Melander, Marju1 aHamsten, Anders1 aHeeringa, Jan1 aDenny, Joshua, C1 aKriebel, Jennifer1 aDarbar, Dawood1 aNewton-Cheh, Christopher1 aShaffer, Christian1 aMacfarlane, Peter, W1 aHeilmann-Heimbach, Stefanie1 aAlmgren, Peter1 aHuang, Paul, L1 aSotoodehnia, Nona1 aSoliman, Elsayed, Z1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aVölker, Uwe1 aJöckel, Karl-Heinz1 aSinner, Moritz, F1 aLin, Henry, J1 aGuo, Xiuqing1 aDichgans, Martin1 aIngelsson, Erik1 aKooperberg, Charles1 aMelander, Olle1 aLoos, Ruth, J F1 aLaurikka, Jari1 aConen, David1 aRosand, Jonathan1 aHarst, Pim1 aLokki, Marja-Liisa1 aKathiresan, Sekar1 aPereira, Alexandre1 aJukema, Wouter1 aHayward, Caroline1 aRotter, Jerome, I1 aMärz, Winfried1 aLehtimäki, Terho1 aStricker, Bruno, H1 aChung, Mina, K1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aRoden, Dan, M1 aKääb, Stefan1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aTanaka, Toshihiro1 aLunetta, Kathryn, L1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aMETASTROKE Consortium of the ISGC1 aNeurology Working Group of the CHARGE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/739608664nas a2202749 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2018 eng d a1546-171800aMulti-ethnic genome-wide association study for atrial fibrillation.0 aMultiethnic genomewide association study for atrial fibrillation c2018 Sep a1225-12330 v503 aAtrial 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.
1 aRoselli, Carolina1 aChaffin, Mark, D1 aWeng, Lu-Chen1 aAeschbacher, Stefanie1 aAhlberg, Gustav1 aAlbert, Christine, M1 aAlmgren, Peter1 aAlonso, Alvaro1 aAnderson, Christopher, D1 aAragam, Krishna, G1 aArking, Dan, E1 aBarnard, John1 aBartz, Traci, M1 aBenjamin, Emelia, J1 aBihlmeyer, Nathan, A1 aBis, Joshua, C1 aBloom, Heather, L1 aBoerwinkle, Eric1 aBottinger, Erwin, B1 aBrody, Jennifer, A1 aCalkins, Hugh1 aCampbell, Archie1 aCappola, Thomas, P1 aCarlquist, John1 aChasman, Daniel, I1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aChoi, Eue-Keun1 aChoi, Seung, Hoan1 aChristophersen, Ingrid, E1 aChung, Mina, K1 aCole, John, W1 aConen, David1 aCook, James1 aCrijns, Harry, J1 aCutler, Michael, J1 aDamrauer, Scott, M1 aDaniels, Brian, R1 aDarbar, Dawood1 aDelgado, Graciela1 aDenny, Joshua, C1 aDichgans, Martin1 aDörr, Marcus1 aDudink, Elton, A1 aDudley, Samuel, C1 aEsa, Nada1 aEsko, Tõnu1 aEskola, Markku1 aFatkin, Diane1 aFelix, Stephan, B1 aFord, Ian1 aFranco, Oscar, H1 aGeelhoed, Bastiaan1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGupta, Namrata1 aGustafsson, Stefan1 aGutmann, Rebecca1 aHamsten, Anders1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHernesniemi, Jussi1 aHocking, Lynne, J1 aHofman, Albert1 aHorimoto, Andrea, R V R1 aHuang, Jie1 aHuang, Paul, L1 aHuffman, Jennifer1 aIngelsson, Erik1 aIpek, Esra, Gucuk1 aIto, Kaoru1 aJimenez-Conde, Jordi1 aJohnson, Renee1 aJukema, Wouter1 aKääb, Stefan1 aKähönen, Mika1 aKamatani, Yoichiro1 aKane, John, P1 