03189nas a2200433 4500008004100000022001400041245005100055210005000106260001300156300001300169490000700182520196300189100002202152700002302174700002502197700002202222700001802244700003002262700001902292700002102311700002202332700001902354700002502373700002102398700002602419700001702445700002002462700002002482700002402502700002202526700002402548700002402572700002302596700001902619700002402638700001902662710003802681856003602719 2016 eng d a1553-740400aWhole Exome Sequencing in Atrial Fibrillation.0 aWhole Exome Sequencing in Atrial Fibrillation c2016 Sep ae10062840 v123 a
Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.
1 aLubitz, Steven, A1 aBrody, Jennifer, A1 aBihlmeyer, Nathan, A1 aRoselli, Carolina1 aWeng, Lu-Chen1 aChristophersen, Ingrid, E1 aAlonso, Alvaro1 aBoerwinkle, Eric1 aGibbs, Richard, A1 aBis, Joshua, C1 aCupples, Adrienne, L1 aMohler, Peter, J1 aNickerson, Deborah, A1 aMuzny, Donna1 aPerez, Marco, V1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aLunetta, Kathryn, L1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aArking, Dan, E1 aEllinor, Patrick, T1 aLin, Honghuang1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/725006088nas 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/736306999nas 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/739616401nas a2205425 4500008004100000022001400041245013100055210006900186260001300255300001200268490000700280520096800287100001801255700002001273700002101293700003301314700002001347700001901367700002401386700002301410700002801433700002701461700002901488700001901517700002201536700001701558700001901575700002201594700001401616700002001630700002401650700001701674700002801691700002101719700002501740700001801765700001901783700002301802700001801825700001801843700001901861700002201880700002101902700001701923700002501940700002401965700002201989700001502011700002402026700002202050700002602072700002002098700002402118700002302142700002202165700002202187700001902209700002202228700002302250700002702273700001902300700001802319700002602337700002002363700002002383700002502403700001702428700002502445700002202470700001902492700002002511700002002531700002202551700002502573700002402598700001902622700002102641700002302662700002402685700002202709700001702731700001902748700001702767700002202784700001602806700002202822700002002844700002502864700001802889700002102907700002402928700002202952700002502974700002202999700002203021700002403043700002503067700002003092700001903112700002503131700002503156700002403181700001803205700002103223700002003244700002103264700002303285700002203308700002003330700002003350700001803370700002203388700002003410700002303430700002203453700002403475700001803499700001903517700002203536700002403558700002403582700002303606700002003629700002403649700002503673700002803698700001903726700002003745700002403765700002303789700002103812700002503833700003203858700002103890700002203911700001603933700001703949700001903966700001903985700002004004700002004024700001804044700002804062700002104090700001804111700002304129700002504152700003004177700002204207700002204229700002404251700001904275700002204294700001904316700001404335700001504349700001804364700002204382700002304404700002304427700002704450700001904477700002004496700002004516700003004536700002004566700001704586700001404603700001604617700002104633700002104654700002304675700002104698700002104719700002504740700002304765700002004788700002004808700002004828700002404848700002304872700002304895700002104918700001804939700002004957700002104977700003304998700002005031700001905051700002405070700002305094700002805117700002705145700002905172700001905201700002205220700001705242700001905259700002205278700001405300700002005314700002405334700001705358700002805375700002105403700002505424700001805449700001905467700002305486700001805509700001805527700001905545700002205564700002105586700001705607700002505624700002405649700002205673700001505695700002405710700002205734700002605756700002005782700002405802700002305826700002205849700002205871700001905893700002205912700002305934700002705957700001905984700001806003700002606021700002006047700002006067700002506087700001706112700002506129700002206154700001906176700002006195700002006215700002206235700002506257700002406282700001906306700002106325700002306346700002406369700002206393700001706415700001906432700001706451700002206468700001606490700002206506700002006528700002506548700001806573700002106591700002406612700002206636700002506658700002206683700002206705700002406727700002506751700002006776700001906796700002506815700002506840700002406865700001806889700002106907700002006