05728nas a2201213 4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520227000293653001002563653000902573653002202582653001002604653002802614653002102642653004002663653001102703653003402714653001302748653001602761653002102777653001102798653000902809653001602818653001502834653001402849653003602863653001702899653003402916653003102950100002702981700002203008700002103030700001903051700002103070700002203091700002303113700002203136700002303158700001903181700002303200700002003223700002203243700002203265700002203287700001903309700002403328700002003352700001803372700001803390700002303408700002103431700001903452700002603471700002203497700002403519700001803543700002003561700001503581700002703596700002703623700001703650700002303667700002103690700001803711700002103729700001703750700002003767700002003787700002303807700003003830700002303860700002303883700002103906700002503927700002603952700001703978700002203995700001804017700002104035700001904056700002404075700002804099700002204127700002004149700002004169700002004189700002004209700002304229700002204252700002204274700002104296700002404317700002204341700002804363700002404391700002004415700001904435700002404454856003604478 2009 eng d a1538-359800aGenetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.0 aGenetic variants associated with cardiac structure and function c2009 Jul 08 a168-780 v3023 a
CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.
OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.
DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.
MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.
RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).
CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
10aAdult10aAged10aAged, 80 and over10aAorta10aCardiovascular Diseases10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHeart Ventricles10aHumans10aMale10aMiddle Aged10aOrgan Size10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aVentricular Dysfunction, Left10aVentricular Function, Left1 aVasan, Ramachandran, S1 aGlazer, Nicole, L1 aFelix, Janine, F1 aLieb, Wolfgang1 aWild, Philipp, S1 aFelix, Stephan, B1 aWatzinger, Norbert1 aLarson, Martin, G1 aSmith, Nicholas, L1 aDehghan, Abbas1 aGrosshennig, Anika1 aSchillert, Arne1 aTeumer, Alexander1 aSchmidt, Reinhold1 aKathiresan, Sekar1 aLumley, Thomas1 aAulchenko, Yurii, S1 aKönig, Inke, R1 aZeller, Tanja1 aHomuth, Georg1 aStruchalin, Maksim1 aAragam, Jayashri1 aBis, Joshua, C1 aRivadeneira, Fernando1 aErdmann, Jeanette1 aSchnabel, Renate, B1 aDörr, Marcus1 aZweiker, Robert1 aLind, Lars1 aRodeheffer, Richard, J1 aGreiser, Karin, Halina1 aLevy, Daniel1 aHaritunians, Talin1 aDeckers, Jaap, W1 aStritzke, Jan1 aLackner, Karl, J1 aVölker, Uwe1 aIngelsson, Erik1 aKullo, Iftikhar1 aHaerting, Johannes1 aO'Donnell, Christopher, J1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aZiegler, Andreas1 aReffelmann, Thorsten1 aRedfield, Margaret, M1 aWerdan, Karl1 aMitchell, Gary, F1 aRice, Kenneth1 aArnett, Donna, K1 aHofman, Albert1 aGottdiener, John, S1 aUitterlinden, André, G1 aMeitinger, Thomas1 aBlettner, Maria1 aFriedrich, Nele1 aWang, Thomas, J1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aMunzel, Thomas, F1 aKroemer, Heyo, K1 aBenjamin, Emelia, J1 aRotter, Jerome, I1 aWitteman, Jacqueline, C1 aSchunkert, Heribert1 aSchmidt, Helena1 aVölzke, Henry1 aBlankenberg, Stefan uhttps://chs-nhlbi.org/node/110805521nas a2201561 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520109100256653001201347653002101359653002301380653002601403653002401429653001701453653003401470653002801504653001101532653000901543653002101552653001901573653002201592653004001614653003601654653002001690100002201710700001801732700002501750700001801775700002901793700001901822700001501841700002101856700002201877700001901899700002101918700002501939700002201964700002601986700001902012700002302031700001702054700002202071700002602093700001802119700002002137700002202157700001202179700001902191700002602210700001902236700001902255700001802274700001802292700001902310700001802329700001802347700002702365700001902392700002402411700001902435700001702454700002002471700002702491700001702518700002602535700002202561700001702583700002302600700002202623700002402645700002402669700002002693700001902713700002502732700002002757700002302777700002802800700001902828700002402847700001702871700002102888700002402909700002202933700002002955700001702975700002202992700001903014700003003033700002103063700002003084700002303104700002203127700001903149700002003168700002103188700002803209700002903237700003003266700002603296700002303322700002103345700001903366700001603385700001703401700002603418700002403444700002203468700002203490700002903512700002003541700002003561700001803581700001603599700002003615700002103635700002603656700002403682700002003706700002403726700002303750700002203773700002203795700002003817700002603837700002203863700001903885700001903904856003603923 2010 eng d a1546-171800aCommon variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.0 aCommon variants in 22 loci are associated with QRS duration and c2010 Dec a1068-760 v423 aThe QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
10aAnimals10aAnimals, Newborn10aChromosomes, Human10aComputational Biology10aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMice10aMice, Transgenic10aModels, Animal10aMyocytes, Cardiac10aNAV1.8 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aSodium Channels1 aSotoodehnia, Nona1 aIsaacs, Aaron1 ade Bakker, Paul, I W1 aDörr, Marcus1 aNewton-Cheh, Christopher1 aNolte, Ilja, M1 aHarst, Pim1 aMüller, Martina1 aEijgelsheim, Mark1 aAlonso, Alvaro1 aHicks, Andrew, A1 aPadmanabhan, Sandosh1 aHayward, Caroline1 aSmith, Albert, Vernon1 aPolasek, Ozren1 aGiovannone, Steven1 aFu, Jingyuan1 aMagnani, Jared, W1 aMarciante, Kristin, D1 aPfeufer, Arne1 aGharib, Sina, A1 aTeumer, Alexander1 aLi, Man1 aBis, Joshua, C1 aRivadeneira, Fernando1 aAspelund, Thor1 aKöttgen, Anna1 aJohnson, Toby1 aRice, Kenneth1 aSie, Mark, P S1 aWang, Ying, A1 aKlopp, Norman1 aFuchsberger, Christian1 aWild, Sarah, H1 aLeach, Irene, Mateo1 aEstrada, Karol1 aVölker, Uwe1 aWright, Alan, F1 aAsselbergs, Folkert, W1 aQu, Jiaxiang1 aChakravarti, Aravinda1 aSinner, Moritz, F1 aKors, Jan, A1 aPetersmann, Astrid1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aOostra, Ben, A1 aCupples, Adrienne, L1 aPerz, Siegfried1 ade Boer, Rudolf, A1 aUitterlinden, André, G1 aVölzke, Henry1 aSpector, Timothy, D1 aLiu, Fang-Yu1 aBoerwinkle, Eric1 aDominiczak, Anna, F1 aRotter, Jerome, I1 avan Herpen, Gé1 aLevy, Daniel1 aWichmann, H-Erich1 aGilst, Wiek, H1 aWitteman, Jacqueline, C M1 aKroemer, Heyo, K1 aKao, Linda, W H1 aHeckbert, Susan, R1 aMeitinger, Thomas1 aHofman, Albert1 aCampbell, Harry1 aFolsom, Aaron, R1 avan Veldhuisen, Dirk, J1 aSchwienbacher, Christine1 aO'Donnell, Christopher, J1 aVolpato, Claudia, Beu1 aCaulfield, Mark, J1 aConnell, John, M1 aLauner, Lenore1 aLu, Xiaowen1 aFranke, Lude1 aFehrmann, Rudolf, S N1 aMeerman, Gerard, te1 aGroen, Harry, J M1 aWeersma, Rinse, K1 avan den Berg, Leonard, H1 aWijmenga, Cisca1 aOphoff, Roel, A1 aNavis, Gerjan1 aRudan, Igor1 aSnieder, Harold1 aWilson, James, F1 aPramstaller, Peter, P1 aSiscovick, David, S1 aWang, Thomas, J1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aFelix, Stephan, B1 aFishman, Glenn, I1 aJamshidi, Yalda1 aStricker, Bruno, H Ch1 aSamani, Nilesh, J1 aKääb, Stefan1 aArking, Dan, E uhttps://chs-nhlbi.org/node/124405113nas a2201189 4500008004100000022001400041245009300055210006900148260001600217300001200233490000700245520181400252653001002066653000902076653001702085653001902102653001102121653001702132653001802149653003402167653001502201653001102216653000902227653001602236653003602252653000902288100002202297700002902319700002202348700002502370700002102395700002402416700002102440700001802461700001802479700001802497700001702515700002702532700001902559700001902578700001902597700002002616700001902636700002402655700001902679700002202698700002402720700002602744700002502770700002102795700002002816700001902836700002002855700001702875700002402892700002302916700001802939700001902957700001902976700002202995700002303017700002303040700001903063700002203082700002103104700001903125700002103144700002003165700002003185700001803205700001903223700002103242700001803263700001903281700002003300700002203320700001703342700003003359700002003389700002203409700002203431700001903453700002403472700002003496700002803516700002103544700002203565700002103587700002303608700002003631700002603651700002303677700002303700700002203723700002403745700001803769700002303787700002603810700002103836700003003857856003603887 2010 eng d a1460-208300aGenome-wide association analysis identifies multiple loci related to resting heart rate.0 aGenomewide association analysis identifies multiple loci related c2010 Oct 01 a3885-940 v193 aHigher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
10aAdult10aAged10aBase Pairing10aCohort Studies10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHeart Rate10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRest1 aEijgelsheim, Mark1 aNewton-Cheh, Christopher1 aSotoodehnia, Nona1 ade Bakker, Paul, I W1 aMüller, Martina1 aMorrison, Alanna, C1 aSmith, Albert, V1 aIsaacs, Aaron1 aSanna, Serena1 aDörr, Marcus1 aNavarro, Pau1 aFuchsberger, Christian1 aNolte, Ilja, M1 aGeus, Eco, J C1 aEstrada, Karol1 aHwang, Shih-Jen1 aBis, Joshua, C1 aRückert, Ina-Maria1 aAlonso, Alvaro1 aLauner, Lenore, J1 aHottenga, Jouke Jan1 aRivadeneira, Fernando1 aNoseworthy, Peter, A1 aRice, Kenneth, M1 aPerz, Siegfried1 aArking, Dan, E1 aSpector, Tim, D1 aKors, Jan, A1 aAulchenko, Yurii, S1 aTarasov, Kirill, V1 aHomuth, Georg1 aWild, Sarah, H1 aMarroni, Fabio1 aGieger, Christian1 aLicht, Carmilla, M1 aPrineas, Ronald, J1 aHofman, Albert1 aRotter, Jerome, I1 aHicks, Andrew, A1 aErnst, Florian1 aNajjar, Samer, S1 aWright, Alan, F1 aPeters, Annette1 aFox, Ervin, R1 aOostra, Ben, A1 aKroemer, Heyo, K1 aCouper, David1 aVölzke, Henry1 aCampbell, Harry1 aMeitinger, Thomas1 aUda, Manuela1 aWitteman, Jacqueline, C M1 aPsaty, Bruce, M1 aWichmann, H-Erich1 aHarris, Tamara, B1 aKääb, Stefan1 aSiscovick, David, S1 aJamshidi, Yalda1 aUitterlinden, André, G1 aFolsom, Aaron, R1 aLarson, Martin, G1 aWilson, James, F1 aPenninx, Brenda, W1 aSnieder, Harold1 aPramstaller, Peter, P1 aDuijn, Cornelia, M1 aLakatta, Edward, G1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aPfeufer, Arne1 aHeckbert, Susan, R1 aStricker, Bruno, H Ch1 aBoerwinkle, Eric1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/121712698nas a2203781 4500008004100000022001400041245009600055210006900151260001600220300001000236490000800246520210000254653001602354653003102370653001702401653003802418653001802456653003402474653001102508653003602519653003102555653001402586653003602600100002302636700001902659700002202678700002102700700002302721700002602744700002302770700002102793700002202814700002502836700002102861700002002882700002202902700002302924700002802947700002102975700002002996700001803016700001503034700002503049700002603074700002303100700001103123700002603134700001803160700001903178700001803197700001803215700001803233700002503251700002303276700002403299700001703323700002003340700003103360700002403391700001903415700002503434700002103459700001603480700001803496700002003514700001703534700002103551700002103572700001803593700001803611700001903629700002203648700002203670700002403692700002103716700002303737700002103760700001903781700001903800700002003819700002103839700002303860700003203883700002303915700002403938700002103962700001703983700001904000700002004019700002004039700001904059700002104078700001704099700002404116700002704140700001604167700001904183700002104202700002304223700002304246700002004269700001804289700002304307700001904330700001904349700002004368700001204388700002104400700001904421700002304440700002004463700001504483700002404498700002504522700002304547700002204570700002204592700002104614700002204635700001904657700002004676700001904696700001704715700001804732700001704750700001604767700002204783700002404805700002404829700002604853700002204879700002204901700002104923700001904944700002604963700002004989700002105009700002605030700002105056700001605077700001805093700002005111700002305131700002305154700001905177700002105196700001805217700002805235700002205263700002105285700001605306700001605322700001805338700001605356700001905372700002805391700002105419700001805440700002005458700001805478700002005496700001705516700002305533700001705556700002005573700002205593700002105615700002105636700002005657700001905677700002305696700001905719700002705738700001805765700002605783700002205809700002605831700002105857700002905878700001905907700001705926700002605943700001905969700002105988700001906009700002306028700001806051700001606069700001906085700002006104700002006124700002206144700001606166700002506182700002006207700002606227700001906253700002306272700002506295700002006320700002406340700001906364700002406383700001806407700002406425700002406449700002106473700002206494700002006516700002306536700002206559700002006581700001906601700002206620700002406642700001906666700002206685700002206707700001906729700001906748700002006767700002406787700003006811700001906841700001606860700002006876700002006896700002006916700001906936700001906955700001906974700002406993700002307017700002407040700002207064700001807086700002307104700002407127700001907151700002107170700002407191700002507215700002507240700002007265700002107285700002107306700002107327700002407348700002007372700002207392700002207414700001407436700002607450700002807476700002207504700002107526700002007547700002207567700001707589700002107606700002007627700002907647700001907676700001907695700002107714700002307735700002307758700002507781700002207806700002107828700002407849700002007873700002207893700002207915700002707937700002007964700002407984700002408008700002308032700002608055700002408081700001608105700002208121700002408143700001908167700001808186700002108204700001908225700002308244700001708267700002208284700002108306700001908327700002408346700002508370700002108395700002608416700002308442700002208465700002308487700002308510700002008533700002808553700002008581700002808601700002308629700002508652700002008677700002108697700002208718700002008740700002508760700002508785700002108810700002508831700002408856856003608880 2010 eng d a1476-468700aHundreds of variants clustered in genomic loci and biological pathways affect human height.0 aHundreds of variants clustered in genomic loci and biological pa c2010 Oct 14 a832-80 v4673 aMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