aKastrati, Adnan1 aKathiresan, Sekar1 aKatschnig-Winter, Petra1 aKavousi, Maryam1 aKessler, Thorsten1 aKietselaer, Bas, L1 aKirchhof, Paulus1 aKleber, Marcus, E1 aKnight, Stacey1 aKrieger, Jose, E1 aKubo, Michiaki1 aLauner, Lenore, J1 aLaurikka, Jari1 aLehtimäki, Terho1 aLeineweber, Kirsten1 aLemaitre, Rozenn, N1 aLi, Man1 aLim, Hong, Euy1 aLin, Henry, J1 aLin, Honghuang1 aLind, Lars1 aLindgren, Cecilia, M1 aLokki, Marja-Liisa1 aLondon, Barry1 aLoos, Ruth, J F1 aLow, Siew-Kee1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMacfarlane, Peter, W1 aMagnusson, Patrik, K1 aMahajan, Anubha1 aMalik, Rainer1 aMansur, Alfredo, J1 aMarcus, Gregory, M1 aMargolin, Lauren1 aMargulies, Kenneth, B1 aMärz, Winfried1 aMcManus, David, D1 aMelander, Olle1 aMohanty, Sanghamitra1 aMontgomery, Jay, A1 aMorley, Michael, P1 aMorris, Andrew, P1 aMüller-Nurasyid, Martina1 aNatale, Andrea1 aNazarian, Saman1 aNeumann, Benjamin1 aNewton-Cheh, Christopher1 aNiemeijer, Maartje, N1 aNikus, Kjell1 aNilsson, Peter1 aNoordam, Raymond1 aOellers, Heidi1 aOlesen, Morten, S1 aOrho-Melander, Marju1 aPadmanabhan, Sandosh1 aPak, Hui-Nam1 aParé, Guillaume1 aPedersen, Nancy, L1 aPera, Joanna1 aPereira, Alexandre1 aPorteous, David1 aPsaty, Bruce, M1 aPulit, Sara, L1 aPullinger, Clive, R1 aRader, Daniel, J1 aRefsgaard, Lena1 aRibasés, Marta1 aRidker, Paul, M1 aRienstra, Michiel1 aRisch, Lorenz1 aRoden, Dan, M1 aRosand, Jonathan1 aRosenberg, Michael, A1 aRost, Natalia1 aRotter, Jerome, I1 aSaba, Samir1 aSandhu, Roopinder, K1 aSchnabel, Renate, B1 aSchramm, Katharina1 aSchunkert, Heribert1 aSchurman, Claudia1 aScott, Stuart, A1 aSeppälä, Ilkka1 aShaffer, Christian1 aShah, Svati1 aShalaby, Alaa, A1 aShim, Jaemin1 aShoemaker, Benjamin1 aSiland, Joylene, E1 aSinisalo, Juha1 aSinner, Moritz, F1 aSlowik, Agnieszka1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Gustav1 aSmith, Jonathan, D1 aSmith, Nicholas, L1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSun, Albert1 aSun, Han1 aSvendsen, Jesper, H1 aTanaka, Toshihiro1 aTanriverdi, Kahraman1 aTaylor, Kent, D1 aTeder-Laving, Maris1 aTeumer, Alexander1 aThériault, Sébastien1 aTrompet, Stella1 aTucker, Nathan, R1 aTveit, Arnljot1 aUitterlinden, André, G1 aHarst, Pim1 aVan Gelder, Isabelle, C1 aVan Wagoner, David, R1 aVerweij, Niek1 aVlachopoulou, Efthymia1 aVölker, Uwe1 aWang, Biqi1 aWeeke, Peter, E1 aWeijs, Bob1 aWeiss, Raul1 aWeiss, Stefan1 aWells, Quinn, S1 aWiggins, Kerri, L1 aWong, Jorge, A1 aWoo, Daniel1 aWorrall, Bradford, B1 aYang, Pil-Sung1 aYao, Jie1 aYoneda, Zachary, T1 aZeller, Tanja1 aZeng, Lingyao1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/781105872nas a2201645 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2018 eng d a2041-172300aPR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.0 aPR interval genomewide association metaanalysis identifies 50 lo c2018 Jul 25 a29040 v93 aElectrocardiographic 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.