928700002106948700002306969700002206992700002007014700002007034700001807054700002207072700002007094700002307114700002207137700002407159700001807183700001907201700002207220700002407242700002407266700002307290700002007313700002407333700002507357700002807382700001907410700002007429700002407449700002307473700002107496700002507517700003207542700002107574700002207595700001607617700001707633700001607650700002207666700002107688700001607709700002107725700001907746700002107765700002407786700001807810700002007828700002207848700002007870700002107890700003007911700002307941700001907964700001807983700002208001700001408023700002408037700002008061700001908081700002008100700001808120700002008138700002208158700002008180700002408200700001908224700002208243700002108265700001708286700002308303700002308326700002408349700001708373700002408390700002108414700002408435700002108459700002508480700001508505700001508520700002508535700002308560700001908583700002008602700001908622700003108641700002008672700002108692700001908713700002208732700001808754700003008772700001708802700002108819700002308840700003308863700002308896700001708919700001908936700002408955700002108979700002109000700002409021700002009045700002009065700001809085700002109103700002309124700001809147700002109165700001909186700002609205700001809231700001909249700001809268700001809286700002409304700001809328700001709346700003109363700001709394700001709411700002009428700002409448700001809472700001809490700001609508700002209524700001809546700002809564700002009592700002309612700002809635700002709663700002509690700001909715700001709734700001609751700002509767700002409792700001709816700001609833700001809849700002709867700001909894700002009913700002009933700003009953700002009983700001710003700001410020700001610034700002110050700002110071700002310092700002110115700002110136700002510157700002310182700002010205700002010225700002010245700002410265700002310289700002310312700002110335710002110356710008510377710006610462710002210528710001210550710004510562710002310607710002410630710002910654710005210683710002610735710005310761710004110814710003110855710002610886710002710912856003610939 2018 eng d a1546-171800aMultiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.0 aMultiancestry genomewide association study of 520000 subjects id c2018 Apr a524-5370 v503 aStroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aBis, Joshua, C1 aPastinen, Tomi1 aRuusalepp, Arno1 aSchadt, Eric, E1 aKoplev, Simon1 aBjörkegren, Johan, L M1 aCodoni, Veronica1 aCivelek, Mete1 aSmith, Nicholas, L1 aTrégouët, David, A1 aChristophersen, Ingrid, E1 aRoselli, Carolina1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aTai, Shyong, E1 aKooner, Jaspal, S1 aKato, Norihiro1 aHe, Jiang1 aHarst, Pim1 aElliott, Paul1 aChambers, John, C1 aTakeuchi, Fumihiko1 aJohnson, Andrew, D1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aAmin, Najaf1 aAparicio, Hugo, S1 aArnett, Donna, K1 aAttia, John1 aBeiser, Alexa, S1 aBerr, Claudine1 aBuring, Julie, E1 aBustamante, Mariana1 aCaso, Valeria1 aCheng, Yu-Ching1 aChoi, Seung, Hoan1 aChowhan, Ayesha1 aCullell, Natalia1 aDartigues, Jean-François1 aDelavaran, Hossein1 aDelgado, Pilar1 aDörr, Marcus1 aEngström, Gunnar1 aFord, Ian1 aGurpreet, Wander, S1 aHamsten, Anders1 aHeitsch, Laura1 aHozawa, Atsushi1 aIbanez, Laura1 aIlinca, Andreea1 aIngelsson, Martin1 aIwasaki, Motoki1 aJackson, Rebecca, D1 aJood, Katarina1 aJousilahti, Pekka1 aKaffashian, Sara1 aKalra, Lalit1 aKamouchi, Masahiro1 aKitazono, Takanari1 aKjartansson, Olafur1 aKloss, Manja1 aKoudstaal, Peter, J1 aKrupinski, Jerzy1 aLabovitz, Daniel, L1 aLaurie, Cathy, C1 aLevi, Christopher, R1 aLi, Linxin1 aLind, Lars1 aLindgren, Cecilia, M1 aLioutas, Vasileios1 aLiu, Yong, Mei1 aLopez, Oscar, L1 aMakoto, Hirata1 aMartinez-Majander, Nicolas1 aMatsuda, Koichi1 aMinegishi, Naoko1 aMontaner, Joan1 aMorris, Andrew, P1 aMuiño, Elena1 aMüller-Nurasyid, Martina1 aNorrving, Bo1 aOgishima, Soichi1 aParati, Eugenio, A1 aPeddareddygari, Leema, Reddy1 aPedersen, Nancy, L1 aPera, Joanna1 aPerola, Markus1 aPezzini, Alessandro1 aPileggi, Silvana1 aRabionet, Raquel1 aRiba-Llena, Iolanda1 aRibasés, Marta1 aRomero, Jose, R1 aRoquer, Jaume1 aRudd, Anthony, G1 aSarin, Antti-Pekka1 aSarju, Ralhan1 aSarnowski, Chloe1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSatoh, Mamoru1 aSattar, Naveed1 aSawada, Norie1 aSibolt, Gerli1 aSigurdsson, Ásgeir1 aSmith, Albert1 aSobue, Kenji1 aSoriano-Tárraga, Carolina1 aStanne, Tara1 aStine, Colin1 aStott, David, J1 aStrauch, Konstantin1 aTakai, Takako1 aTanaka, Hideo1 aTanno, Kozo1 aTeumer, Alexander1 