10aBody Height10aChromosomes, Human, Pair 310aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMetabolic Networks and Pathways10aMultifactorial Inheritance10aPhenotype10aPolymorphism, Single Nucleotide1 aAllen, Hana, Lango1 aEstrada, Karol1 aLettre, Guillaume1 aBerndt, Sonja, I1 aWeedon, Michael, N1 aRivadeneira, Fernando1 aWiller, Cristen, J1 aJackson, Anne, U1 aVedantam, Sailaja1 aRaychaudhuri, Soumya1 aFerreira, Teresa1 aWood, Andrew, R1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aSpeliotes, Elizabeth, K1 aWheeler, Eleanor1 aSoranzo, Nicole1 aPark, Ju-Hyun1 aYang, Jian1 aGudbjartsson, Daniel1 aHeard-Costa, Nancy, L1 aRandall, Joshua, C1 aQi, Lu1 aSmith, Albert, Vernon1 aMägi, Reedik1 aPastinen, Tomi1 aLiang, Liming1 aHeid, Iris, M1 aLuan, Jian'an1 aThorleifsson, Gudmar1 aWinkler, Thomas, W1 aGoddard, Michael, E1 aLo, Ken, Sin1 aPalmer, Cameron1 aWorkalemahu, Tsegaselassie1 aAulchenko, Yurii, S1 aJohansson, Asa1 aZillikens, Carola, M1 aFeitosa, Mary, F1 aEsko, Tõnu1 aJohnson, Toby1 aKetkar, Shamika1 aKraft, Peter1 aMangino, Massimo1 aProkopenko, Inga1 aAbsher, Devin1 aAlbrecht, Eva1 aErnst, Florian1 aGlazer, Nicole, L1 aHayward, Caroline1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aKnowles, Joshua, W1 aKutalik, Zoltán1 aMonda, Keri, L1 aPolasek, Ozren1 aPreuss, Michael1 aRayner, Nigel, W1 aRobertson, Neil, R1 aSteinthorsdottir, Valgerdur1 aTyrer, Jonathan, P1 aVoight, Benjamin, F1 aWiklund, Fredrik1 aXu, Jianfeng1 aZhao, Jing Hua1 aNyholt, Dale, R1 aPellikka, Niina1 aPerola, Markus1 aPerry, John, R B1 aSurakka, Ida1 aTammesoo, Mari-Liis1 aAltmaier, Elizabeth, L1 aAmin, Najaf1 aAspelund, Thor1 aBhangale, Tushar1 aBoucher, Gabrielle1 aChasman, Daniel, I1 aChen, Constance1 aCoin, Lachlan1 aCooper, Matthew, N1 aDixon, Anna, L1 aGibson, Quince1 aGrundberg, Elin1 aHao, Ke1 aJunttila, Juhani1 aKaplan, Lee, M1 aKettunen, Johannes1 aKönig, Inke, R1 aKwan, Tony1 aLawrence, Robert, W1 aLevinson, Douglas, F1 aLorentzon, Mattias1 aMcKnight, Barbara1 aMorris, Andrew, P1 aMüller, Martina1 aNgwa, Julius, Suh1 aPurcell, Shaun1 aRafelt, Suzanne1 aSalem, Rany, M1 aSalvi, Erika1 aSanna, Serena1 aShi, Jianxin1 aSovio, Ulla1 aThompson, John, R1 aTurchin, Michael, C1 aVandenput, Liesbeth1 aVerlaan, Dominique, J1 aVitart, Veronique1 aWhite, Charles, C1 aZiegler, Andreas1 aAlmgren, Peter1 aBalmforth, Anthony, J1 aCampbell, Harry1 aCitterio, Lorena1 aDe Grandi, Alessandro1 aDominiczak, Anna1 aDuan, Jubao1 aElliott, Paul1 aElosua, Roberto1 aEriksson, Johan, G1 aFreimer, Nelson, B1 aGeus, Eco, J C1 aGlorioso, Nicola1 aHaiqing, Shen1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHui, Jennie1 aIgl, Wilmar1 aIllig, Thomas1 aJula, Antti1 aKajantie, Eero1 aKilpeläinen, Tuomas, O1 aKoiranen, Markku1 aKolcic, Ivana1 aKoskinen, Seppo1 aKovacs, Peter1 aLaitinen, Jaana1 aLiu, Jianjun1 aLokki, Marja-Liisa1 aMarusic, Ana1 aMaschio, Andrea1 aMeitinger, Thomas1 aMulas, Antonella1 aParé, Guillaume1 aParker, Alex, N1 aPeden, John, F1 aPetersmann, Astrid1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPouta, Anneli1 aRidderstråle, Martin1 aRotter, Jerome, I1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSchmidt, Carsten, Oliver1 aSinisalo, Juha1 aSmit, Jan, H1 aStringham, Heather, M1 aWalters, Bragi1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aZagato, Laura1 aZgaga, Lina1 aZitting, Paavo1 aAlavere, Helene1 aFarrall, Martin1 aMcArdle, Wendy, L1 aNelis, Mari1 aPeters, Marjolein, J1 aRipatti, Samuli1 avan Meurs, Joyce, B J1 aAben, Katja, K1 aArdlie, Kristin, G1 aBeckmann, Jacques, S1 aBeilby, John, P1 aBergman, Richard, N1 aBergmann, Sven1 aCollins, Francis, S1 aCusi, Daniele1 aHeijer, Martin, den1 aEiriksdottir, Gudny1 aGejman, Pablo, V1 aHall, Alistair, S1 aHamsten, Anders1 aHuikuri, Heikki, V1 aIribarren, Carlos1 aKähönen, Mika1 aKaprio, Jaakko1 aKathiresan, Sekar1 aKiemeney, Lambertus1 aKocher, Thomas1 aLauner, Lenore, J1 aLehtimäki, Terho1 aMelander, Olle1 aMosley, Tom, H1 aMusk, Arthur, W1 aNieminen, Markku, S1 aO'Donnell, Christopher, J1 aOhlsson, Claes1 aOostra, Ben1 aPalmer, Lyle, J1 aRaitakari, Olli1 aRidker, Paul, M1 aRioux, John, D1 aRissanen, Aila1 aRivolta, Carlo1 aSchunkert, Heribert1 aShuldiner, Alan, R1 aSiscovick, David, S1 aStumvoll, Michael1 aTönjes, Anke1 aTuomilehto, Jaakko1 avan Ommen, Gert-Jan1 aViikari, Jorma1 aHeath, Andrew, C1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aProvince, Michael, A1 aKayser, Manfred1 aArnold, Alice, M1 aAtwood, Larry, D1 aBoerwinkle, Eric1 aChanock, Stephen, J1 aDeloukas, Panos1 aGieger, Christian1 aGrönberg, Henrik1 aHall, Per1 aHattersley, Andrew, T1 aHengstenberg, Christian1 aHoffman, Wolfgang1 aLathrop, Mark, G1 aSalomaa, Veikko1 aSchreiber, Stefan1 aUda, Manuela1 aWaterworth, Dawn1 aWright, Alan, F1 aAssimes, Themistocles, L1 aBarroso, Inês1 aHofman, Albert1 aMohlke, Karen, L1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aCupples, Adrienne, L1 aErdmann, Jeanette1 aFox, Caroline, S1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHarris, Tamara, B1 aHayes, Richard, B1 aJarvelin, Marjo-Riitta1 aMooser, Vincent1 aMunroe, Patricia, B1 aOuwehand, Willem, H1 aPenninx, Brenda, W1 aPramstaller, Peter, P1 aQuertermous, Thomas1 aRudan, Igor1 aSamani, Nilesh, J1 aSpector, Timothy, D1 aVölzke, Henry1 aWatkins, Hugh1 aWilson, James, F1 aGroop, Leif, C1 aHaritunians, Talin1 aHu, Frank, B1 aKaplan, Robert, C1 aMetspalu, Andres1 aNorth, Kari, E1 aSchlessinger, David1 aWareham, Nicholas, J1 aHunter, David, J1 aO'Connell, Jeffrey, R1 aStrachan, David, P1 aWichmann, H-Erich1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aSchadt, Eric, E1 aThorsteinsdottir, Unnur1 aPeltonen, Leena1 aUitterlinden, André, G1 aVisscher, Peter, M1 aChatterjee, Nilanjan1 aLoos, Ruth, J F1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aIngelsson, Erik1 aLindgren, Cecilia, M1 aAbecasis, Goncalo, R1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N uhttps://chs-nhlbi.org/node/123411930nas a2203889 4500008004100000022001400041245014500055210006900200260001300269300001100282490000700293520104400300653001901344653001601363653002301379653001101402653001801413653003401431653001101465653000901476653002701485653003601512653002401548653002001572100001801592700002101610700002301631700002301654700001101677700003201688700002501720700002501745700002801770700001801798700003101816700002201847700002501869700002201894700002101916700002001937700002301957700002301980700001802003700002202021700001602043700002802059700002102087700001602108700001902124700001902143700002702162700001902189700001802208700001902226700002302245700001902268700002202287700002002309700002402329700002102353700002102374700002302395700002202418700002102440700002002461700001902481700002402500700002202524700002102546700002002567700001902587700002602606700002302632700001502655700002502670700001802695700002402713700001802737700001602755700001902771700001802790700002202808700002202830700002602852700002402878700001902902700001802921700002102939700001702960700002002977700002302997700001703020700001903037700002003056700002603076700002203102700002203124700001603146700002103162700002503183700001903208700002103227700002103248700002003269700002603289700002303315700001803338700001603356700001703372700002203389700002603411700002203437700001903459700003503478700002103513700001603534700002403550700002103574700001903595700002203614700002003636700002003656700001703676700002403693700002403717700002803741700002503769700001603794700002303810700002303833700002303856700002303879700002403902700002003926700001903946700002403965700002003989700001904009700002104028700002304049700001904072700002504091700002504116700002404141700002004165700001804185700001704203700001804220700001804238700002204256700002304278700002304301700001204324700001804336700001904354700002304373700002104396700002304417700002704440700002204467700002804489700002204517700002204539700002304561700002104584700001604605700001604621700002204637700001604659700001904675700002004694700001804714700002004732700001804752700002104770700002204791700002204813700001904835700002004854700002204874700002104896700002304917700002104940700002004961700002204981700001905003700002105022700001605043700002105059700002105080700002005101700001905121700001905140700002705159700002205186700001805208700002605226700002205252700002005274700001905294700001705313700002505330700002605355700001805381700002405399700001905423700002005442700002605462700002405488700001905512700002405531700002505555700002205580700002105602700001905623700002305642700002105665700001605686700001905702700002005721700001905741700002005760700002205780700002405802700001905826700002005845700002005865700002005885700002205905700001805927700001905945700002105964700002105985700002406006700001906030700002406049700001806073700002206091700001906113700002806132700002006160700001506180700002306195700001906218700001806237700001906255700002206274700001806296700002206314700002106336700002406357700001906381700002006400700002406420700002206444700002306466700001906489700002506508700002106533700002506554700001906579700002106598700002306619700002306642700002406665700002406689700002406713700002006737700002006757700002606777700001906803700001706822700001806839700002206857700002706879700002006906700001906926700002206945700002406967700001606991700002307007700002607030700002007056700002407076700001907100700001607119700002307135700002007158700002407178700002807202700001707230700002407247700001907271700002407290700002107314700002807335700002007363700002507383700002107408700002307429700002007452700002507472700001907497700002307516700002107539700002207560700001907582700002607601700002007627700002407647700002307671700002407694700002907718700002207747700002807769700002307797700002107820700002507841700002007866700001907886700002207905700002107927700002107948700002507969710001007994856003608004 2010 eng d a1546-171800aMeta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.0 aMetaanalysis identifies 13 new loci associated with waisthip rat c2010 Nov a949-600 v423 aWaist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
10aAdipose Tissue10aAge Factors10aChromosome Mapping10aFemale10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist-Hip Ratio1 aHeid, Iris, M1 aJackson, Anne, U1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aQi, Lu1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aZillikens, Carola, M1 aSpeliotes, Elizabeth, K1 aMägi, Reedik1 aWorkalemahu, Tsegaselassie1 aWhite, Charles, C1 aBouatia-Naji, Nabila1 aHarris, Tamara, B1 aBerndt, Sonja, I1 aIngelsson, Erik1 aWiller, Cristen, J1 aWeedon, Michael, N1 aLuan, Jian'an1 aVedantam, Sailaja1 aEsko, Tõnu1 aKilpeläinen, Tuomas, O1 aKutalik, Zoltán1 aLi, Shengxu1 aMonda, Keri, L1 aDixon, Anna, L1 aHolmes, Christopher, C1 aKaplan, Lee, M1 aLiang, Liming1 aMin, Josine, L1 aMoffatt, Miriam, F1 aMolony, Cliona1 aNicholson, George1 aSchadt, Eric, E1 aZondervan, Krina, T1 aFeitosa, Mary, F1 aFerreira, Teresa1 aAllen, Hana, Lango1 aWeyant, Robert, J1 aWheeler, Eleanor1 aWood, Andrew, R1 aEstrada, Karol1 aGoddard, Michael, E1 aLettre, Guillaume1 aMangino, Massimo1 aNyholt, Dale, R1 aPurcell, Shaun1 aSmith, Albert, Vernon1 aVisscher, Peter, M1 aYang, Jian1 aMcCarroll, Steven, A1 aNemesh, James1 aVoight, Benjamin, F1 aAbsher, Devin1 aAmin, Najaf1 aAspelund, Thor1 aCoin, Lachlan1 aGlazer, Nicole, L1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKapur, Karen1 aKetkar, Shamika1 aKnowles, Joshua, W1 aKraft, Peter1 aKraja, Aldi, T1 aLamina, Claudia1 aLeitzmann, Michael, F1 aMcKnight, Barbara1 aMorris, Andrew, P1 aOng, Ken, K1 aPerry, John, R B1 aPeters, Marjolein, J1 aPolasek, Ozren1 aProkopenko, Inga1 aRayner, Nigel, W1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRobertson, Neil, R1 aSanna, Serena1 aSovio, Ulla1 aSurakka, Ida1 aTeumer, Alexander1 avan Wingerden, Sophie1 aVitart, Veronique1 aZhao, Jing Hua1 aCavalcanti-Proença, Christine1 aChines, Peter, S1 aFisher, Eva1 aKulzer, Jennifer, R1 aLecoeur, Cécile1 aNarisu, Narisu1 aSandholt, Camilla1 aScott, Laura, J1 aSilander, Kaisa1 aStark, Klaus1 aTammesoo, Mari-Liis1 aTeslovich, Tanya, M1 aTimpson, Nicholas, John1 aWatanabe, Richard, M1 aWelch, Ryan1 aChasman, Daniel, I1 aCooper, Matthew, N1 aJansson, John-Olov1 aKettunen, Johannes1 aLawrence, Robert, W1 aPellikka, Niina1 aPerola, Markus1 aVandenput, Liesbeth1 aAlavere, Helene1 aAlmgren, Peter1 aAtwood, Larry, D1 aBennett, Amanda, J1 aBiffar, Reiner1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBuchanan, Thomas, A1 aCampbell, Harry1 aDay, Ian, N M1 aDei, Mariano1 aDörr, Marcus1 aElliott, Paul1 aErdos, Michael, R1 aEriksson, Johan, G1 aFreimer, Nelson, B1 aFu, Mao1 aGaget, Stefan1 aGeus, Eco, J C1 aGjesing, Anette, P1 aGrallert, Harald1 aGrässler, Jürgen1 aGroves, Christopher, J1 aGuiducci, Candace1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHavulinna, Aki, S1 aHerzig, Karl-Heinz1 aHicks, Andrew, A1 aHui, Jennie1 aIgl, Wilmar1 aJousilahti, Pekka1 aJula, Antti1 aKajantie, Eero1 aKinnunen, Leena1 aKolcic, Ivana1 aKoskinen, Seppo1 aKovacs, Peter1 aKroemer, Heyo, K1 aKrzelj, Vjekoslav1 aKuusisto, Johanna1 aKvaloy, Kirsti1 aLaitinen, Jaana1 aLantieri, Olivier1 aLathrop, Mark, G1 aLokki, Marja-Liisa1 aLuben, Robert, N1 aLudwig, Barbara1 aMcArdle, Wendy, L1 aMcCarthy, Anne1 aMorken, Mario, A1 aNelis, Mari1 aNeville, Matt, J1 aParé, Guillaume1 aParker, Alex, N1 aPeden, John, F1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPlatou, Carl, G P1 aPouta, Anneli1 aRidderstråle, Martin1 aSamani, Nilesh, J1 aSaramies, Jouko1 aSinisalo, Juha1 aSmit, Jan, H1 aStrawbridge, Rona, J1 aStringham, Heather, M1 aSwift, Amy, J1 aTeder-Laving, Maris1 aThomson, Brian1 aUsala, Gianluca1 avan Meurs, Joyce, B J1 avan Ommen, Gert-Jan1 aVatin, Vincent1 aVolpato, Claudia, B1 aWallaschofski, Henri1 aWalters, Bragi, G1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitte, Daniel, R1 aZgaga, Lina1 aZitting, Paavo1 aBeilby, John, P1 aJames, Alan, L1 aKähönen, Mika1 aLehtimäki, Terho1 aNieminen, Markku, S1 aOhlsson, Claes1 aPalmer, Lyle, J1 aRaitakari, Olli1 aRidker, Paul, M1 aStumvoll, Michael1 aTönjes, Anke1 aViikari, Jorma1 aBalkau, Beverley1 aBen-Shlomo, Yoav1 aBergman, Richard, N1 aBoeing, Heiner1 aSmith, George Davey1 aEbrahim, Shah1 aFroguel, Philippe1 aHansen, Torben1 aHengstenberg, Christian1 aHveem, Kristian1 aIsomaa, Bo1 aJørgensen, Torben1 aKarpe, Fredrik1 