1 avan Setten, Jessica1 aBrody, Jennifer, A1 aJamshidi, Yalda1 aSwenson, Brenton, R1 aButler, Anne, M1 aCampbell, Harry1 aDel Greco, Fabiola, M1 aEvans, Daniel, S1 aGibson, Quince1 aGudbjartsson, Daniel, F1 aKerr, Kathleen, F1 aKrijthe, Bouwe, P1 aLyytikäinen, Leo-Pekka1 aMüller, Christian1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRitchie, Marylyn, D1 aRobino, Antonietta1 aSmith, Albert, V1 aSteri, Maristella1 aTanaka, Toshiko1 aTeumer, Alexander1 aTrompet, Stella1 aUlivi, Sheila1 aVerweij, Niek1 aYin, Xiaoyan1 aArnar, David, O1 aAsselbergs, Folkert, W1 aBader, Joel, S1 aBarnard, John1 aBis, Josh1 aBlankenberg, Stefan1 aBoerwinkle, Eric1 aBradford, Yuki1 aBuckley, Brendan, M1 aChung, Mina, K1 aCrawford, Dana1 aHoed, Marcel, den1 aDenny, Josh, C1 aDominiczak, Anna, F1 aEhret, Georg, B1 aEijgelsheim, Mark1 aEllinor, Patrick, T1 aFelix, Stephan, B1 aFranco, Oscar, H1 aFranke, Lude1 aHarris, Tamara, B1 aHolm, Hilma1 aIlaria, Gandin1 aIorio, Annamaria1 aKähönen, Mika1 aKolcic, Ivana1 aKors, Jan, A1 aLakatta, Edward, G1 aLauner, Lenore, J1 aLin, Honghuang1 aLin, Henry, J1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aLeach, Irene, Mateo1 aMeitinger, Thomas1 aMitchell, Braxton, D1 aMünzel, Thomas1 aPapanicolaou, George, J1 aPeters, Annette1 aPfeufer, Arne1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRotter, Jerome, I1 aRudan, Igor1 aSamani, Nilesh, J1 aSchlessinger, David1 aAldana, Claudia, T Silva1 aSinner, Moritz, F1 aSmith, Jonathan, D1 aSnieder, Harold1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStott, David, J1 aStrauch, Konstantin1 aTarasov, Kirill, V1 aThorsteinsdottir, Unnur1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWestra, Harm, Jan1 aWild, Philipp, S1 aZeller, Tanja1 aAlonso, Alvaro1 aAvery, Christy, L1 aBandinelli, Stefania1 aBenjamin, Emelia, J1 aCucca, Francesco1 aDörr, Marcus1 aFerrucci, Luigi1 aGasparini, Paolo1 aGudnason, Vilmundur1 aHayward, Caroline1 aHeckbert, Susan, R1 aHicks, Andrew, A1 aJukema, Wouter1 aKääb, Stefan1 aLehtimäki, Terho1 aLiu, Yongmei1 aMunroe, Patricia, B1 aParsa, Afshin1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRoden, Dan, M1 aSchnabel, Renate, B1 aSinagra, Gianfranco1 aStefansson, Kari1 aStricker, Bruno, H1 aHarst, Pim1 aDuijn, Cornelia, M1 aWilson, James, F1 aGharib, Sina, A1 ade Bakker, Paul, I W1 aIsaacs, Aaron1 aArking, Dan, E1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/781506570nas a2201753 4500008004100000022001400041245007100055210006900126260001200195300001200207490000800219520164100227100002301868700002501891700002601916700002201942700001701964700002401981700002002005700001902025700002602044700001902070700001602089700002002105700002902125700002702154700001602181700002202197700002002219700002002239700002502259700002402284700001902308700002002327700001902347700002002366700002402386700002002410700002602430700002702456700002502483700002402508700001402532700002202546700002302568700002102591700002302612700001902635700002302654700001702677700002302694700001802717700002102735700001902756700002302775700002502798700002202823700002402845700002402869700001902893700002702912700001902939700001702958700002202975700001902997700002103016700001903037700002203056700001903078700001903097700002003116700002203136700002203158700002503180700001903205700002103224700002303245700002103268700002303289700002303312700002203335700001903357700001803376700002203394700002103416700002203437700002103459700002103480700002003501700001903521700002003540700002203560700001803582700002203600700002003622700001703642700001703659700001603676700001503692700002703707700002303734700001703757700002403774700002103798700002003819700002103839700002403860700002503884700002403909700002303933700002503956700002303981700002104004700001904025700002004044700001904064700002804083700001804111700002104129700002104150700002304171700001804194700002004212700002304232700001804255700002404273700002104297700002504318700002104343700001704364700001704381700001804398700002104416700002204437700002104459700001704480700002204497700002004519700002304539700002304562700002504585700002404610700002204634700002304656700002204679700002304701710005604724856003604780 