aTomppo, Liisa1 aTorres-Aguila, Nuria, P1 aTouze, Emmanuel1 aTsugane, Shoichiro1 aUitterlinden, André, G1 aValdimarsson, Einar, M1 avan der Lee, Sven, J1 aVölzke, Henry1 aWakai, Kenji1 aWeir, David1 aWilliams, Stephen, R1 aWolfe, Charles, D A1 aWong, Quenna1 aXu, Huichun1 aYamaji, Taiki1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aAFGen Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium1 aInternational Genomics of Blood Pressure (iGEN-BP) Consortium1 aINVENT Consortium1 aSTARNET1 aBioBank Japan Cooperative Hospital Group1 aCOMPASS Consortium1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aInternational Stroke Genetics Consortium (ISGC)1 aMETASTROKE Consortium1 aNeurology Working Group of the CHARGE Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aUK Young Lacunar DNA Study1 aMEGASTROKE Consortium1 aMEGASTROKE Consortium: uhttps://chs-nhlbi.org/node/768308664nas a2202749 4500008004100000022001400041245007200055210006900127260001300196300001400209490000700223520107000230100002201300700002101322700001801343700002601361700002001387700002501407700001901432700001901451700002901470700002301499700001901522700001801541700002001559700002401579700002501603700001901628700002201647700002101669700002401690700002301714700001801737700002101755700002301776700002001799700002301819700001701842700002201859700001901881700002201900700003001922700001901952700001801971700001701989700001602006700002102022700002302043700002302066700002202089700001902111700002202130700002102152700002102173700001802194700002102212700002202233700001402255700001602269700001902285700001802304700002202322700001402344700002102358700002302379700002002402700002402422700001702446700001902463700002302482700002102505700002002526700002202546700002202568700002302590700002302613700002202636700001902658700002802677700001502705700001902720700002202739700002002761700002202781700001502803700002502818700001902843700001902862700001902881700002002900700002302920700001802943700002002961700002202981700002803003700002003031700002203051700002303073700002103096700002203117700001903139700002103158700001903179700002203198700001903220700002203239700002403261700002403285700001203309700001903321700001803340700001903358700001503377700002503392700002303417700001803440700002003458700001803478700001803496700002803514700002503542700002503567700002003592700001803612700002303630700002303653700002103676700002603697700002003723700002203743700001903765700002503784700002303809700002303832700002203855700003003877700001903907700002003926700002203946700002903968700002603997700001704023700001904040700002104059700001904080700002204099700002504121700002504146700001704171700002104188700002304209700001704232700002304249700002004272700002004292700001904312700002404331700002104355700002004376700002004396700002004416700002204436700001804458700001804476700002104494700002604515700001804541700002204559700001604581700002504597700002404622700002304646700002404669700002204693700002104715700002104736700002304757700001604780700002104796700001704817700002404834700002304858700001904881700002204900700002204922700002104944700002004965700001804985700002305003700002305026700002405049700002205073700002305095700001605118700001305134700002405147700002205171700002505193700002005218700002405238700002205262700002705284700002005311700002205331700001905353700002805372700001505400700002805415700002605443700001805469700002705487700001705514700001505531700002005546700001505566700001605581700001805597700002005615700002205635700001905657700001605676700002505692700001905717700001305736700002305749700001805772700001805790700002205808700002405830700002405854856003605878 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/781104940nas a2200661 4500008004100000022001400041245014200055210006900197260001600266520300700282100002403289700002203313700003003335700001903365700001903384700002303403700002003426700001903446700002303465700001703488700002203505700001803527700001903545700002203564700002203586700002303608700002103631700001803652700001803670700002103688700001803709700002403727700002003751700002103771700002003792700002003812700002003832700001503852700002003867700001903887700002403906700002203930700002103952700001803973700001903991700002104010700002204031700001604053700002204069700002204091700002404113700002204137700002004159700001504179700002504194700002304219856003604242 2019 eng d a2380-659100aAssessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study.0 aAssessment of the Relationship Between Genetic Determinants of T c2019 Jan 233 aImportance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.