aKhaw, Kay-Tee1 aLaakso, Markku1 aLawlor, Debbie, A1 aMarre, Michel1 aMeitinger, Thomas1 aMetspalu, Andres1 aMidthjell, Kristian1 aPedersen, Oluf1 aSalomaa, Veikko1 aSchwarz, Peter, E H1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aValle, Timo, T1 aWareham, Nicholas, J1 aArnold, Alice, M1 aBeckmann, Jacques, S1 aBergmann, Sven1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aCollins, Francis, S1 aEiriksdottir, Gudny1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHattersley, Andrew, T1 aHofman, Albert1 aHu, Frank, B1 aIllig, Thomas1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aKao, Linda, W H1 aKaprio, Jaakko1 aLauner, Lenore, J1 aMunroe, Patricia, B1 aOostra, Ben1 aPenninx, Brenda, W1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRissanen, Aila1 aRudan, Igor1 aShuldiner, Alan, R1 aSoranzo, Nicole1 aSpector, Timothy, D1 aSyvänen, Ann-Christine1 aUda, Manuela1 aUitterlinden, Andre1 aVölzke, Henry1 aVollenweider, Peter1 aWilson, James, F1 aWitteman, Jacqueline, C1 aWright, Alan, F1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFrayling, Timothy, M1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David, J1 aKaplan, Robert, C1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPeltonen, Leena1 aSchlessinger, David1 aStrachan, David, P1 aHirschhorn, Joel, N1 aAssimes, Themistocles, L1 aWichmann, H-Erich1 aThorsteinsdottir, Unnur1 aDuijn, Cornelia, M1 aStefansson, Kari1 aCupples, Adrienne, L1 aLoos, Ruth, J F1 aBarroso, Inês1 aMcCarthy, Mark, I1 aFox, Caroline, S1 aMohlke, Karen, L1 aLindgren, Cecilia, M1 aMAGIC uhttps://chs-nhlbi.org/node/123606326nas a2201873 4500008004100000022001400041245007300055210006900128260001300197300001100210490000700221520118400228653001901412653001501431653001501446653000901461653001101470653002001481653003401501653003101535653001101566653001101577653002801588653002001616653001701636100001901653700002201672700002301694700002701717700002001744700002201764700001801786700001601804700001601820700002101836700002601857700001201883700002001895700002001915700001801935700002001953700002001973700002301993700001902016700002202035700002102057700002702078700001802105700001702123700002502140700002902165700002402194700001802218700002202236700001902258700002402277700002202301700002202323700002402345700002502369700001902394700002102413700002302434700002602457700002202483700002602505700002002531700002002551700002302571700001902594700002102613700002002634700002502654700001902679700001802698700002202716700002302738700002302761700002002784700002102804700002102825700002402846700001802870700002202888700002202910700001802932700001802950700002302968700002202991700002103013700001603034700002203050700001803072700002103090700001703111700001903128700001603147700001903163700001903182700002003201700002003221700002203241700002203263700002403285700002103309700002603330700002803356700001903384700001903403700002103422700002503443700002303468700002203491700001803513700002203531700001803553700001803571700002003589700002203609700001903631700002103650700002003671700001703691700001903708700002203727700001903749700002503768700002003793700002403813700002403837700001703861700002003878700001803898700002003916700002403936700002103960700001403981700002403995700002304019700001804042700002204060700002004082700002404102700002304126700002004149700002504169700001604194700002004210700002104230700002804251700002604279700001904305700001704324700002304341700001304364700001804377700002104395856003604416 2010 eng d a1546-171800aNew loci associated with kidney function and chronic kidney disease.0 aNew loci associated with kidney function and chronic kidney dise c2010 May a376-840 v423 aChronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
10aCohort Studies10aCreatinine10aCystatin C10aDiet10aEurope10aGenetic Markers10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aModels, Genetic10aRisk Factors1 aKöttgen, Anna1 aPattaro, Cristian1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aGlazer, Nicole, L1 aParsa, Afshin1 aGao, Xiaoyi1 aYang, Qiong1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aLi, Man1 aSchmidt, Helena1 aTanaka, Toshiko1 aIsaacs, Aaron1 aKetkar, Shamika1 aHwang, Shih-Jen1 aJohnson, Andrew, D1 aDehghan, Abbas1 aTeumer, Alexander1 aParé, Guillaume1 aAtkinson, Elizabeth, J1 aZeller, Tanja1 aLohman, Kurt1 aCornelis, Marilyn, C1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aTönjes, Anke1 aHayward, Caroline1 aAspelund, Thor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aRampersaud, Evadnie1 aMitchell, Braxton, D1 aArking, Dan, E1 aBoerwinkle, Eric1 aStruchalin, Maksim1 aCavalieri, Margherita1 aSingleton, Andrew1 aGiallauria, Francesco1 aMetter, Jeffrey1 ade Boer, Ian, H1 aHaritunians, Talin1 aLumley, Thomas1 aSiscovick, David1 aPsaty, Bruce, M1 aZillikens, Carola, M1 aOostra, Ben, A1 aFeitosa, Mary1 aProvince, Michael1 ade Andrade, Mariza1 aTurner, Stephen, T1 aSchillert, Arne1 aZiegler, Andreas1 aWild, Philipp, S1 aSchnabel, Renate, B1 aWilde, Sandra1 aMunzel, Thomas, F1 aLeak, Tennille, S1 aIllig, Thomas1 aKlopp, Norman1 aMeisinger, Christa1 aWichmann, H-Erich1 aKoenig, Wolfgang1 aZgaga, Lina1 aZemunik, Tatijana1 aKolcic, Ivana1 aMinelli, Cosetta1 aHu, Frank, B1 aJohansson, Asa1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aSchreiber, Stefan1 aAulchenko, Yurii, S1 aFelix, Janine, F1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aImboden, Medea1 aNitsch, Dorothea1 aBrandstätter, Anita1 aKollerits, Barbara1 aKedenko, Lyudmyla1 aMägi, Reedik1 aStumvoll, Michael1 aKovacs, Peter1 aBoban, Mladen1 aCampbell, Susan1 aEndlich, Karlhans1 aVölzke, Henry1 aKroemer, Heyo, K1 aNauck, Matthias1 aVölker, Uwe1 aPolasek, Ozren1 aVitart, Veronique1 aBadola, Sunita1 aParker, Alexander, N1 aRidker, Paul, M1 aKardia, Sharon, L R1 aBlankenberg, Stefan1 aLiu, Yongmei1 aCurhan, Gary, C1 aFranke, Andre1 aRochat, Thierry1 aPaulweber, Bernhard1 aProkopenko, Inga1 aWang, Wei1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aShlipak, Michael, G1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKrämer, Bernhard, K1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aWitteman, Jacqueline, C1 aPramstaller, Peter, P1 aRettig, Rainer1 aHastie, Nick1 aChasman, Daniel, I1 aKao, W H1 aHeid, Iris, M1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/118305938nas a2201621 4500008004100000022001400041245004200055210004100097260001300138300001100151490000700162520145500169653003901624653001601663653004001679653001701719653003801736653001101774653002301785653002801808100002301836700002001859700001801879700002001897700001901917700002001936700002701956700002601983700002202009700002202031700001802053700002202071700001202093700002602105700002002131700002302151700002102174700001802195700001902213700002002232700002202252700001802274700001502292700002102307700001702328700002302345700002202368700002302390700001802413700001902431700002002450700002402470700002202494700002202516700002302538700002502561700001902586700002302605700002102628700002002649700002002669700002102689700002502710700001902735700002402754700002002778700002202798700002302820700001902843700002402862700002002886700002002906700002102926700002302947700002002970700002002990700001703010700002303027700002703050700002203077700001903099700001903118700002803137700001803165700001803183700002103201700002503222700002103247700002603268700002103294700002503315700002203340700002403362700002003386700002203406700002103428700001903449700002003468700001903488700002203507700001803529700002003547700002203567700002403589700002403613700002403637700001703661700001903678700001703697700002403714700002103738700001603759700001903775700001803794700001803812700001803830700002003848700001803868700002403886700002103910700002603931700002203957700002503979700002004004700002204024700002604046700002504072700002504097700001604122700001804138700001904156700002504175700002104200700002104221700001604242710002204258856003604280 2011 eng d a1533-345000aCUBN is a gene locus for albuminuria.0 aCUBN is a gene locus for albuminuria c2011 Mar a555-700 v223 aIdentification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
10aAfrican Continental Ancestry Group10aAlbuminuria10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aHumans10aMutation, Missense10aReceptors, Cell Surface1 aBöger, Carsten, A1 aChen, Ming-Huei1 aTin, Adrienne1 aOlden, Matthias1 aKöttgen, Anna1 ade Boer, Ian, H1 aFuchsberger, Christian1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 aTeumer, Alexander1 aLiu, Ching-Ti1 aGlazer, Nicole, L1 aLi, Man1 aO'Connell, Jeffrey, R1 aTanaka, Toshiko1 aPeralta, Carmen, A1 aKutalik, Zoltán1 aLuan, Jian'an1 aZhao, Jing Hua1 aHwang, Shih-Jen1 aAkylbekova, Ermeg1 aKramer, Holly1 aHarst, Pim1 aSmith, Albert, V1 aLohman, Kurt1 ade Andrade, Mariza1 aHayward, Caroline1 aKollerits, Barbara1 aTönjes, Anke1 aAspelund, Thor1 aIngelsson, Erik1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aShuldiner, Alan, R1 aMitchell, Braxton, D1 aArking, Dan, E1 aFranceschini, Nora1 aBoerwinkle, Eric1 aEgan, Josephine1 aHernandez, Dena1 aReilly, Muredach1 aTownsend, Raymond, R1 aLumley, Thomas1 aSiscovick, David, S1 aPsaty, Bruce, M1 aKestenbaum, Bryan1 aHaritunians, Talin1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aMooser, Vincent1 aWaterworth, Dawn1 aJohnson, Andrew, D1 aFlorez, Jose, C1 aMeigs, James, B1 aLu, Xiaoning1 aTurner, Stephen, T1 aAtkinson, Elizabeth, J1 aLeak, Tennille, S1 aAasarød, Knut1 aSkorpen, Frank1 aSyvänen, Ann-Christine1 aIllig, Thomas1 aBaumert, Jens1 aKoenig, Wolfgang1 aKrämer, Bernhard, K1 aDevuyst, Olivier1 aMychaleckyj, Josyf, C1 aMinelli, Cosetta1 aBakker, Stephan, J L1 aKedenko, Lyudmyla1 aPaulweber, Bernhard1 aCoassin, Stefan1 aEndlich, Karlhans1 aKroemer, Heyo, K1 aBiffar, Reiner1 aStracke, Sylvia1 aVölzke, Henry1 aStumvoll, Michael1 aMägi, Reedik1 aCampbell, Harry1 aVitart, Veronique1 aHastie, Nicholas, D1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPolasek, Ozren1 aCurhan, Gary1 aKronenberg, Florian1 aProkopenko, Inga1 aRudan, Igor1 aArnlöv, Johan1 aHallan, Stein1 aNavis, Gerjan1 aParsa, Afshin1 aFerrucci, Luigi1 aCoresh, Josef1 aShlipak, Michael, G1 aBull, Shelley, B1 aPaterson, Nicholas, J1 aWichmann, H-Erich1 aWareham, Nicholas, J1 aLoos, Ruth, J F1 aRotter, Jerome, I1 aPramstaller, Peter, P1 aCupples, Adrienne, L1 aBeckmann, Jacques, S1 aYang, Qiong1 aHeid, Iris, M1 aRettig, Rainer1 aDreisbach, Albert, W1 aBochud, Murielle1 aFox, Caroline, S1 aKao, W, H L1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/127113785nas a2204513 4500008004100000022001400041245009700055210006900152260001600221300001000237490000800247520127300255653001101528653000901539653001901548653002801567653002801595653001101623653003801634653003401672653001101706653001701717653002001734653003601754653001101790110008001801700002001881700002401901700002101925700002101946700002301967700002301990700002102013700002102034700002602055700002002081700001702101700002402118700002202142700001602164700003102180700002202211700002202233700001902255700001902274700002102293700001702314700001702331700001802348700001802366700001802384700001902402700001602421700001702437700002102454700002102475700001902496700002002515700001902535700001602554700001602570700002102586700002002607700002002627700002202647700001802669700001802687700001602705700001502721700002402736700002202760700001502782700002202797700002102819700002202840700002202862700001702884700001402901700002202915700001902937700002002956700001702976700002902993700002203022700002203044700001303066700001803079700003103097700002303128700002203151700001403173700001903187700002003206700001803226700002203244700002103266700002403287700002703311700002303338700001903361700002003380700002003400700002403420700002103444700002603465700001903491700002003510700002203530700002603552700002403578700002603602700001903628700002203647700002403669700002003693700001803713700002203731700001803753700002103771700002103792700002403813700001803837700002203855700002003877700002403897700001903921700002303940700001703963700002503980700001304005700002104018700001904039700002004058700001904078700002004097700002004117700002004137700002004157700002204177700003004199700001904229700001904248700002004267700002104287700002504308700002004333700002104353700002204374700002304396700002504419700002304444700001604467700002404483700002304507700001904530700001904549700002404568700002004592700002004612700001804632700001904650700001804669700001904687700002004706700001604726700002404742700002404766700002504790700002004815700002604835700002004861700001904881700002204900700002504922700002104947700002004968700002004988700002605008700001705034700002005051700001905071700001705090700002005107700002105127700002305148700002305171700002205194700001805216700002005234700001905254700002105273700001805294700002605312700002005338700002305358700002205381700001905403700002205422700002205444700002405466700001705490700002305507700001805530700001805548700002005566700002005586700002205606700002205628700002305650700002105673700002405694700002205718700002205740700001905762700001905781700002005800700001705820700002005837700001805857700001605875700001905891700002405910700001705934700001905951700002505970700002205995700001306017700002206030700003006052700002506082700002006107700002006127700002206147700002006169700002206189700002006211700002106231700001806252700002006270700002106290700001906311700002206330700002406352700001706376700001806393700001506411700002006426700001806446700002506464700001906489700002606508700001906534700002806553700001906581700003306600700001906633700001906652700001806671700002606689700002306715700001706738700002006755700002206775700002106797700002806818700001906846700002006865700001806885700002306903700001806926700002106944700001706965700001906982700001707001700002007018700001807038700002007056700002007076700002107096700002007117700001807137700002207155700002207177700001907199700001807218700002407236700002107260700003107281700002607312700002407338700002207362700002407384700002207408700001707430700002007447700002107467700001507488700002207503700001907525700002407544700002007568700001507588700001607603700002007619700002007639700002207659700001907681700002107700700001807721700002007739700002207759700001807781700001907799700002307818700001907841700002007860700002207880700002307902700002407925700001907949700002307968700001807991700002108009700002408030700001808054700001808072700002008090700001808110700001808128700002208146700001908168700002008187700002508207700002308232700002008255700002108275700002008296700002008316700002308336700002608359700002008385700002008405700002508425700002108450700002008471700002308491700002208514700002008536700002808556700002508584700002408609700002208633700001908655700001708674700002308691700003008714700002808744700002508772700002108797700002708818700002108845700002208866700002708888700002008915700002508935700002608960700001808986700002309004700002909027700001709056700002309073700001809096710002609114710002209140710002509162710002309187710002509210856003609235 2011 eng d a1476-468700aGenetic variants in novel pathways influence blood pressure and cardiovascular disease risk.0 aGenetic variants in novel pathways influence blood pressure and c2011 Sep 11 a103-90 v4783 aBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