2020 eng d a1476-468700aInherited causes of clonal haematopoiesis in 97,691 whole genomes.0 aInherited causes of clonal haematopoiesis in 97691 whole genomes c2020 10 a763-7680 v5863 aAge is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
1 aBick, Alexander, G1 aWeinstock, Joshua, S1 aNandakumar, Satish, K1 aFulco, Charles, P1 aBao, Erik, L1 aZekavat, Seyedeh, M1 aSzeto, Mindy, D1 aLiao, Xiaotian1 aLeventhal, Matthew, J1 aNasser, Joseph1 aChang, Kyle1 aLaurie, Cecelia1 aBurugula, Bala, Bharathi1 aGibson, Christopher, J1 aLin, Amy, E1 aTaub, Margaret, A1 aAguet, Francois1 aArdlie, Kristin1 aMitchell, Braxton, D1 aBarnes, Kathleen, C1 aMoscati, Arden1 aFornage, Myriam1 aRedline, Susan1 aPsaty, Bruce, M1 aSilverman, Edwin, K1 aWeiss, Scott, T1 aPalmer, Nicholette, D1 aVasan, Ramachandran, S1 aBurchard, Esteban, G1 aKardia, Sharon, L R1 aHe, Jiang1 aKaplan, Robert, C1 aSmith, Nicholas, L1 aArnett, Donna, K1 aSchwartz, David, A1 aCorrea, Adolfo1 ade Andrade, Mariza1 aGuo, Xiuqing1 aKonkle, Barbara, A1 aCuster, Brian1 aPeralta, Juan, M1 aGui, Hongsheng1 aMeyers, Deborah, A1 aMcGarvey, Stephen, T1 aChen, Ida Yii-Der1 aShoemaker, Benjamin1 aPeyser, Patricia, A1 aBroome, Jai, G1 aGogarten, Stephanie, M1 aWang, Fei, Fei1 aWong, Quenna1 aMontasser, May, E1 aDaya, Michelle1 aKenny, Eimear, E1 aNorth, Kari, E1 aLauner, Lenore, J1 aCade, Brian, E1 aBis, Joshua, C1 aCho, Michael, H1 aLasky-Su, Jessica1 aBowden, Donald, W1 aCupples, Adrienne, L1 aC Y Mak, Angel1 aBecker, Lewis, C1 aSmith, Jennifer, A1 aKelly, Tanika, N1 aAslibekyan, Stella1 aHeckbert, Susan, R1 aTiwari, Hemant, K1 aYang, Ivana, V1 aHeit, John, A1 aLubitz, Steven, A1 aJohnsen, Jill, M1 aCurran, Joanne, E1 aWenzel, Sally, E1 aWeeks, Daniel, E1 aRao, Dabeeru, C1 aDarbar, Dawood1 aMoon, Jee-Young1 aTracy, Russell, P1 aButh, Erin, J1 aRafaels, Nicholas1 aLoos, Ruth, J F1 aDurda, Peter1 aLiu, Yongmei1 aHou, Lifang1 aLee, Jiwon1 aKachroo, Priyadarshini1 aFreedman, Barry, I1 aLevy, Daniel1 aBielak, Lawrence, F1 aHixson, James, E1 aFloyd, James, S1 aWhitsel, Eric, A1 aEllinor, Patrick, T1 aIrvin, Marguerite, R1 aFingerlin, Tasha, E1 aRaffield, Laura, M1 aArmasu, Sebastian, M1 aWheeler, Marsha, M1 aSabino, Ester, C1 aBlangero, John1 aWilliams, Keoki1 aLevy, Bruce, D1 aSheu, Wayne, Huey-Herng1 aRoden, Dan, M1 aBoerwinkle, Eric1 aManson, JoAnn, E1 aMathias, Rasika, A1 aDesai, Pinkal1 aTaylor, Kent, D1 aJohnson, Andrew, D1 aAuer, Paul, L1 aKooperberg, Charles1 aLaurie, Cathy, C1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aZhao, Hongyu1 aLange, Ethan1 aLange, Leslie1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aScheet, Paul1 aKitzman, Jacob, O1 aLander, Eric, S1 aEngreitz, Jesse, M1 aEbert, Benjamin, L1 aReiner, Alexander, P1 aJaiswal, Siddhartha1 aAbecasis, Goncalo1 aSankaran, Vijay, G1 aKathiresan, Sekar1 aNatarajan, Pradeep1 aNHLBI Trans-Omics for Precision Medicine Consortium uhttps://chs-nhlbi.org/node/862107958nas a2202377 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2020 eng d a2041-172300aMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.0 aMultiancestry GWAS of the electrocardiographic PR interval ident c2020 May 21 a25420 v113 aThe 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.