Objective: To evaluate the potential direct involvement of thyroid traits on AF.
Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.
Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.
Main Outcomes and Measures: Prevalent and incident AF.
Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).
Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.
1 aEllervik, Christina1 aRoselli, Carolina1 aChristophersen, Ingrid, E1 aAlonso, Alvaro1 aPietzner, Maik1 aSitlani, Collen, M1 aTrompet, Stella1 aArking, Dan, E1 aGeelhoed, Bastiaan1 aGuo, Xiuqing1 aKleber, Marcus, E1 aLin, Henry, J1 aLin, Honghuang1 aMacfarlane, Peter1 aSelvin, Elizabeth1 aShaffer, Christian1 aSmith, Albert, V1 aVerweij, Niek1 aWeiss, Stefan1 aCappola, Anne, R1 aDörr, Marcus1 aGudnason, Vilmundur1 aHeckbert, Susan1 aMooijaart, Simon1 aMärz, Winfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRoden, Dan1 aStott, David, J1 aVölzke, Henry1 aBenjamin, Emelia, J1 aDelgado, Graciela1 aEllinor, Patrick1 aHomuth, Georg1 aKöttgen, Anna1 aJukema, Johan, W1 aLubitz, Steven, A1 aMora, Samia1 aRienstra, Michiel1 aRotter, Jerome, I1 aShoemaker, Benjamin1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aHarst, Pim1 aAlbert, Christine, M1 aChasman, Daniel, I uhttps://chs-nhlbi.org/node/797307958nas a2202377 4500008004100000022001400041245011500055210006900170260001600239300000900255490000700264520122900271100001901500700001801519700002501537700002401562700002701586700002201613700002201635700002101657700002201678700002301700700002001723700002101743700002201764700002101786700002201807700002401829700002101853700002001874700001801894700001901912700001601931700002401947700003201971700002902003700002002032700002902052700002602081700002002107700002002127700002202147700002602169700001602195700002002211700002102231700001902252700001502271700002502286700002202311700002702333700002202360700002202382700002402404700001802428700002002446700002502466700001802491700001702509700002302526700002102549700002502570700002202595700002302617700001902640700002302659700002602682700001702708700001802725700002702743700002602770700002202796700002802818700002302846700002602869700002002895700002002915700002102935700001802956700001702974700002302991700001903014700002403033700002203057700002203079700002103101700002403122700002003146700002403166700002303190700001903213700001303232700001803245700002203263700003003285700002003315700002603335700002103361700002403382700002203406700002703428700001503455700001803470700001903488700002303507700002203530700002403552700002303576700001803599700001803617700001903635700001803654700002403672700001803696700001903714700001903733700002303752700002003775700001803795700002203813700002603835700002703861700002203888700002603910700001403936700001903950700002503969700002003994700001804014700002204032700001704054700001804071700002204089700001604111700002504127700002004152700001704172700002304189700001804212700002204230700002004252700001304272700002304285700001804308700002904326700002104355700002104376700001404397700002304411700001504434700002304449700001704472700001904489700003204508700002404540700002204564700002304586700002004609700002304629700002404652700002804676700002204704700002404726700002404750700001904774700002504793700002104818700001904839700001904858700002104877700002004898700002404918700002204942700002704964700002204991700002105013700002305034700002005057700001705077700001905094700002405113700002205137700001905159700001905178700002905197700002005226700002805246700001605274700001905290700002505309700002805334700002805362700002405390700001905414700002105433700002405454700002005478700002205498700002405520856003605544 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/8368