10aAfrica10aAsia10aBlood Pressure10aCardiovascular Diseases10aCoronary Artery Disease10aEurope10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aKidney Diseases10aPolymorphism, Single Nucleotide10aStroke1 aInternational Consortium for Blood Pressure Genome-Wide Association Studies1 aEhret, Georg, B1 aMunroe, Patricia, B1 aRice, Kenneth, M1 aBochud, Murielle1 aJohnson, Andrew, D1 aChasman, Daniel, I1 aSmith, Albert, V1 aTobin, Martin, D1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aPihur, Vasyl1 aVollenweider, Peter1 aO'Reilly, Paul, F1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aTeumer, Alexander1 aGlazer, Nicole, L1 aLauner, Lenore1 aZhao, Jing Hua1 aAulchenko, Yurii1 aHeath, Simon1 aSõber, Siim1 aParsa, Afshin1 aLuan, Jian'an1 aArora, Pankaj1 aDehghan, Abbas1 aZhang, Feng1 aLucas, Gavin1 aHicks, Andrew, A1 aJackson, Anne, U1 aPeden, John, F1 aTanaka, Toshiko1 aWild, Sarah, H1 aRudan, Igor1 aIgl, Wilmar1 aMilaneschi, Yuri1 aParker, Alex, N1 aFava, Cristiano1 aChambers, John, C1 aFox, Ervin, R1 aKumari, Meena1 aGo, Min Jin1 aHarst, Pim1 aKao, Wen Hong Linda1 aSjögren, Marketa1 aVinay, D G1 aAlexander, Myriam1 aTabara, Yasuharu1 aShaw-Hawkins, Sue1 aWhincup, Peter, H1 aLiu, Yongmei1 aShi, Gang1 aKuusisto, Johanna1 aTayo, Bamidele1 aSeielstad, Mark1 aSim, Xueling1 aNguyen, Khanh-Dung Hoang1 aLehtimäki, Terho1 aMatullo, Giuseppe1 aWu, Ying1 aGaunt, Tom, R1 aOnland-Moret, Charlotte, N1 aCooper, Matthew, N1 aPlatou, Carl, G P1 aOrg, Elin1 aHardy, Rebecca1 aDahgam, Santosh1 aPalmen, Jutta1 aVitart, Veronique1 aBraund, Peter, S1 aKuznetsova, Tatiana1 aUiterwaal, Cuno, S P M1 aAdeyemo, Adebowale1 aPalmas, Walter1 aCampbell, Harry1 aLudwig, Barbara1 aTomaszewski, Maciej1 aTzoulaki, Ioanna1 aPalmer, Nicholette, D1 aAspelund, Thor1 aGarcia, Melissa1 aChang, Yen-Pei, C1 aO'Connell, Jeffrey, R1 aSteinle, Nanette, I1 aGrobbee, Diederick, E1 aArking, Dan, E1 aKardia, Sharon, L1 aMorrison, Alanna, C1 aHernandez, Dena1 aNajjar, Samer1 aMcArdle, Wendy, L1 aHadley, David1 aBrown, Morris, J1 aConnell, John, M1 aHingorani, Aroon, D1 aDay, Ian, N M1 aLawlor, Debbie, A1 aBeilby, John, P1 aLawrence, Robert, W1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aDreisbach, Albert, W1 aLi, Yali1 aYoung, Hunter, J1 aBis, Joshua, C1 aKähönen, Mika1 aViikari, Jorma1 aAdair, Linda, S1 aLee, Nanette, R1 aChen, Ming-Huei1 aOlden, Matthias1 aPattaro, Cristian1 aBolton, Judith Hoffman, A1 aKöttgen, Anna1 aBergmann, Sven1 aMooser, Vincent1 aChaturvedi, Nish1 aFrayling, Timothy, M1 aIslam, Muhammad1 aJafar, Tazeen, H1 aErdmann, Jeanette1 aKulkarni, Smita, R1 aBornstein, Stefan, R1 aGrässler, Jürgen1 aGroop, Leif1 aVoight, Benjamin, F1 aKettunen, Johannes1 aHoward, Philip1 aTaylor, Andrew1 aGuarrera, Simonetta1 aRicceri, Fulvio1 aEmilsson, Valur1 aPlump, Andrew1 aBarroso, Inês1 aKhaw, Kay-Tee1 aWeder, Alan, B1 aHunt, Steven, C1 aSun, Yan, V1 aBergman, Richard, N1 aCollins, Francis, S1 aBonnycastle, Lori, L1 aScott, Laura, J1 aStringham, Heather, M1 aPeltonen, Leena1 aPerola, Markus1 aVartiainen, Erkki1 aBrand, Stefan-Martin1 aStaessen, Jan, A1 aWang, Thomas, J1 aBurton, Paul, R1 aArtigas, Maria, Soler1 aDong, Yanbin1 aSnieder, Harold1 aWang, Xiaoling1 aZhu, Haidong1 aLohman, Kurt, K1 aRudock, Megan, E1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aDoumatey, Ayo1 aShriner, Daniel1 aVeldre, Gudrun1 aViigimaa, Margus1 aKinra, Sanjay1 aPrabhakaran, Dorairaj1 aTripathy, Vikal1 aLangefeld, Carl, D1 aRosengren, Annika1 aThelle, Dag, S1 aCorsi, Anna Maria1 aSingleton, Andrew1 aForrester, Terrence1 aHilton, Gina1 aMcKenzie, Colin, A1 aSalako, Tunde1 aIwai, Naoharu1 aKita, Yoshikuni1 aOgihara, Toshio1 aOhkubo, Takayoshi1 aOkamura, Tomonori1 aUeshima, Hirotsugu1 aUmemura, Satoshi1 aEyheramendy, Susana1 aMeitinger, Thomas1 aWichmann, H-Erich1 aCho, Yoon Shin1 aKim, Hyung-Lae1 aLee, Jong-Young1 aScott, James1 aSehmi, Joban, S1 aZhang, Weihua1 aHedblad, Bo1 aNilsson, Peter1 aSmith, George Davey1 aWong, Andrew1 aNarisu, Narisu1 aStančáková, Alena1 aRaffel, Leslie, J1 aYao, Jie1 aKathiresan, Sekar1 aO'Donnell, Christopher, J1 aSchwartz, Stephen, M1 aIkram, Arfan, M1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aShrine, Nick, R G1 aWain, Louise, V1 aMorken, Mario, A1 aSwift, Amy, J1 aLaitinen, Jaana1 aProkopenko, Inga1 aZitting, Paavo1 aCooper, Jackie, A1 aHumphries, Steve, E1 aDanesh, John1 aRasheed, Asif1 aGoel, Anuj1 aHamsten, Anders1 aWatkins, Hugh1 aBakker, Stephan, J L1 aGilst, Wiek, H1 aJanipalli, Charles, S1 aMani, Radha, K1 aYajnik, Chittaranjan, S1 aHofman, Albert1 aMattace-Raso, Francesco, U S1 aOostra, Ben, A1 aDemirkan, Ayse1 aIsaacs, Aaron1 aRivadeneira, Fernando1 aLakatta, Edward, G1 aOrrù, Marco1 aScuteri, Angelo1 aAla-Korpela, Mika1 aKangas, Antti, J1 aLyytikäinen, Leo-Pekka1 aSoininen, Pasi1 aTukiainen, Taru1 aWürtz, Peter1 aOng, Rick Twee-Hee1 aDörr, Marcus1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aZelenika, Diana1 aDeloukas, Panos1 aMangino, Massimo1 aSpector, Tim, D1 aZhai, Guangju1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aTerzic, Janos1 aKumar, Kranthi, M V1 aDenniff, Matthew1 aZukowska-Szczechowska, Ewa1 aWagenknecht, Lynne, E1 aFowkes, Gerald, F R1 aCharchar, Fadi, J1 aSchwarz, Peter, E H1 aHayward, Caroline1 aGuo, Xiuqing1 aRotimi, Charles1 aBots, Michiel, L1 aBrand, Eva1 aSamani, Nilesh, J1 aPolasek, Ozren1 aTalmud, Philippa, J1 aNyberg, Fredrik1 aKuh, Diana1 aLaan, Maris1 aHveem, Kristian1 aPalmer, Lyle, J1 aSchouw, Yvonne, T1 aCasas, Juan, P1 aMohlke, Karen, L1 aVineis, Paolo1 aRaitakari, Olli1 aGanesh, Santhi, K1 aWong, Tien, Y1 aTai, Shyong, E1 aCooper, Richard, S1 aLaakso, Markku1 aRao, Dabeeru, C1 aHarris, Tamara, B1 aMorris, Richard, W1 aDominiczak, Anna, F1 aKivimaki, Mika1 aMarmot, Michael, G1 aMiki, Tetsuro1 aSaleheen, Danish1 aChandak, Giriraj, R1 aCoresh, Josef1 aNavis, Gerjan1 aSalomaa, Veikko1 aHan, Bok-Ghee1 aZhu, Xiaofeng1 aKooner, Jaspal, S1 aMelander, Olle1 aRidker, Paul, M1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWright, Alan, F1 aWilson, James, F1 aFerrucci, Luigi1 aFarrall, Martin1 aTuomilehto, Jaakko1 aPramstaller, Peter, P1 aElosua, Roberto1 aSoranzo, Nicole1 aSijbrands, Eric, J G1 aAltshuler, David1 aLoos, Ruth, J F1 aShuldiner, Alan, R1 aGieger, Christian1 aMeneton, Pierre1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aRettig, Rainer1 aUda, Manuela1 aStrachan, David, P1 aWitteman, Jacqueline, C M1 aHartikainen, Anna-Liisa1 aBeckmann, Jacques, S1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aBoehnke, Michael1 aLarson, Martin, G1 aJarvelin, Marjo-Riitta1 aPsaty, Bruce, M1 aAbecasis, Goncalo, R1 aChakravarti, Aravinda1 aElliott, Paul1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aCaulfield, Mark, J1 aJohnson, Toby1 aCARDIoGRAM consortium1 aCKDGen Consortium1 aKidneyGen Consortium1 aEchoGen consortium1 aCHARGE-HF consortium uhttps://chs-nhlbi.org/node/132507169nas a2202257 4500008004100000022001400041245010400055210006900159260001600228300001200244490000700256520086500263653001001128653004001138653003401178653001101212653004301223653003101266100002601297700001801323700002001341700002001361700001901381700001601400700001801416700001901434700002601453700002501479700001801504700002601522700002001548700001701568700002001585700002101605700002001626700001801646700002401664700001901688700001901707700002001726700002501746700002101771700002401792700002301816700002001839700002201859700002901881700001901910700002801929700002101957700002201978700002602000700002302026700002402049700001802073700001902091700001902110700002102129700002302150700002102173700001802194700001602212700002802228700002202256700001702278700002002295700001702315700002002332700001902352700002602371700001602397700001702413700001702430700002002447700001802467700001902485700001902504700002102523700002202544700001802566700001902584700002002603700001802623700001802641700002202659700001902681700001902700700002002719700001702739700002302756700001902779700002102798700002002819700001802839700002402857700001902881700002102900700001602921700002302937700001902960700002202979700001903001700001803020700002403038700001803062700002303080700002103103700002203124700002103146700002303167700002203190700002103212700001903233700002603252700002003278700002203298700001603320700001803336700002403354700001703378700001903395700002803414700002003442700002203462700002203484700002003506700001903526700001703545700002103562700002603583700002203609700001903631700002403650700001903674700001903693700002003712700002703732700001803759700002603777700001803803700002003821700002803841700002003869700002003889700002203909700001603931700002403947700001903971700001803990700002004008700001704028700002204045700001904067700002504086700002604111700002204137700001904159700001904178700001904197700002004216700001604236700002204252700002204274700002004296700001504316700002204331700001904353700002204372700002304394700002604417700001904443700002104462700002204483700002004505700002204525700002004547700002304567700001804590700002704608700002604635700001804661700002404679700002304703700002504726700001704751700002404768700002104792710004104813710002104854856003604875 2011 eng d a1546-171800aGenome-wide association and large-scale follow up identifies 16 new loci influencing lung function.0 aGenomewide association and largescale follow up identifies 16 ne c2011 Sep 25 a1082-900 v433 aPulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
10aChild10aEuropean Continental Ancestry Group10aGenome-Wide Association Study10aHumans10aPulmonary Disease, Chronic Obstructive10aRespiratory Function Tests1 aArtigas, Maria, Soler1 aLoth, Daan, W1 aWain, Louise, V1 aGharib, Sina, A1 aObeidat, Ma'en1 aTang, Wenbo1 aZhai, Guangju1 aZhao, Jing Hua1 aSmith, Albert, Vernon1 aHuffman, Jennifer, E1 aAlbrecht, Eva1 aJackson, Catherine, M1 aEvans, David, M1 aCadby, Gemma1 aFornage, Myriam1 aManichaikul, Ani1 aLopez, Lorna, M1 aJohnson, Toby1 aAldrich, Melinda, C1 aAspelund, Thor1 aBarroso, Inês1 aCampbell, Harry1 aCassano, Patricia, A1 aCouper, David, J1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aGarcia, Melissa1 aGieger, Christian1 aGislason, Gauti, Kjartan1 aGrkovic, Ivica1 aHammond, Christopher, J1 aHancock, Dana, B1 aHarris, Tamara, B1 aRamasamy, Adaikalavan1 aHeckbert, Susan, R1 aHeliövaara, Markku1 aHomuth, Georg1 aHysi, Pirro, G1 aJames, Alan, L1 aJankovic, Stipan1 aJoubert, Bonnie, R1 aKarrasch, Stefan1 aKlopp, Norman1 aKoch, Beate1 aKritchevsky, Stephen, B1 aLauner, Lenore, J1 aLiu, Yongmei1 aLoehr, Laura, R1 aLohman, Kurt1 aLoos, Ruth, J F1 aLumley, Thomas1 aBalushi, Khalid, A Al1 aAng, Wei, Q1 aBarr, Graham1 aBeilby, John1 aBlakey, John, D1 aBoban, Mladen1 aBoraska, Vesna1 aBrisman, Jonas1 aBritton, John, R1 aBrusselle, Guy, G1 aCooper, Cyrus1 aCurjuric, Ivan1 aDahgam, Santosh1 aDeary, Ian, J1 aEbrahim, Shah1 aEijgelsheim, Mark1 aFrancks, Clyde1 aGaysina, Darya1 aGranell, Raquel1 aGu, Xiangjun1 aHankinson, John, L1 aHardy, Rebecca1 aHarris, Sarah, E1 aHenderson, John1 aHenry, Amanda1 aHingorani, Aroon, D1 aHofman, Albert1 aHolt, Patrick, G1 aHui, Jennie1 aHunter, Michael, L1 aImboden, Medea1 aJameson, Karen, A1 aKerr, Shona, M1 aKolcic, Ivana1 aKronenberg, Florian1 aLiu, Jason, Z1 aMarchini, Jonathan1 aMcKeever, Tricia1 aMorris, Andrew, D1 aOlin, Anna-Carin1 aPorteous, David, J1 aPostma, Dirkje, S1 aRich, Stephen, S1 aRing, Susan, M1 aRivadeneira, Fernando1 aRochat, Thierry1 aSayer, Avan Aihie1 aSayers, Ian1 aSly, Peter, D1 aSmith, George Davey1 aSood, Akshay1 aStarr, John, M1 aUitterlinden, André, G1 aVonk, Judith, M1 aWannamethee, Goya1 aWhincup, Peter, H1 aWijmenga, Cisca1 aWilliams, Dale1 aWong, Andrew1 aMangino, Massimo1 aMarciante, Kristin, D1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorrison, Alanna, C1 aNorth, Kari, E1 aOmenaas, Ernst1 aPalmer, Lyle, J1 aPietiläinen, Kirsi, H1 aPin, Isabelle1 aEk, Ozren, Pola Sbrev1 aPouta, Anneli1 aPsaty, Bruce, M1 aHartikainen, Anna-Liisa1 aRantanen, Taina1 aRipatti, Samuli1 aRotter, Jerome, I1 aRudan, Igor1 aRudnicka, Alicja, R1 aSchulz, Holger1 aShin, So-Youn1 aSpector, Tim, D1 aSurakka, Ida1 aVitart, Veronique1 aVölzke, Henry1 aWareham, Nicholas, J1 aWarrington, Nicole, M1 aWichmann, H-Erich1 aWild, Sarah, H1 aWilk, Jemma, B1 aWjst, Matthias1 aWright, Alan, F1 aZgaga, Lina1 aZemunik, Tatijana1 aPennell, Craig, E1 aNyberg, Fredrik1 aKuh, Diana1 aHolloway, John, W1 aBoezen, Marike1 aLawlor, Debbie, A1 aMorris, Richard, W1 aProbst-Hensch, Nicole1 aKaprio, Jaakko1 aWilson, James, F1 aHayward, Caroline1 aKähönen, Mika1 aHeinrich, Joachim1 aMusk, Arthur, W1 aJarvis, Deborah, L1 aGläser, Sven1 aJarvelin, Marjo-Riitta1 aStricker, Bruno, H Ch1 aElliott, Paul1 aO'Connor, George, T1 aStrachan, David, P1 aLondon, Stephanie, J1 aHall, Ian, P1 aGudnason, Vilmundur1 aTobin, Martin, D1 aInternational Lung Cancer Consortium1 aGIANT Consortium uhttps://chs-nhlbi.org/node/609604132nas a2200709 4500008004100000022001400041245010500055210006900160260001600229300001200245490000700257520206100264653000902325653003102334653001902365653004002384653001102424653003402435653001102469653004902480653003302529653000902562653003602571100002202607700002602629700002002655700002202675700002202697700002002719700002202739700002002761700001702781700002102798700001602819700001802835700001802853700001802871700001702889700001902906700002002925700002202945700002302967700001902990700002203009700002203031700002203053700001903075700001803094700002303112700002103135700001903156700002403175700002003199700002503219700002203244700002003266700002303286700002503309700002703334700002503361856003603386 2011 eng d a1460-208300aA genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.0 agenomewide association study identifies novel loci associated wi c2011 Mar 15 a1241-510 v203 aInsulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