1 aNtalla, Ioanna1 aWeng, Lu-Chen1 aCartwright, James, H1 aHall, Amelia, Weber1 aSveinbjornsson, Gardar1 aTucker, Nathan, R1 aChoi, Seung, Hoan1 aChaffin, Mark, D1 aRoselli, Carolina1 aBarnes, Michael, R1 aMifsud, Borbala1 aWarren, Helen, R1 aHayward, Caroline1 aMarten, Jonathan1 aCranley, James, J1 aConcas, Maria, Pina1 aGasparini, Paolo1 aBoutin, Thibaud1 aKolcic, Ivana1 aPolasek, Ozren1 aRudan, Igor1 aAraujo, Nathalia, M1 aLima-Costa, Maria, Fernanda1 aRibeiro, Antonio, Luiz P1 aSouza, Renan, P1 aTarazona-Santos, Eduardo1 aGiedraitis, Vilmantas1 aIngelsson, Erik1 aMahajan, Anubha1 aMorris, Andrew, P1 aM, Fabiola, del Greco1 aFoco, Luisa1 aGögele, Martin1 aHicks, Andrew, A1 aCook, James, P1 aLind, Lars1 aLindgren, Cecilia, M1 aSundström, Johan1 aNelson, Christopher, P1 aRiaz, Muhammad, B1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aUlivi, Sheila1 aKähönen, Mika1 aMishra, Pashupati, P1 aMononen, Nina1 aNikus, Kjell1 aCaulfield, Mark, J1 aDominiczak, Anna1 aPadmanabhan, Sandosh1 aMontasser, May, E1 aO'Connell, Jeff, R1 aRyan, Kathleen1 aShuldiner, Alan, R1 aAeschbacher, Stefanie1 aConen, David1 aRisch, Lorenz1 aThériault, Sébastien1 aHutri-Kähönen, Nina1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aRaitakari, Olli, T1 aBarnes, Catriona, L K1 aCampbell, Harry1 aJoshi, Peter, K1 aWilson, James, F1 aIsaacs, Aaron1 aKors, Jan, A1 aDuijn, Cornelia, M1 aHuang, Paul, L1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aLauner, Lenore, J1 aSmith, Albert, V1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aNadkarni, Girish, N1 aPreuss, Michael, H1 aCorrea, Adolfo1 aMei, Hao1 aWilson, James1 aMeitinger, Thomas1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aWaldenberger, Melanie1 aMangino, Massimo1 aSpector, Timothy, D1 aRienstra, Michiel1 avan de Vegte, Yordi, J1 aHarst, Pim1 aVerweij, Niek1 aKääb, Stefan1 aSchramm, Katharina1 aSinner, Moritz, F1 aStrauch, Konstantin1 aCutler, Michael, J1 aFatkin, Diane1 aLondon, Barry1 aOlesen, Morten1 aRoden, Dan, M1 aShoemaker, Benjamin1 aSmith, Gustav1 aBiggs, Mary, L1 aBis, Joshua, C1 aBrody, Jennifer, A1 aPsaty, Bruce, M1 aRice, Kenneth1 aSotoodehnia, Nona1 aDe Grandi, Alessandro1 aFuchsberger, Christian1 aPattaro, Cristian1 aPramstaller, Peter, P1 aFord, Ian1 aJukema, Wouter1 aMacfarlane, Peter, W1 aTrompet, Stella1 aDörr, Marcus1 aFelix, Stephan, B1 aVölker, Uwe1 aWeiss, Stefan1 aHavulinna, Aki, S1 aJula, Antti1 aSääksjärvi, Katri1 aSalomaa, Veikko1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aLin, Henry, J1 aRotter, Jerome, I1 aTaylor, Kent, D1 aYao, Jie1 ade Mutsert, Renée1 aMaan, Arie, C1 aMook-Kanamori, Dennis, O1 aNoordam, Raymond1 aCucca, Francesco1 aDing, Jun1 aLakatta, Edward, G1 aQian, Yong1 aTarasov, Kirill, V1 aLevy, Daniel1 aLin, Honghuang1 aNewton-Cheh, Christopher, H1 aLunetta, Kathryn, L1 aMurray, Alison, D1 aPorteous, David, J1 aSmith, Blair, H1 aStricker, Bruno, H1 aUitterlinden, Andre1 avan den Berg, Marten, E1 aHaessler, Jeffrey1 aJackson, Rebecca, D1 aKooperberg, Charles1 aPeters, Ulrike1 aReiner, Alexander, P1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBoerwinkle, Eric1 aEhret, Georg, B1 aSoliman, Elsayed, Z1 aAvery, Christy, L1 aGogarten, Stephanie, M1 aKerr, Kathleen, F1 aLaurie, Cathy, C1 aSeyerle, Amanda, A1 aStilp, Adrienne1 aAssa, Solmaz1 aSaid, Abdullah1 avan der Ende, Yldau1 aLambiase, Pier, D1 aOrini, Michele1 aRamirez, Julia1 aVan Duijvenboden, Stefan1 aArnar, David, O1 aGudbjartsson, Daniel, F1 aHolm, Hilma1 aSulem, Patrick1 aThorleifsson, Gudmar1 aThorolfsdottir, Rosa, B1 aThorsteinsdottir, Unnur1 aBenjamin, Emelia, J1 aTinker, Andrew1 aStefansson, Kari1 aEllinor, Patrick, T1 aJamshidi, Yalda1 aLubitz, Steven, A1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/836806073nas a2201597 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2023 eng d a1476-468700aAberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.0 aAberrant activation of TCL1A promotes stem cell expansion in clo c2023 Apr a755-7630 v6163 aMutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
10aAlleles10aAnimals10aClonal Hematopoiesis10aGenome-Wide Association Study10aHematopoiesis10aHematopoietic Stem Cells10aHumans10aMice10aMutation10aPromoter Regions, Genetic1 aWeinstock, Joshua, S1 aGopakumar, Jayakrishnan1 aBurugula, Bala, Bharathi1 aUddin, Md, Mesbah1 aJahn, Nikolaus1 aBelk, Julia, A1 aBouzid, Hind1 aDaniel, Bence1 aMiao, Zhuang1 aLy, Nghi1 aMack, Taralynn, M1 aLuna, Sofia, E1 aProthro, Katherine, P1 aMitchell, Shaneice, R1 aLaurie, Cecelia, A1 aBroome, Jai, G1 aTaylor, Kent, D1 aGuo, Xiuqing1 aSinner, Moritz, F1 avon Falkenhausen, Aenne, S1 aKääb, Stefan1 aShuldiner, Alan, R1 aO'Connell, Jeffrey, R1 aLewis, Joshua, P1 aBoerwinkle, Eric1 aBarnes, Kathleen, C1 aChami, Nathalie1 aKenny, Eimear, E1 aLoos, Ruth, J F1 aFornage, Myriam1 aHou, Lifang1 aLloyd-Jones, Donald, M1 aRedline, Susan1 aCade, Brian, E1 aPsaty, Bruce, M1 aBis, Joshua, C1 aBrody, Jennifer, A1 aSilverman, Edwin, K1 aYun, Jeong, H1 aQiao, Dandi1 aPalmer, Nicholette, D1 aFreedman, Barry, I1 aBowden, Donald, W1 aCho, Michael, H1 aDeMeo, Dawn, L1 aVasan, Ramachandran, S1 aYanek, Lisa, R1 aBecker, Lewis, C1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aHe, Jiang1 aRienstra, Michiel1 aHarst, Pim1 aKaplan, Robert1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aArnett, Donna, K1 aIrvin, Marguerite, R1 aTiwari, Hemant1 aCutler, Michael, J1 aKnight, Stacey1 aMuhlestein, Brent1 aCorrea, Adolfo1 aRaffield, Laura, M1 aGao, Yan1 ade Andrade, Mariza1 aRotter, Jerome, I1 aRich, Stephen, S1 aTracy, Russell, P1 aKonkle, Barbara, A1 aJohnsen, Jill, M1 aWheeler, Marsha, M1 aSmith, Gustav1 aMelander, Olle1 aNilsson, Peter, M1 aCuster, Brian, S1 aDuggirala, Ravindranath1 aCurran, Joanne, E1 aBlangero, John1 aMcGarvey, Stephen1 aWilliams, Keoki1 aXiao, Shujie1 aYang, Mao1 aGu, Charles1 aChen, Yii-Der Ida1 aLee, Wen-Jane1 aMarcus, Gregory, M1 aKane, John, P1 aPullinger, Clive, R1 aShoemaker, Benjamin1 aDarbar, Dawood1 aRoden, Dan, M1 aAlbert, Christine1 aKooperberg, Charles1 aZhou, Ying1 aManson, JoAnn, E1 aDesai, Pinkal1 aJohnson, Andrew, D1 aMathias, Rasika, A1 aBlackwell, Thomas, W1 aAbecasis, Goncalo, R1 aSmith, Albert, V1 aKang, Hyun, M1 aSatpathy, Ansuman, T1 aNatarajan, Pradeep1 aKitzman, Jacob, O1 aWhitsel, Eric, A1 aReiner, Alexander, P1 aBick, Alexander, G1 aJaiswal, Siddhartha1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/938702868nas a2200625 