10aAged10aChromosomes, Human, Pair 710aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aPolymorphism, Single Nucleotide1 aKaplan, Robert, C1 aPetersen, Ann-Kristin1 aChen, Ming-Huei1 aTeumer, Alexander1 aGlazer, Nicole, L1 aDöring, Angela1 aLam, Carolyn, S P1 aFriedrich, Nele1 aNewman, Anne1 aMüller, Martina1 aYang, Qiong1 aHomuth, Georg1 aCappola, Anne1 aKlopp, Norman1 aSmith, Holly1 aErnst, Florian1 aPsaty, Bruce, M1 aWichmann, H-Erich1 aSawyer, Douglas, B1 aBiffar, Reiner1 aRotter, Jerome, I1 aGieger, Christian1 aSullivan, Lisa, S1 aVölzke, Henry1 aRice, Kenneth1 aSpyroglou, Ariadni1 aKroemer, Heyo, K1 aChen, Y-D, Ida1 aManolopoulou, Jenny1 aNauck, Matthias1 aStrickler, Howard, D1 aGoodarzi, Mark, O1 aReincke, Martin1 aPollak, Michael, N1 aBidlingmaier, Martin1 aVasan, Ramachandran, S1 aWallaschofski, Henri uhttps://chs-nhlbi.org/node/126109449nas a2203037 4500008004100000022001400041245011300055210006900168260001600237300001200253490000700265520102300272653001301295653001901308653002501327653002201352653001701374653003401391653001101425653001701436653002701453653003601480100002001516700002601536700002201562700001401584700001801598700002301616700002101639700002101660700002001681700002101701700002001722700001601742700002201758700002001780700001801800700001801818700001901836700001901855700001601874700002601890700001901916700001701935700001601952700001701968700002001985700001802005700001802023700001702041700002002058700001902078700002102097700002402118700001602142700001902158700002002177700002002197700002002217700001602237700002102253700002402274700002202298700002302320700002002343700003102363700002502394700002202419700001702441700002202458700002102480700002002501700001902521700001802540700002702558700002402585700001702609700002202626700001902648700001702667700003302684700002602717700002502743700002802768700002002796700002702816700002002843700001902863700002402882700002002906700002002926700001802946700001902964700002202983700002103005700001703026700001903043700002203062700002003084700002203104700002003126700001903146700001503165700002403180700002103204700001903225700001803244700001703262700002003279700001803299700002403317700001403341700001703355700001603372700001903388700002303407700001803430700002303448700001703471700001603488700002403504700001903528700003003547700002003577700002403597700002403621700002003645700001803665700002603683700002303709700002403732700002403756700002003780700001703800700001803817700002103835700001803856700002003874700001803894700001503912700002003927700001803947700002303965700002103988700002004009700002104029700001704050700001904067700002204086700002204108700001904130700002304149700002004172700001904192700002104211700001704232700001704249700001704266700003004283700001804313700001704331700001704348700002204365700002204387700002004409700001904429700002004448700002204468700001704490700001904507700002004526700001804546700002104564700002404585700002004609700002104629700001904650700002304669700001704692700002204709700002304731700002404754700002004778700002204798700002304820700001604843700002104859700002504880700002804905700002204933700002004955700001604975700002204991700001805013700002205031700002305053700001905076700002205095700002105117700001905138700002005157700002305177700002505200700002305225700002105248700002005269700002205289700002005311700002005331700002005351700002305371700001805394700002105412700002105433700002105454700002005475700002105495700002005516700002205536700002005558700002505578700001905603700002105622700001905643700001905662700002305681700002505704700003005729700002205759700002105781700002105802700002105823700002005844700002705864700002605891700002505917700002405942700002905966700001705995700002406012700002006036700002306056700002006079700002106099700001806120700002306138710002706161710002306188710002406211710005006235710002506285710002206310710002806332710001506360856003606375 2011 eng d a1546-171800aGenome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.0 aGenomewide association study identifies six new loci influencing c2011 Sep 11 a1005-110 v433 aNumerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
10aArteries10aBlood Pressure10aCase-Control Studies10aFollow-Up Studies10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aLinkage Disequilibrium10aPolymorphism, Single Nucleotide1 aWain, Louise, V1 aVerwoert, Germaine, C1 aO'Reilly, Paul, F1 aShi, Gang1 aJohnson, Toby1 aJohnson, Andrew, D1 aBochud, Murielle1 aRice, Kenneth, M1 aHenneman, Peter1 aSmith, Albert, V1 aEhret, Georg, B1 aAmin, Najaf1 aLarson, Martin, G1 aMooser, Vincent1 aHadley, David1 aDörr, Marcus1 aBis, Joshua, C1 aAspelund, Thor1 aEsko, Tõnu1 aJanssens, Cecile, J W1 aZhao, Jing Hua1 aHeath, Simon1 aLaan, Maris1 aFu, Jingyuan1 aPistis, Giorgio1 aLuan, Jian'an1 aArora, Pankaj1 aLucas, Gavin1 aPirastu, Nicola1 aPichler, Irene1 aJackson, Anne, U1 aWebster, Rebecca, J1 aZhang, Feng1 aPeden, John, F1 aSchmidt, Helena1 aTanaka, Toshiko1 aCampbell, Harry1 aIgl, Wilmar1 aMilaneschi, Yuri1 aHottenga, Jouke-Jan1 aVitart, Veronique1 aChasman, Daniel, I1 aTrompet, Stella1 aBragg-Gresham, Jennifer, L1 aAlizadeh, Behrooz, Z1 aChambers, John, C1 aGuo, Xiuqing1 aLehtimäki, Terho1 aKuhnel, Brigitte1 aLopez, Lorna, M1 aPolasek, Ozren1 aBoban, Mladen1 aNelson, Christopher, P1 aMorrison, Alanna, C1 aPihur, Vasyl1 aGanesh, Santhi, K1 aHofman, Albert1 aKundu, Suman1 aMattace-Raso, Francesco, U S1 aRivadeneira, Fernando1 aSijbrands, Eric, J G1 aUitterlinden, André, G1 aHwang, Shih-Jen1 aVasan, Ramachandran, S1 aWang, Thomas, J1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aLaitinen, Jaana1 aPouta, Anneli1 aZitting, Paavo1 aMcArdle, Wendy, L1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGlazer, Nicole, L1 aTaylor, Kent, D1 aHarris, Tamara, B1 aAlavere, Helene1 aHaller, Toomas1 aKeis, Aime1 aTammesoo, Mari-Liis1 aAulchenko, Yurii1 aBarroso, Inês1 aKhaw, Kay-Tee1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aEyheramendy, Susana1 aOrg, Elin1 aSõber, Siim1 aLu, Xiaowen1 aNolte, Ilja, M1 aPenninx, Brenda, W1 aCorre, Tanguy1 aMasciullo, Corrado1 aSala, Cinzia1 aGroop, Leif1 aVoight, Benjamin, F1 aMelander, Olle1 aO'Donnell, Christopher, J1 aSalomaa, Veikko1 ad'Adamo, Adamo, Pio1 aFabretto, Antonella1 aFaletra, Flavio1 aUlivi, Sheila1 aDel Greco, Fabiola, M1 aFacheris, Maurizio1 aCollins, Francis, S1 aBergman, Richard, N1 aBeilby, John, P1 aHung, Joseph1 aMusk, William1 aMangino, Massimo1 aShin, So-Youn1 aSoranzo, Nicole1 aWatkins, Hugh1 aGoel, Anuj1 aHamsten, Anders1 aGider, Pierre1 aLoitfelder, Marisa1 aZeginigg, Marion1 aHernandez, Dena1 aNajjar, Samer, S1 aNavarro, Pau1 aWild, Sarah, H1 aCorsi, Anna Maria1 aSingleton, Andrew1 aGeus, Eco, J C1 aWillemsen, Gonneke1 aParker, Alex, N1 aRose, Lynda, M1 aBuckley, Brendan1 aStott, David1 aOrrù, Marco1 aUda, Manuela1 avan der Klauw, Melanie, M1 aZhang, Weihua1 aLi, Xinzhong1 aScott, James1 aChen, Yii-Der Ida1 aBurke, Gregory, L1 aKähönen, Mika1 aViikari, Jorma1 aDöring, Angela1 aMeitinger, Thomas1 aDavies, Gail1 aStarr, John, M1 aEmilsson, Valur1 aPlump, Andrew1 aLindeman, Jan, H1 aHoen, Peter, A C 't1 aKönig, Inke, R1 aFelix, Janine, F1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aBreteler, Monique1 aDebette, Stephanie1 aDeStefano, Anita, L1 aFornage, Myriam1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aHolm, Hilma1 aStefansson, Kari1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aSamani, Nilesh, J1 aPreuss, Michael1 aRudan, Igor1 aHayward, Caroline1 aDeary, Ian, J1 aWichmann, H-Erich1 aRaitakari, Olli, T1 aPalmas, Walter1 aKooner, Jaspal, S1 aStolk, Ronald, P1 aJukema, Wouter1 aWright, Alan, F1 aBoomsma, Dorret, I1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWilson, James, F1 aFerrucci, Luigi1 aSchmidt, Reinhold1 aFarrall, Martin1 aSpector, Tim, D1 aPalmer, Lyle, J1 aTuomilehto, Jaakko1 aPfeufer, Arne1 aGasparini, Paolo1 aSiscovick, David1 aAltshuler, David1 aLoos, Ruth, J F1 aToniolo, Daniela1 aSnieder, Harold1 aGieger, Christian1 aMeneton, Pierre1 aWareham, Nicholas, J1 aOostra, Ben, A1 aMetspalu, Andres1 aLauner, Lenore1 aRettig, Rainer1 aStrachan, David, P1 aBeckmann, Jacques, S1 aWitteman, Jacqueline, C M1 aErdmann, Jeanette1 aDijk, Ko Willems1 aBoerwinkle, Eric1 aBoehnke, Michael1 aRidker, Paul, M1 aJarvelin, Marjo-Riitta1 aChakravarti, Aravinda1 aAbecasis, Goncalo, R1 aGudnason, Vilmundur1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aRao, Dabeeru, C1 aTobin, Martin, D1 aElliott, Paul1 aDuijn, Cornelia, M1 aLifeLines Cohort Study1 aEchoGen consortium1 aAortaGen Consortium1 aCHARGE Consortium Heart Failure Working Group1 aKidneyGen Consortium1 aCKDGen Consortium1 aCardiogenics consortium1 aCardioGram uhttps://chs-nhlbi.org/node/132405459nas a2201501 4500008004100000022001400041245016600055210006900221260001600290300001000306490000700316520120500323653001001528653000901538653001001547653002001557653003501577653001901612653002801631653004001659653001701699653003801716653001801754653003401772653001301806653001001819653001101829653001601840653001401856653002801870653003601898653001701934100001901951700002001970700002301990700001802013700002502031700001802056700001902074700002102093700002502114700002002139700002202159700002502181700002202206700001802228700002002246700002302266700001902289700001602308700001602324700001702340700002502357700002202382700002002404700002302424700002002447700001802467700001902485700002002504700002002524700002102544700001802565700002602583700001702609700001902626700002302645700002002668700002302688700002402711700001802735700001802753700001902771700002302790700002202813700002402835700001702859700002402876700002102900700002102921700002002942700001802962700002102980700001703001700001903018700002303037700002403060700002203084700002203106700001903128700002103147700001803168700002003186700001903206700002203225700002503247700002303272700002503295700002003320700002103340700002303361700002703384700002203411700002003433700002003453700002103473700001203494700002303506700001703529700002103546700001803567700002003585700002103605700001903626700002103645700002403666700002003690700002503710700001903735700002403754700002003778700001803798700002503816700002403841700003003865710002603895856003603921 2011 eng d a1546-171800aMeta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.0 aMetaanalysis of genomewide association studies from the CHARGE c c2011 Sep 11 a940-70 v433 aCarotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
10aAdult10aAged10aAging10aAtherosclerosis10aCarotid Intima-Media Thickness10aCohort Studies10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMiddle Aged10aPhenotype10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aRisk Factors1 aBis, Joshua, C1 aKavousi, Maryam1 aFranceschini, Nora1 aIsaacs, Aaron1 aAbecasis, Goncalo, R1 aSchminke, Ulf1 aPost, Wendy, S1 aSmith, Albert, V1 aCupples, Adrienne, L1 aMarkus, Hugh, S1 aSchmidt, Reinhold1 aHuffman, Jennifer, E1 aLehtimäki, Terho1 aBaumert, Jens1 aMünzel, Thomas1 aHeckbert, Susan, R1 aDehghan, Abbas1 aNorth, Kari1 aOostra, Ben1 aBevan, Steve1 aStoegerer, Eva-Maria1 aHayward, Caroline1 aRaitakari, Olli1 aMeisinger, Christa1 aSchillert, Arne1 aSanna, Serena1 aVölzke, Henry1 aCheng, Yu-Ching1 aThorsson, Bolli1 aFox, Caroline, S1 aRice, Kenneth1 aRivadeneira, Fernando1 aNambi, Vijay1 aHalperin, Eran1 aPetrovic, Katja, E1 aPeltonen, Leena1 aWichmann, Erich, H1 aSchnabel, Renate, B1 aDörr, Marcus1 aParsa, Afshin1 aAspelund, Thor1 aDemissie, Serkalem1 aKathiresan, Sekar1 aReilly, Muredach, P1 aTaylor, Kent1 aUitterlinden, Andre1 aCouper, David, J1 aSitzer, Matthias1 aKähönen, Mika1 aIllig, Thomas1 aWild, Philipp, S1 aOrrù, Marco1 aLüdemann, Jan1 aShuldiner, Alan, R1 aEiriksdottir, Gudny1 aWhite, Charles, C1 aRotter, Jerome, I1 aHofman, Albert1 aSeissler, Jochen1 aZeller, Tanja1 aUsala, Gianluca1 aErnst, Florian1 aLauner, Lenore, J1 aD'Agostino, Ralph, B1 aO'Leary, Daniel, H1 aBallantyne, Christie1 aThiery, Joachim1 aZiegler, Andreas1 aLakatta, Edward, G1 aChilukoti, Ravi, Kumar1 aHarris, Tamara, B1 aWolf, Philip, A1 aPsaty, Bruce, M1 aPolak, Joseph, F1 aLi, Xia1 aRathmann, Wolfgang1 aUda, Manuela1 aBoerwinkle, Eric1 aKlopp, Norman1 aSchmidt, Helena1 aWilson, James, F1 aViikari, Jorma1 aKoenig, Wolfgang1 aBlankenberg, Stefan1 aNewman, Anne, B1 aWitteman, Jacqueline1 aHeiss, Gerardo1 avan Duijn, Cornelia1 aScuteri, Angelo1 aHomuth, Georg1 aMitchell, Braxton, D1 aGudnason, Vilmundur1 aO'Donnell, Christopher, J1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/132306092nas a2201597 4500008004100000022001400041245012900055210006900184260001600253300001000269490000800279520159300287653001501880653002301895653002801918653003801946653003401984653001102018653001702029653001502046100001902061700001902080700001902099700001902118700002402137700001302161700002002174700002502194700002302219700002002242700001802262700002302280700002702303700002202330700002102352700002102373700001902394700002102413700001702434700001902451700002502470700001902495700002002514700002002534700002102554700002402575700001702599700002002616700002002636700002002656700002302676700002102699700002002720700001702740700001702757700001902774700001902793700002202812700002202834700002302856700002202879700002202901700002202923700002102945700002602966700002102992700002503013700001803038700001803056700002003074700001303094700002303107700002103130700001903151700001903170700001903189700001803208700001703226700002203243700001703265700004103282700002003323700002003343700001903363700002003382700002403402700001903426700002503445700001903470700001703489700001803506700001403524700002403538700001703562700002203579700001703601700002403618700001603642700002103658700002303679700002103702700002203723700001603745700002303761700002203784700002803806700002703834700001803861700001803879700002003897700002603917700002103943700002703964700002003991700002204011700002504033700002004058700002304078700001904101700002004120700002204140700002604162700002304188700002004211700002004231700002404251700002004275700001804295700002104313700002804334700003004362700002404392700001904416700002304435856003604458 2011 eng d a1524-453900aMeta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.0 aMetaanalysis of genomewide association studies in 80 000 subject c2011 Feb 22 a731-80 v1233 aBACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.
METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.
CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aRisk Factors10aVasculitis1 aDehghan, Abbas1 aDupuis, Josée1 aBarbalic, Maja1 aBis, Joshua, C1 aEiriksdottir, Gudny1 aLu, Chen1 aPellikka, Niina1 aWallaschofski, Henri1 aKettunen, Johannes1 aHenneman, Peter1 aBaumert, Jens1 aStrachan, David, P1 aFuchsberger, Christian1 aVitart, Veronique1 aWilson, James, F1 aParé, Guillaume1 aNaitza, Silvia1 aRudock, Megan, E1 aSurakka, Ida1 aGeus, Eco, J C1 aAlizadeh, Behrooz, Z1 aGuralnik, Jack1 aShuldiner, Alan1 aTanaka, Toshiko1 aZee, Robert, Y L1 aSchnabel, Renate, B1 aNambi, Vijay1 aKavousi, Maryam1 aRipatti, Samuli1 aNauck, Matthias1 aSmith, Nicholas, L1 aSmith, Albert, V1 aSundvall, Jouko1 aScheet, Paul1 aLiu, Yongmei1 aRuokonen, Aimo1 aRose, Lynda, M1 aLarson, Martin, G1 aHoogeveen, Ron, C1 aFreimer, Nelson, B1 aTeumer, Alexander1 aTracy, Russell, P1 aLauner, Lenore, J1 aBuring, Julie, E1 aYamamoto, Jennifer, F1 aFolsom, Aaron, R1 aSijbrands, Eric, J G1 aPankow, James1 aElliott, Paul1 aKeaney, John, F1 aSun, Wei1 aSarin, Antti-Pekka1 aFontes, João, D1 aBadola, Sunita1 aAstor, Brad, C1 aHofman, Albert1 aPouta, Anneli1 aWerdan, Karl1 aGreiser, Karin, H1 aKuss, Oliver1 aMeyer zu Schwabedissen, Henriette, E1 aThiery, Joachim1 aJamshidi, Yalda1 aNolte, Ilja, M1 aSoranzo, Nicole1 aSpector, Timothy, D1 aVölzke, Henry1 aParker, Alexander, N1 aAspelund, Thor1 aBates, David1 aYoung, Lauren1 aTsui, Kim1 aSiscovick, David, S1 aGuo, Xiuqing1 aRotter, Jerome, I1 aUda, Manuela1 aSchlessinger, David1 aRudan, Igor1 aHicks, Andrew, A1 aPenninx, Brenda, W1 aThorand, Barbara1 aGieger, Christian1 aCoresh, Joe1 aWillemsen, Gonneke1 aHarris, Tamara, B1 aUitterlinden, André, G1 aJarvelin, Marjo-Riitta1 aRice, Kenneth1 aRadke, Dörte1 aSalomaa, Veikko1 avan Dijk, Ko, Willems1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aFerrucci, Luigi1 aGibson, Quince, D1 aBandinelli, Stefania1 aSnieder, Harold1 aBoomsma, Dorret, I1 aXiao, Xiangjun1 aCampbell, Harry1 aHayward, Caroline1 aPramstaller, Peter, P1 aDuijn, Cornelia, M1 aPeltonen, Leena1 aPsaty, Bruce, M1 aGudnason, Vilmundur1 aRidker, Paul, M1 aHomuth, Georg1 aKoenig, Wolfgang1 aBallantyne, Christie, M1 aWitteman, Jacqueline, C M1 aBenjamin, Emelia, J1 aPerola, Markus1 aChasman, Daniel, I uhttps://chs-nhlbi.org/node/126703965nas a2200493 4500008004100000022001400041245019200055210006900247260001600316300001200332490000800344520243000352653002802782653003502810653002402845653002202869653001102891653002602902653001402928653002002942653001102962100002402973700002102997700002003018700002603038700001903064700002603083700001703109700002303126700002603149700002803175700001903203700002003222700002303242700001503265700002103280700002803301700001203329700002503341700002103366700002303387710002503410856003603435 2012 eng d a1474-547X00aCarotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data.0 aCarotid intimamedia thickness progression to predict cardiovascu c2012 Jun 02 a2053-620 v3793 aBACKGROUND: Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association.
METHODS: We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis.
FINDINGS: Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02).
INTERPRETATION: The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials.
FUNDING: Deutsche Forschungsgemeinschaft.
10aCardiovascular Diseases10aCarotid Intima-Media Thickness10aDisease Progression10aFollow-Up Studies10aHumans10aMyocardial Infarction10aPrognosis10aRisk Assessment10aStroke1 aLorenz, Matthias, W1 aPolak, Joseph, F1 aKavousi, Maryam1 aMathiesen, Ellisiv, B1 aVölzke, Henry1 aTuomainen, Tomi-Pekka1 aSander, Dirk1 aPlichart, Matthieu1 aCatapano, Alberico, L1 aRobertson, Christine, M1 aKiechl, Stefan1 aRundek, Tatjana1 aDesvarieux, Moïse1 aLind, Lars1 aSchmid, Caroline1 aDasMahapatra, Pronabesh1 aGao, Lu1 aZiegelbauer, Kathrin1 aBots, Michiel, L1 aThompson, Simon, G1 aPROG-IMT Study Group uhttps://chs-nhlbi.org/node/138207422nas a2202413 4500008004100000022001400041245009100055210006900146260000900215300001300224490000600237520076400243653002201007653000901029653001201038653001401050653002901064653002701093653001801120653004001138653001101178653002201189653003001211653003401241653003101275653001101306653001101317653002801328653000901356653001601365653003401381653001401415100002201429700001901451700002201470700001901492700002301511700002701534700002001561700002001581700001801601700001901619700001201638700001601650700002001666700001601686700002501702700002401727700002601751700001901777700001801796700001801814700002101832700002601853700002301879700002001902700001201922700002301934700002201957700001801979700002001997700002702017700001702044700002502061700001902086700001802105700001902123700002202142700002702164700002102191700002102212700002202233700001602255700002202271700001802293700001902311700002102330700002002351700001902371700002302390700002002413700002202433700002202455700001902477700002402496700002502520700002102545700002002566700002602586700002002612700001702632700001902649700001902668700002302687700002302710700002002733700002502753700002302778700002102801700001802822700002002840700002202860700001802882700002202900700001802922700002102940700002402961700001602985700001903001700001903020700002003039700002003059700002203079700002003101700001903121700001903140700002203159700001903181700001803200700002103218700002003239700002003259700001703279700001903296700001803315700002203333700001803355700001903373700002803392700002603420700002403446700001903470700001703489700002203506700002203528700001903550700002203569700001903591700002003610700001903630700002203649700002203671700002003693700001903713700001603732700002303748700002303771700002503794700001803819700001403837700002403851700001703875700002103892700002403913700001703937700001703954700001903971700001903990700001904009700001904028700002404047700002004071700002104091700001804112700002104130700001904151700001904170700002904189700002404218700002104242700002404263700002304287700001804310700002204328700002004350700002404370700002304394700002004417700002404437700001704461700002004478700001604498700002004514700002104534700001804555700002604573700001904599700002104618700003004639700002204669700001704691700001804708700002104726700001804747700002304765700002304788700002004811700002104831710002604852710002004878710002004898710005404918856003604972 2012 eng d a1553-740400aGenome-wide association and functional follow-up reveals new loci for kidney function.0 aGenomewide association and functional followup reveals new loci c2012 ae10025840 v83 aChronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
10aAfrican Americans10aAged10aAnimals10aCaspase 910aCyclin-Dependent Kinases10aDEAD-box RNA Helicases10aDNA Helicases10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aGene Knockdown Techniques10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aMale10aMiddle Aged10aPhosphoric Diester Hydrolases10aZebrafish1 aPattaro, Cristian1 aKöttgen, Anna1 aTeumer, Alexander1 aGarnaas, Maija1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aTaliun, Daniel1 aLi, Man1 aGao, Xiaoyi1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aO'Seaghdha, Conall, M1 aGlazer, Nicole1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aJohnson, Andrew, D1 aGierman, Hinco, J1 aFeitosa, Mary1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aChouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aCavalieri, Margherita1 aRao, Madhumathi1 aHu, Frank, B1 aDemirkan, Ayse1 aOostra, Ben, A1 ade Andrade, Mariza1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aKolcic, Ivana1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aEndlich, Karlhans1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aKetkar, Shamika1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aGiulianini, Franco1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMetzger, Marie1 aMitchell, Paul1 aCiullo, Marina1 aKim, Stuart, K1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aSiscovick, David, S1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline, C M1 aHayward, Caroline1 aRidker, Paul1 aParsa, Afshin1 aBochud, Murielle1 aHeid, Iris, M1 aGoessling, Wolfram1 aChasman, Daniel, I1 aKao, Linda, W H1 aFox, Caroline, S1 aCARDIoGRAM consortium1 aICBP Consortium1 aCARe Consortium1 aWellcome Trust Case Control Consortium 2 (WTCCC2) uhttps://chs-nhlbi.org/node/137705536nas a2201405 4500008004100000022001400041245012000055210006900175260000900244300001300253490000600266520151700272653002901789653002001818653001801838653003401856653002001890653002301910653001101933653000901944653002601953653003601979653004402015653004302059653002802102653001202130653003002142653001902172100002102191700002602212700002002238700001802258700002102276700002602297700001802323700001902341700001602360700002202376700002102398700002202419700001702441700001602458700001902474700001802493700001902511700002002530700002402550700001902574700002202593700001802615700001702633700002202650700002102672700001802693700001902711700001802730700002002748700001702768700002002785700002202805700002602827700001902853700002202872700002402894700002202918700001902940700002402959700002302983700002203006700002203028700002003050700001903070700002003089700001903109700002103128700001903149700002403168700002303192700002603215700002103241700002803262700001703290700001903307700002003326700002003346700002803366700002003394700002103414700002003435700002403455700001903479700002103498700001903519700002203538700001803560700002803578700002803606700001803634700002303652700001703675700002503692700001903717700002503736700002403761700002903785700002003814700002703834700002303861700002403884700001903908700001703927700002503944700002303969700002003992700001704012700001904029700002104048700002504069856003604094 2012 eng d a1553-740400aGenome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.0 aGenomewide joint metaanalysis of SNP and SNPbysmoking interactio c2012 ae10030980 v83 aGenome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
10aForced Expiratory Volume10aGene Expression10aGenome, Human10aGenome-Wide Association Study10aHLA-DQ Antigens10aHLA-DQ beta-Chains10aHumans10aLung10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPotassium Channels, Inwardly Rectifying10aPulmonary Disease, Chronic Obstructive10aReceptors, Cell Surface10aSmoking10aSOX9 Transcription Factor10aVital Capacity1 aHancock, Dana, B1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aHenry, Amanda1 aManichaikul, Ani1 aRamasamy, Adaikalavan1 aLoth, Daan, W1 aImboden, Medea1 aKoch, Beate1 aMcArdle, Wendy, L1 aSmith, Albert, V1 aSmolonska, Joanna1 aSood, Akshay1 aTang, Wenbo1 aWilk, Jemma, B1 aZhai, Guangju1 aZhao, Jing Hua1 aAschard, Hugues1 aBurkart, Kristin, M1 aCurjuric, Ivan1 aEijgelsheim, Mark1 aElliott, Paul1 aGu, Xiangjun1 aHarris, Tamara, B1 aJanson, Christer1 aHomuth, Georg1 aHysi, Pirro, G1 aLiu, Jason, Z1 aLoehr, Laura, R1 aLohman, Kurt1 aLoos, Ruth, J F1 aManning, Alisa, K1 aMarciante, Kristin, D1 aObeidat, Ma'en1 aPostma, Dirkje, S1 aAldrich, Melinda, C1 aBrusselle, Guy, G1 aChen, Ting-Hsu1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aHeinrich, Joachim1 aRotter, Jerome, I1 aWijmenga, Cisca1 aWilliams, Dale1 aBentley, Amy, R1 aHofman, Albert1 aLaurie, Cathy, C1 aLumley, Thomas1 aMorrison, Alanna, C1 aJoubert, Bonnie, R1 aRivadeneira, Fernando1 aCouper, David, J1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aWjst, Matthias1 aWain, Louise, V1 aVonk, Judith, M1 aUitterlinden, André, G1 aRochat, Thierry1 aRich, Stephen, S1 aPsaty, Bruce, M1 aO'Connor, George, T1 aNorth, Kari, E1 aMirel, Daniel, B1 aMeibohm, Bernd1 aLauner, Lenore, J1 aKhaw, Kay-Tee1 aHartikainen, Anna-Liisa1 aHammond, Christopher, J1 aGläser, Sven1 aMarchini, Jonathan1 aKraft, Peter1 aWareham, Nicholas, J1 aVölzke, Henry1 aStricker, Bruno, H C1 aSpector, Timothy, D1 aProbst-Hensch, Nicole, M1 aJarvis, Deborah1 aJarvelin, Marjo-Riitta1 aHeckbert, Susan, R1 aGudnason, Vilmundur1 aBoezen, Marike1 aBarr, Graham1 aCassano, Patricia, A1 aStrachan, David, P1 aFornage, Myriam1 aHall, Ian, P1 aDupuis, Josée1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/608807748nas a2202497 4500008004100000022001400041245011400055210006900169260001600238300001000254490000700264520075000271653001601021653001801037653002501055653001601080653001501096653002301111653003201134653004001166653002601206653001101232653001701243653003401260653001101294653001301305653001401318653003601332653001301368100001901381700002101400700002301421700001601444700002101460700001901481700001901500700001701519700001901536700001901555700001601574700002301590700002801613700002401641700001701665700002401682700002001706700001801726700002101744700002601765700001801791700001901809700001801828700002501846700001901871700002501890700002501915700002501940700001801965700002101983700002402004700001802028700002002046700002402066700002002090700002502110700001802135700002402153700001702177700001702194700001802211700001902229700001802248700002702266700002502293700001802318700002402336700002002360700002302380700002402403700001902427700002002446700002002466700002102486700002302507700002102530700002202551700001902573700002602592700001402618700001902632700002402651700001602675700002202691700002102713700001902734700002002753700002602773700002302799700001902822700002402841700001802865700002102883700001802904700002102922700001602943700001602959700001702975700002102992700002203013700001703035700002003052700002303072700002703095700001903122700002403141700003003165700002303195700002203218700002203240700001803262700002003280700001703300700002003317700002003337700003103357700001903388700002103407700002003428700002303448700002403471700002003495700002103515700001903536700002103555700002003576700002303596700001903619700002203638700001603660700001703676700002103693700002003714700002203734700002303756700002003779700002003799700002103819700001903840700002703859700002303886700002103909700002603930700001603956700001903972700002103991700002104012700002604033700001404059700001804073700002004091700002204111700002304133700002204156700002404178700002304202700002204225700002004247700002504267700002304292700002104315700003404336700002304370700002104393700003004414700002004444700003104464700002204495700001604517700002504533700001904558700002104577700002304598700002104621700002004642700002304662700002404685700002204709700001704731700002104748700002204769700002104791700002504812700001904837700002004856700001804876700002404894700002004918700002104938700002704959700002804986700001705014700002805031700002305059700001905082700001705101700002405118700002105142700002405163710002705187856003605214 2012 eng d a1546-171800aMeta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.0 aMetaanalyses identify 13 loci associated with age at menopause a c2012 Jan 22 a260-80 v443 aTo newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
10aAge Factors10aDNA Helicases10aDNA Polymerase gamma10aDNA Primase10aDNA Repair10aDNA Repair Enzymes10aDNA-Directed DNA Polymerase10aEuropean Continental Ancestry Group10aExodeoxyribonucleases10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aImmunity10aMenopause10aPolymorphism, Single Nucleotide10aProteins1 aStolk, Lisette1 aPerry, John, R B1 aChasman, Daniel, I1 aHe, Chunyan1 aMangino, Massimo1 aSulem, Patrick1 aBarbalic, Maja1 aBroer, Linda1 aByrne, Enda, M1 aErnst, Florian1 aEsko, Tõnu1 aFranceschini, Nora1 aGudbjartsson, Daniel, F1 aHottenga, Jouke-Jan1 aKraft, Peter1 aMcArdle, Patrick, F1 aPorcu, Eleonora1 aShin, So-Youn1 aSmith, Albert, V1 avan Wingerden, Sophie1 aZhai, Guangju1 aZhuang, Wei, V1 aAlbrecht, Eva1 aAlizadeh, Behrooz, Z1 aAspelund, Thor1 aBandinelli, Stefania1 aLauc, Lovorka, Barac1 aBeckmann, Jacques, S1 aBoban, Mladen1 aBoerwinkle, Eric1 aBroekmans, Frank, J1 aBurri, Andrea1 aCampbell, Harry1 aChanock, Stephen, J1 aChen, Constance1 aCornelis, Marilyn, C1 aCorre, Tanguy1 aCoviello, Andrea, D1 aD'Adamo, Pio1 aDavies, Gail1 ade Faire, Ulf1 aGeus, Eco, J C1 aDeary, Ian, J1 aDedoussis, George, V Z1 aDeloukas, Panagiotis1 aEbrahim, Shah1 aEiriksdottir, Gudny1 aEmilsson, Valur1 aEriksson, Johan, G1 aFauser, Bart, C J M1 aFerreli, Liana1 aFerrucci, Luigi1 aFischer, Krista1 aFolsom, Aaron, R1 aGarcia, Melissa, E1 aGasparini, Paolo1 aGieger, Christian1 aGlazer, Nicole1 aGrobbee, Diederick, E1 aHall, Per1 aHaller, Toomas1 aHankinson, Susan, E1 aHass, Merli1 aHayward, Caroline1 aHeath, Andrew, C1 aHofman, Albert1 aIngelsson, Erik1 aJanssens, Cecile, J W1 aJohnson, Andrew, D1 aKarasik, David1 aKardia, Sharon, L R1 aKeyzer, Jules1 aKiel, Douglas, P1 aKolcic, Ivana1 aKutalik, Zoltán1 aLahti, Jari1 aLai, Sandra1 aLaisk, Triin1 aLaven, Joop, S E1 aLawlor, Debbie, A1 aLiu, Jianjun1 aLopez, Lorna, M1 aLouwers, Yvonne, V1 aMagnusson, Patrik, K E1 aMarongiu, Mara1 aMartin, Nicholas, G1 aKlaric, Irena, Martinovic1 aMasciullo, Corrado1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMelzer, David1 aMooser, Vincent1 aNavarro, Pau1 aNewman, Anne, B1 aNyholt, Dale, R1 aOnland-Moret, Charlotte, N1 aPalotie, Aarno1 aParé, Guillaume1 aParker, Alex, N1 aPedersen, Nancy, L1 aPeeters, Petra, H M1 aPistis, Giorgio1 aPlump, Andrew, S1 aPolasek, Ozren1 aPop, Victor, J M1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRehnberg, Emil1 aRotter, Jerome, I1 aRudan, Igor1 aSala, Cinzia1 aSalumets, Andres1 aScuteri, Angelo1 aSingleton, Andrew1 aSmith, Jennifer, A1 aSnieder, Harold1 aSoranzo, Nicole1 aStacey, Simon, N1 aStarr, John, M1 aStathopoulou, Maria, G1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStyrkarsdottir, Unnur1 aSun, Yan, V1 aTenesa, Albert1 aThorand, Barbara1 aToniolo, Daniela1 aTryggvadottir, Laufey1 aTsui, Kim1 aUlivi, Sheila1 avan Dam, Rob, M1 aSchouw, Yvonne, T1 avan Gils, Carla, H1 avan Nierop, Peter1 aVink, Jacqueline, M1 aVisscher, Peter, M1 aVoorhuis, Marlies1 aWaeber, Gérard1 aWallaschofski, Henri1 aWichmann, Erich, H1 aWiden, Elisabeth1 avan Gent, Colette, J M Wijnan1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWright, Alan, F1 aYerges-Armstrong, Laura, M1 aZemunik, Tatijana1 aZgaga, Lina1 aZillikens, Carola, M1 aZygmunt, Marek1 aArnold, Alice, M1 aBoomsma, Dorret, I1 aBuring, Julie, E1 aCrisponi, Laura1 aDemerath, Ellen, W1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHu, Frank, B1 aHunter, David, J1 aLauner, Lenore, J1 aMetspalu, Andres1 aMontgomery, Grant, W1 aOostra, Ben, A1 aRidker, Paul, M1 aSanna, Serena1 aSchlessinger, David1 aSpector, Tim, D1 aStefansson, Kari1 aStreeten, Elizabeth, A1 aThorsteinsdottir, Unnur1 aUda, Manuela1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aMurray, Anna1 aMurabito, Joanne, M1 aVisser, Jenny, A1 aLunetta, Kathryn, L1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/136004917nas 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/138304117nas a2200721 4500008004100000022001400041245008600055210006900141260001600210300001200226490000800238520212100246653001502367653001002382653002102392653000902413653002202422653002402444653001902468653001902487653002802506653001102534653001102545653002002556653000902576653001602585653001402601653002402615653002002639653003002659653002102689653002202710653001602732653002702748653001602775653001602791100002102807700002402828700002202852700002602874700002102900700002102921700002102942700002202963700002102985700001903006700001903025700002103044700002203065700002303087700002103110700002503131700002003156700002003176700001803196700002603214700002303240700002203263700001903285700002103304710003403325856003603359 2012 eng d a1538-367900aSubclinical hyperthyroidism and the risk of coronary heart disease and mortality.0 aSubclinical hyperthyroidism and the risk of coronary heart disea c2012 May 28 a799-8090 v1723 aBACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.
METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.
RESULTS: Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR,1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95%CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03).
CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.
10aAdolescent10aAdult10aAge Distribution10aAged10aAged, 80 and over10aAtrial Fibrillation10aCause of Death10aCohort Studies10aCoronary Artery Disease10aFemale10aHumans10aHyperthyroidism10aMale10aMiddle Aged10aPrognosis10aProspective Studies10aRisk Assessment10aSeverity of Illness Index10aSex Distribution10aSurvival Analysis10aSwitzerland10aThyroid Function Tests10aThyrotropin10aYoung Adult1 aCollet, Tinh-Hai1 aGussekloo, Jacobijn1 aBauer, Douglas, C1 aElzen, Wendy, P J den1 aCappola, Anne, R1 aBalmer, Philippe1 aIervasi, Giorgio1 aAsvold, Bjørn, O1 aSgarbi, José, A1 aVölzke, Henry1 aGencer, Bariş1 aMaciel, Rui, M B1 aMolinaro, Sabrina1 aBremner, Alexandra1 aLuben, Robert, N1 aMaisonneuve, Patrick1 aCornuz, Jacques1 aNewman, Anne, B1 aKhaw, Kay-Tee1 aWestendorp, Rudi, G J1 aFranklyn, Jayne, A1 aVittinghoff, Eric1 aWalsh, John, P1 aRodondi, Nicolas1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/154507440nas a2202173 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520143200253653002301685653004001708653001901748653002201767653003401789653001101823653001101834653003701845653001401882653003601896653003301932100001801965700002701983700001902010700002602029700002202055700002302077700002302100700002202123700002202145700002002167700002002187700001802207700001802225700001902243700001202262700001802274700002002292700001602312700002502328700002402353700001902377700001802396700002002414700002102434700002602455700002302481700002002504700001202524700002002536700002702556700001702583700002502600700001902625700001802644700001902662700002102681700002702702700002102729700002102750700002202771700001602793700002202809700001802831700001902849700002102868700002002889700001902909700002302928700002002951700002202971700002202993700001903015700002403034700002503058700002103083700002003104700001703124700001403141700001903155700001903174700002303193700002003216700002503236700002303261700002303284700002103307700001803328700002003346700002203366700001603388700002203404700001803426700002103444700002403465700001603489700001903505700001903524700002003543700002003563700002203583700002003605700001903625700001903644700001903663700001803682700002103700700002003721700002003741700001703761700001903778700001803797700002203815700001803837700001903855700002803874700002603902700002403928700001903952700001703971700002203988700002204010700001904032700002504051700002204076700001904098700002004117700001904137700002204156700002204178700001904200700001604219700002304235700002504258700001804283700001404301700002404315700001704339700002104356700002404377700001704401700001704418700001904435700001904454700002404473700002004497700002104517700001804538700002104556700001904577700001904596700002904615700002404644700002104668700002404689700002304713700001804736700002204754700002004776700002304796700002004819700002404839700001704863700002004880700001604900700002004916700002104936700001804957700002604975700001905001700002105020700002505041700002205066700002005088700002105108700001805129700002405147700002105171700001505192700002305207856003605230 2013 eng d a1533-345000aCommon variants in Mendelian kidney disease genes and their association with renal function.0 aCommon variants in Mendelian kidney disease genes and their asso c2013 Dec a2105-170 v243 aMany common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
10aDatabases, Genetic10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aHumans10aKidney10aMendelian Randomization Analysis10aPhenotype10aPolymorphism, Single Nucleotide10aRenal Insufficiency, Chronic1 aParsa, Afshin1 aFuchsberger, Christian1 aKöttgen, Anna1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 ade Andrade, Mariza1 aChasman, Daniel, I1 aTeumer, Alexander1 aEndlich, Karlhans1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aKim, Young, J1 aTaliun, Daniel1 aLi, Man1 aFeitosa, Mary1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aGlazer, Nicole1 aIsaacs, Aaron1 aRao, Madhumathi1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aCouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aHofer, Edith1 aHu, Frank1 aDemirkan, Ayse1 aOostra, Ben, A1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aGiulianini, Franco1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aZgaga, Lina1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aStengel, Bénédicte1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMitchell, Paul1 aCiullo, Marina1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline1 aHayward, Caroline1 aRidker, Paul, M1 aBochud, Murielle1 aHeid, Iris, M1 aSiscovick, David, S1 aFox, Caroline, S1 aKao, Linda1 aBöger, Carsten, A uhttps://chs-nhlbi.org/node/628809406nas a2203037 4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520104700257653002501304653004001329653001901369653001701388653003401405653001201439653000901451653001101460653001301471653003601484653002401520653001401544100001901558700001801577700002201595700002201617700001801639700002501657700002001682700002201702700002601724700001901750700001601769700002001785700002301805700002101828700002101849700001501870700002301885700002601908700002101934700002101955700002001976700001201996700002202008700002202030700002202052700001602074700001902090700001902109700002102128700001402149700002202163700002002185700001502205700001702220700002202237700002102259700001902280700001902299700002102318700001902339700002502358700001902383700001902402700002202421700001902443700002002462700001702482700002102499700001902520700002202539700002202561700002002583700001802603700002302621700002702644700001802671700002002689700001702709700002002726700002202746700002102768700002902789700002202818700002202840700002102862700002302883700002102906700001802927700002002945700002302965700002402988700002503012700001903037700002103056700002203077700002403099700002203123700002103145700001503166700001703181700001803198700002203216700002003238700002403258700002003282700002003302700002103322700001703343700001803360700002103378700002103399700002203420700001603442700002103458700001903479700002403498700002503522700001803547700001603565700001903581700002103600700002103621700002703642700001403669700002103683700002503704700002303729700001803752700002503770700002103795700002003816700001603836700002403852700001803876700002603894700002203920700001703942700001703959700002403976700002104000700002204021700001804043700002804061700002304089700001904112700002304131700002204154700001704176700001904193700002204212700001804234700001904252700001704271700002104288700002404309700001904333700001504352700001704367700001904384700002604403700002804429700001904457700002804476700002104504700002204525700002504547700002004572700002304592700001904615700001904634700002504653700002404678700002104702700002204723700001604745700001904761700002004780700001804800700002004818700001704838700002004855700002004875700001904895700002804914700002704942700002204969700002204991700001905013700002505032700002205057700001805079700002005097700001605117700001605133700001805149700002105167700002005188700001505208700001905223700001705242700002905259700001905288700002405307700001805331700002205349700002305371700002005394700002105414700002405435700001905459700002005478700001605498700002505514700002105539700002005560700002305580700002305603700002005626700002205646700001805668700003005686700002205716700002005738700002605758700002005784700002005804700002005824700001805844700001805862700003005880700001805910700001905928700002305947700001805970700002005988700002006008700002106028700002306049700002006072700002006092700001906112700002106131700002006152700002106172700002206193710002706215710002606242710002306268710002006291710002106311856003606332 2013 eng d a1546-171800aGenome-wide association analyses identify 18 new loci associated with serum urate concentrations.0 aGenomewide association analyses identify 18 new loci associated c2013 Feb a145-540 v453 aElevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
10aAnalysis of Variance10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aGlucose10aGout10aHumans10aInhibins10aPolymorphism, Single Nucleotide10aSignal Transduction10aUric Acid1 aKöttgen, Anna1 aAlbrecht, Eva1 aTeumer, Alexander1 aVitart, Veronique1 aKrumsiek, Jan1 aHundertmark, Claudia1 aPistis, Giorgio1 aRuggiero, Daniela1 aO'Seaghdha, Conall, M1 aHaller, Toomas1 aYang, Qiong1 aTanaka, Toshiko1 aJohnson, Andrew, D1 aKutalik, Zoltán1 aSmith, Albert, V1 aShi, Julia1 aStruchalin, Maksim1 aMiddelberg, Rita, P S1 aBrown, Morris, J1 aGaffo, Angelo, L1 aPirastu, Nicola1 aLi, Guo1 aHayward, Caroline1 aZemunik, Tatijana1 aHuffman, Jennifer1 aYengo, Loic1 aZhao, Jing Hua1 aDemirkan, Ayse1 aFeitosa, Mary, F1 aLiu, Xuan1 aMalerba, Giovanni1 aLopez, Lorna, M1 aHarst, Pim1 aLi, Xinzhong1 aKleber, Marcus, E1 aHicks, Andrew, A1 aNolte, Ilja, M1 aJohansson, Asa1 aMurgia, Federico1 aWild, Sarah, H1 aBakker, Stephan, J L1 aPeden, John, F1 aDehghan, Abbas1 aSteri, Maristella1 aTenesa, Albert1 aLagou, Vasiliki1 aSalo, Perttu1 aMangino, Massimo1 aRose, Lynda, M1 aLehtimäki, Terho1 aWoodward, Owen, M1 aOkada, Yukinori1 aTin, Adrienne1 aMüller, Christian1 aOldmeadow, Christopher1 aPutku, Margus1 aCzamara, Darina1 aKraft, Peter1 aFrogheri, Laura1 aThun, Gian, Andri1 aGrotevendt, Anne1 aGislason, Gauti, Kjartan1 aHarris, Tamara, B1 aLauner, Lenore, J1 aMcArdle, Patrick1 aShuldiner, Alan, R1 aBoerwinkle, Eric1 aCoresh, Josef1 aSchmidt, Helena1 aSchallert, Michael1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aKubo, Michiaki1 aNakamura, Yusuke1 aTanaka, Toshihiro1 aMunroe, Patricia, B1 aSamani, Nilesh, J1 aJacobs, David, R1 aLiu, Kiang1 aD'Adamo, Pio1 aUlivi, Sheila1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aVollenweider, Peter1 aWaeber, Gérard1 aCampbell, Susan1 aDevuyst, Olivier1 aNavarro, Pau1 aKolcic, Ivana1 aHastie, Nicholas1 aBalkau, Beverley1 aFroguel, Philippe1 aEsko, Tõnu1 aSalumets, Andres1 aKhaw, Kay, Tee1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aIsaacs, Aaron1 aKraja, Aldi1 aZhang, Qunyuan1 aWild, Philipp, S1 aScott, Rodney, J1 aHolliday, Elizabeth, G1 aOrg, Elin1 aViigimaa, Margus1 aBandinelli, Stefania1 aMetter, Jeffrey, E1 aLupo, Antonio1 aTrabetti, Elisabetta1 aSorice, Rossella1 aDöring, Angela1 aLattka, Eva1 aStrauch, Konstantin1 aTheis, Fabian1 aWaldenberger, Melanie1 aWichmann, H-Erich1 aDavies, Gail1 aGow, Alan, J1 aBruinenberg, Marcel1 aStolk, Ronald, P1 aKooner, Jaspal, S1 aZhang, Weihua1 aWinkelmann, Bernhard, R1 aBoehm, Bernhard, O1 aLucae, Susanne1 aPenninx, Brenda, W1 aSmit, Johannes, H1 