4500008004100000245005900041210005800100260001600158520116400174100001801338700001901356700002001375700002501395700002301420700002501443700002101468700002101489700001801510700002001528700001401548700002101562700002101583700002001604700001901624700002001643700001901663700001701682700002401699700002001723700001501743700001601758700001701774700002001791700002001811700001901831700001801850700001601868700002301884700001801907700002301925700002101948700002201969700001701991700001502008700001802023700002302041700001802064700001702082700001802099700001702117700002402134700002502158700002302183856003602206 2023 eng d00aDeterminants of mosaic chromosomal alteration fitness.0 aDeterminants of mosaic chromosomal alteration fitness c2023 Oct 213 aClonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.
1 aPershad, Yash1 aMack, Taralynn1 aPoisner, Hannah1 aJakubek, Yasminka, A1 aStilp, Adrienne, M1 aMitchell, Braxton, D1 aLewis, Joshua, P1 aBoerwinkle, Eric1 aLoos, Ruth, J1 aChami, Nathalie1 aWang, Zhe1 aBarnes, Kathleen1 aPankratz, Nathan1 aFornage, Myriam1 aRedline, Susan1 aPsaty, Bruce, M1 aBis, Joshua, C1 aShojaie, Ali1 aSilverman, Edwin, K1 aCho, Michael, H1 aYun, Jeong1 aDeMeo, Dawn1 aLevy, Daniel1 aJohnson, Andrew1 aMathias, Rasika1 aTaub, Margaret1 aArnett, Donna1 aNorth, Kari1 aRaffield, Laura, M1 aCarson, April1 aDoyle, Margaret, F1 aRich, Stephen, S1 aRotter, Jerome, I1 aGuo, Xiuqing1 aCox, Nancy1 aRoden, Dan, M1 aFranceschini, Nora1 aDesai, Pinkal1 aReiner, Alex1 aAuer, Paul, L1 aScheet, Paul1 aJaiswal, Siddhartha1 aWeinstock, Joshua, S1 aBick, Alexander, G uhttps://chs-nhlbi.org/node/958805493nas a2201573 4500008004100000245011200041210006900153260001600222520100600238100001801244700002301262700002201285700002501307700002001332700001501352700001401367700002001381700002101401700002201422700001401444700001401458700002401472700002101496700002401517700001901541700002901560700002201589700001901611700001801630700002801648700002001676700001901696700001901715700002101734700002401755700001901779700001701798700002801815700001701843700002201860700002301882700002401905700001701929700001801946700002501964700002001989700002102009700001602030700002002046700001602066700001302082700001802095700002402113700001702137700002102154700002402175700002102199700002002220700002002240700001702260700002202277700002802299700002302327700002402350700001702374700002302391700003002414700002602444700002102470700002002491700001902511700002302530700001402553700002402567700002402591700001802615700002802633700002402661700002302685700002202708700002702730700001702757700002102774700002102795700002202816700002202838700002302860700001902883700002302902700001402925700002402939700002102963700002802984700002403012700001903036700002103055700002503076700002103101700002303122700002203145700002203167700002003189700002303209700001403232700002303246700001603269700002503285700002403310700002103334700002503355700001903380700002003399700002303419700002503442700002103467700002203488700002403510700002303534700002003557700002203577700002003599700001803619700002503637700001603662700001603678700002503694700002103719700001803740700002003758700001903778700002103797710006503818856003603883 2023 eng d00aWHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.0 aWHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES N c2023 Aug 223 aObesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.
1 aZhang, Xinruo1 aBrody, Jennifer, A1 aGraff, Mariaelisa1 aHighland, Heather, M1 aChami, Nathalie1 aXu, Hanfei1 aWang, Zhe1 aFerrier, Kendra1 aChittoor, Geetha1 aJosyula, Navya, S1 aLi, Xihao1 aLi, Zilin1 aAllison, Matthew, A1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBoorgula, Meher, Preethi1 aBowden, Donald, W1 aBroome, Jai, G1 aButh, Erin, J1 aCarlson, Christopher, S1 aChang, Kyong-Mi1 aChavan, Sameer1 aChiu, Yen-Feng1 aChuang, Lee-Ming1 aConomos, Matthew, P1 aDeMeo, Dawn, L1 aDu, Margaret1 aDuggirala, Ravindranath1 aEng, Celeste1 aFohner, Alison, E1 aFreedman, Barry, I1 aGarrett, Melanie, E1 aGuo, Xiuqing1 aHaiman, Chris1 aHeavner, Benjamin, D1 aHidalgo, Bertha1 aHixson, James, E1 aHo, Yuk-Lam1 aHobbs, Brian, D1 aHu, Donglei1 aHui, Qin1 aHwu, Chii-Min1 aJackson, Rebecca, D1 aJain, Deepti1 aKalyani, Rita, R1 aKardia, Sharon, L R1 aKelly, Tanika, N1 aLange, Ethan, M1 aLeNoir, Michael1 aLi, Changwei1 aLe Marchand, Loic1 aMcDonald, Merry-Lynn, N1 aMcHugh, Caitlin, P1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey1 aO'Donnell, Christopher, J1 aPalmer, Nicholette, D1 aPankow, James, S1 aPerry, James, A1 aPeters, Ulrike1 aPreuss, Michael, H1 aRao, D, C1 aRegan, Elizabeth, A1 aReupena, Sefuiva, M1 aRoden, Dan, M1 aRodriguez-Santana, Jose1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aTiwari, Hemant, K1 aVasan, Ramachandran, S1 aWang, Zeyuan1 aWeeks, Daniel, E1 aWessel, Jennifer1 aWiggins, Kerri, L1 aWilkens, Lynne, R1 aWilson, Peter, W F1 aYanek, Lisa, R1 aYoneda, Zachary, T1 aZhao, Wei1 aZöllner, Sebastian1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBlangero, John1 aBoerwinkle, Eric1 aBurchard, Esteban, G1 aCarson, April, P1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aCurran, Joanne, E1 aFornage, Myriam1 aGordeuk, Victor, R1 aHe, Jiang1 aHeckbert, Susan, R1 aHou, Lifang1 aIrvin, Marguerite, R1 aKooperberg, Charles1 aMinster, Ryan, L1 aMitchell, Braxton, D1 aNouraie, Mehdi1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aReiner, Alexander, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aShoemaker, Benjamin1 aSmith, Nicholas, L1 aTaylor, Kent, D1 aTelen, Marilyn, J1 aWeiss, Scott, T1 aZhang, Yingze1 aCosta, Nancy, Heard-1 aSun, Yan, V1 aLin, Xihong1 aCupples, Adrienne, L1 aLange, Leslie, A1 aLiu, Ching-Ti1 aLoos, Ruth, J F1 aNorth, Kari, E1 aJustice, Anne, E1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/9484