aCurhan, Gary1 aMudgal, Poorva1 aPlenge, Robert, M1 aPortas, Laura1 aPersico, Ivana1 aKirin, Mirna1 aWilson, James, F1 aLeach, Irene, Mateo1 aGilst, Wiek, H1 aGoel, Anuj1 aOngen, Halit1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aImboden, Medea1 avon Eckardstein, Arnold1 aCucca, Francesco1 aNagaraja, Ramaiah1 aPiras, Maria, Grazia1 aNauck, Matthias1 aSchurmann, Claudia1 aBudde, Kathrin1 aErnst, Florian1 aFarrington, Susan, M1 aTheodoratou, Evropi1 aProkopenko, Inga1 aStumvoll, Michael1 aJula, Antti1 aPerola, Markus1 aSalomaa, Veikko1 aShin, So-Youn1 aSpector, Tim, D1 aSala, Cinzia1 aRidker, Paul, M1 aKähönen, Mika1 aViikari, Jorma1 aHengstenberg, Christian1 aNelson, Christopher, P1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aSingleton, Andrew, B1 aKamatani, Naoyuki1 aZeller, Tanja1 aBurnier, Michel1 aAttia, John1 aLaan, Maris1 aKlopp, Norman1 aHillege, Hans, L1 aKloiber, Stefan1 aChoi, Hyon1 aPirastu, Mario1 aTore, Silvia1 aProbst-Hensch, Nicole, M1 aVölzke, Henry1 aGudnason, Vilmundur1 aParsa, Afshin1 aSchmidt, Reinhold1 aWhitfield, John, B1 aFornage, Myriam1 aGasparini, Paolo1 aSiscovick, David, S1 aPolasek, Ozren1 aCampbell, Harry1 aRudan, Igor1 aBouatia-Naji, Nabila1 aMetspalu, Andres1 aLoos, Ruth, J F1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aFerrucci, Luigi1 aGambaro, Giovanni1 aDeary, Ian, J1 aWolffenbuttel, Bruce, H R1 aChambers, John, C1 aMärz, Winfried1 aPramstaller, Peter, P1 aSnieder, Harold1 aGyllensten, Ulf1 aWright, Alan, F1 aNavis, Gerjan1 aWatkins, Hugh1 aWitteman, Jacqueline, C M1 aSanna, Serena1 aSchipf, Sabine1 aDunlop, Malcolm, G1 aTönjes, Anke1 aRipatti, Samuli1 aSoranzo, Nicole1 aToniolo, Daniela1 aChasman, Daniel, I1 aRaitakari, Olli1 aKao, Linda, W H1 aCiullo, Marina1 aFox, Caroline, S1 aCaulfield, Mark1 aBochud, Murielle1 aGieger, Christian1 aLifeLines Cohort Study1 aCARDIoGRAM consortium1 aDIAGRAM Consortium1 aICBP Consortium1 aMAGIC Consortium uhttps://chs-nhlbi.org/node/607505039nas a2201297 4500008004100000022001400041245006000055210005600115260001600171300001100187490000700198520149400205653000901699653002201708653003101730653001501761653001101776653003801787653003401825653001101859653000901870653001601879653003601895100001501931700001901946700001601965700002501981700002202006700002502028700001602053700001802069700001802087700002002105700001702125700002302142700002202165700002202187700001602209700002302225700001202248700002502260700002402285700002202309700002002331700002302351700002002374700001702394700002402411700002202435700001902457700001702476700001902493700002102512700002202533700001702555700001802572700002002590700002202610700002202632700001902654700002302673700002002696700002002716700002002736700002402756700001902780700001802799700001902817700002602836700002102862700001702883700002002900700002302920700001802943700002102961700002402982700001703006700001903023700001903042700002003061700002303081700002103104700001703125700001803142700002003160700001903180700002303199700002503222700002103247700002303268700002803291700001903319700002103338700002003359700002303379700002103402700001903423700002303442700002403465700002303489700002003512700002303532700001903555700002203574700002403596700002203620700002003642700002203662700002103684856003603705 2013 eng d a1873-240200aA genome-wide association study of depressive symptoms.0 agenomewide association study of depressive symptoms c2013 Apr 01 a667-780 v733 aBACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
10aAged10aAged, 80 and over10aChromosomes, Human, Pair 510aDepression10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aHek, Karin1 aDemirkan, Ayse1 aLahti, Jari1 aTerracciano, Antonio1 aTeumer, Alexander1 aCornelis, Marilyn, C1 aAmin, Najaf1 aBakshis, Erin1 aBaumert, Jens1 aDing, Jingzhong1 aLiu, Yongmei1 aMarciante, Kristin1 aMeirelles, Osorio1 aNalls, Michael, A1 aSun, Yan, V1 aVogelzangs, Nicole1 aYu, Lei1 aBandinelli, Stefania1 aBenjamin, Emelia, J1 aBennett, David, A1 aBoomsma, Dorret1 aCannas, Alessandra1 aCoker, Laura, H1 ade Geus, Eco1 aDe Jager, Philip, L1 aDiez-Roux, Ana, V1 aPurcell, Shaun1 aHu, Frank, B1 aRimma, Eric, B1 aHunter, David, J1 aJensen, Majken, K1 aCurhan, Gary1 aRice, Kenneth1 aPenman, Alan, D1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aEmeny, Rebecca1 aEriksson, Johan, G1 aEvans, Denis, A1 aFerrucci, Luigi1 aFornage, Myriam1 aGudnason, Vilmundur1 aHofman, Albert1 aIllig, Thomas1 aKardia, Sharon1 aKelly-Hayes, Margaret1 aKoenen, Karestan1 aKraft, Peter1 aKuningas, Maris1 aMassaro, Joseph, M1 aMelzer, David1 aMulas, Antonella1 aMulder, Cornelis, L1 aMurray, Anna1 aOostra, Ben, A1 aPalotie, Aarno1 aPenninx, Brenda1 aPetersmann, Astrid1 aPilling, Luke, C1 aPsaty, Bruce1 aRawal, Rajesh1 aReiman, Eric, M1 aSchulz, Andrea1 aShulman, Joshua, M1 aSingleton, Andrew, B1 aSmith, Albert, V1 aSutin, Angelina, R1 aUitterlinden, André, G1 aVölzke, Henry1 aWiden, Elisabeth1 aYaffe, Kristine1 aZonderman, Alan, B1 aCucca, Francesco1 aHarris, Tamara1 aLadwig, Karl-Heinz1 aLlewellyn, David, J1 aRäikkönen, Katri1 aTanaka, Toshiko1 aDuijn, Cornelia, M1 aGrabe, Hans, J1 aLauner, Lenore, J1 aLunetta, Kathryn, L1 aMosley, Thomas, H1 aNewman, Anne, B1 aTiemeier, Henning1 aMurabito, Joanne uhttps://chs-nhlbi.org/node/607008187nas a2202209 4500008004100000022001400041245023300055210006900288260001600357300001200373490000800385520188600393653001502279653001002294653003902304653000902343653002202352653002802374653002802402653004002430653001102470653001502481653001702496653003802513653003402551653002302585653001102608653000902619653001602628653002602644653003602670653001702706653001102723653002702734653001602761100002502777700001502802700002002817700001902837700001902856700002302875700002202898700002002920700002102940700001702961700002402978700002003002700002303022700001803045700001903063700001703082700002303099700001803122700002003140700001603160700002003176700001903196700002803215700002103243700001703264700002503281700002203306700001903328700001703347700002003364700001603384700002003400700001803420700001903438700001903457700002003476700001603496700002003512700001503532700002203547700002103569700002103590700002503611700002303636700002103659700001903680700002003699700001703719700001703736700001703753700002103770700002203791700001903813700002703832700002003859700002403879700002503903700002103928700002003949700002603969700002803995700002104023700001904044700002204063700002304085700002304108700001304131700002504144700002304169700002204192700001904214700002004233700002204253700002004275700002004295700002204315700001804337700002104355700001804376700001904394700001904413700001504432700002704447700001704474700001904491700002204510700002304532700001804555700002404573700002004597700001904617700002404636700001604660700002004676700002204696700002004718700002404738700001804762700002104780700002104801700001904822700002804841700002204869700002004891700002204911700001704933700002104950700002304971700002404994700002305018700002205041700002105063700002205084700001705106700002705123700002205150700002405172700002205196700002405218700002905242700002005271700002305291700001805314700001805332700002005350700003005370700001905400700002205419700002205441700002105463700002105484700001905505700001805524700002005542700002005562700001805582700002205600700002505622700002305647700002005670700002005690700001805710700002305728700002005751700003005771710001905801710002205820710005405842710001905896710002605915856003605941 2013 eng d a1524-453900aMultiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.0 aMultiethnic metaanalysis of genomewide association studies in 10 c2013 Sep 17 a1310-240 v1283 aBACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.
METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.
CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aCardiovascular Diseases10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHispanic Americans10aHumans10aMale10aMiddle Aged10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke10aVenous Thromboembolism10aYoung Adult1 aSabater-Lleal, Maria1 aHuang, Jie1 aChasman, Daniel1 aNaitza, Silvia1 aDehghan, Abbas1 aJohnson, Andrew, D1 aTeumer, Alexander1 aReiner, Alex, P1 aFolkersen, Lasse1 aBasu, Saonli1 aRudnicka, Alicja, R1 aTrompet, Stella1 aMälarstig, Anders1 aBaumert, Jens1 aBis, Joshua, C1 aGuo, Xiuqing1 aHottenga, Jouke, J1 aShin, So-Youn1 aLopez, Lorna, M1 aLahti, Jari1 aTanaka, Toshiko1 aYanek, Lisa, R1 aOudot-Mellakh, Tiphaine1 aWilson, James, F1 aNavarro, Pau1 aHuffman, Jennifer, E1 aZemunik, Tatijana1 aRedline, Susan1 aMehra, Reena1 aPulanic, Drazen1 aRudan, Igor1 aWright, Alan, F1 aKolcic, Ivana1 aPolasek, Ozren1 aWild, Sarah, H1 aCampbell, Harry1 aCurb, David1 aWallace, Robert1 aLiu, Simin1 aEaton, Charles, B1 aBecker, Diane, M1 aBecker, Lewis, C1 aBandinelli, Stefania1 aRäikkönen, Katri1 aWiden, Elisabeth1 aPalotie, Aarno1 aFornage, Myriam1 aGreen, David1 aGross, Myron1 aDavies, Gail1 aHarris, Sarah, E1 aLiewald, David, C1 aStarr, John, M1 aWilliams, Frances, M K1 aGrant, Peter, J1 aSpector, Timothy, D1 aStrawbridge, Rona, J1 aSilveira, Angela1 aSennblad, Bengt1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aFranco, Oscar, H1 aHofman, Albert1 avan Dongen, Jenny1 aWillemsen, Gonneke1 aBoomsma, Dorret, I1 aYao, Jie1 aJenny, Nancy, Swords1 aHaritunians, Talin1 aMcKnight, Barbara1 aLumley, Thomas1 aTaylor, Kent, D1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aPeters, Annette1 aGieger, Christian1 aIllig, Thomas1 aGrotevendt, Anne1 aHomuth, Georg1 aVölzke, Henry1 aKocher, Thomas1 aGoel, Anuj1 aFranzosi, Maria Grazia1 aSeedorf, Udo1 aClarke, Robert1 aSteri, Maristella1 aTarasov, Kirill, V1 aSanna, Serena1 aSchlessinger, David1 aStott, David, J1 aSattar, Naveed1 aBuckley, Brendan, M1 aRumley, Ann1 aLowe, Gordon, D1 aMcArdle, Wendy, L1 aChen, Ming-Huei1 aTofler, Geoffrey, H1 aSong, Jaejoon1 aBoerwinkle, Eric1 aFolsom, Aaron, R1 aRose, Lynda, M1 aFranco-Cereceda, Anders1 aTeichert, Martina1 aIkram, Arfan, M1 aMosley, Thomas, H1 aBevan, Steve1 aDichgans, Martin1 aRothwell, Peter, M1 aSudlow, Cathie, L M1 aHopewell, Jemma, C1 aChambers, John, C1 aSaleheen, Danish1 aKooner, Jaspal, S1 aDanesh, John1 aNelson, Christopher, P1 aErdmann, Jeanette1 aReilly, Muredach, P1 aKathiresan, Sekar1 aSchunkert, Heribert1 aMorange, Pierre-Emmanuel1 aFerrucci, Luigi1 aEriksson, Johan, G1 aJacobs, David1 aDeary, Ian, J1 aSoranzo, Nicole1 aWitteman, Jacqueline, C M1 aGeus, Eco, J C1 aTracy, Russell, P1 aHayward, Caroline1 aKoenig, Wolfgang1 aCucca, Francesco1 aJukema, Wouter1 aEriksson, Per1 aSeshadri, Sudha1 aMarkus, Hugh, S1 aWatkins, Hugh1 aSamani, Nilesh, J1 aWallaschofski, Henri1 aSmith, Nicholas, L1 aTregouet, David1 aRidker, Paul, M1 aTang, Weihong1 aStrachan, David, P1 aHamsten, Anders1 aO'Donnell, Christopher, J1 aVTE Consortium1 aSTROKE Consortium1 aWellcome Trust Case Control Consortium 2 (WTCCC2)1 aC4D Consortium1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/615511004nas a2203505 4500008004100000022001400041245014700055210006900202260001300271300001300284490000600297520115200303653001801455653001601473653002001489653001601509653003001525653001101555653001701566653001801583653003401601653001101635653000901646653003601655653002401691653002401715653002001739100002301759700002301782700002101805700002101826700002101847700001901868700002801887700001601915700001801931700001601949700003101965700002101996700003002017700001802047700001502065700002102080700002302101700001902124700002002143700001902163700002202182700002002204700001802224700003202242700002502274700003002299700002302329700001902352700001902371700002202390700002202412700001902434700001802453700001902471700002202490700002302512700002302535700002202558700002402580700002102604700002202625700002202647700002602669700002302695700002202718700002302740700002402763700002202787700002202809700001202831700002502843700001802868700002802886700002402914700001802938700002502956700001902981700001603000700001903016700001903035700002503054700002503079700002603104700001903130700002003149700001703169700002403186700002003210700002303230700001603253700002003269700002203289700002803311700002103339700002403360700002003384700002303404700001803427700002203445700002103467700001903488700002603507700002203533700002803555700002003583700002803603700002703631700002003658700002303678700002003701700002103721700002403742700002003766700001503786700002803801700002603829700001903855700002803874700001903902700002503921700002403946700002703970700002003997700001404017700002004031700002204051700001904073700001804092700001804110700002104128700002004149700002204169700001604191700002204207700002204229700002604251700002604277700001704303700002004320700002304340700001904363700002304382700002004405700002304425700001904448700001804467700002304485700002504508700001904533700001904552700002004571700003004591700003504621700002104656700001704677700002104694700001904715700002504734700002404759700001804783700001504801700002404816700002204840700002504862700001504887700002304902700002004925700001904945700002204964700002004986700001805006700002205024700002005046700002105066700002105087700001705108700002105125700002005146700001605166700002105182700001905203700002505222700002405247700002305271700001905294700002205313700001805335700002005353700002005373700001905393700002105412700002405433700001805457700002005475700002105495700002005516700002505536700002105561700002105582700002405603700001805627700001605645700002105661700003705682700002205719700001805741700002005759700002105779700002005800700002605820700002305846700001905869700002005888700002305908700002405931700002005955700001905975700002005994700002406014700002506038700001906063700002106082700002106103700001806124700002106142700003006163700002006193700002306213700002206236700002006258700002806278700002206306700001906328700002406347700002206371700002006393700001906413700002306432700001506455700001706470700001506487700001806502700001906520700002706539700002306566700002206589700002106611700002206632700002206654700002306676700002506699700002106724700001906745700001806764700001906782700002106801700001906822700001806841700002906859700001906888700002106907700002306928700002006951700002106971700002206992700001907014700002307033700001807056700002007074700001907094700002107113700002607134700002407160700002307184700002107207700002307228700002507251700002207276700002407298700001107322700002007333700002507353700001907378700001807397710002307415710002407438856003607462 2013 eng d a1553-740400aSex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.0 aSexstratified genomewide association studies including 270000 in c2013 Jun ae10035000 v93 aGiven the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
10aAnthropometry10aBody Height10aBody Mass Index10aBody Weight10aBody Weights and Measures10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist Circumference10aWaist-Hip Ratio1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aKutalik, Zoltán1 aBerndt, Sonja, I1 aJackson, Anne, U1 aMonda, Keri, L1 aKilpeläinen, Tuomas, O1 aEsko, Tõnu1 aMägi, Reedik1 aLi, Shengxu1 aWorkalemahu, Tsegaselassie1 aFeitosa, Mary, F1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aFall, Tove1 aFerreira, Teresa1 aGustafsson, Stefan1 aLocke, Adam, E1 aMathieson, Iain1 aScherag, Andre1 aVedantam, Sailaja1 aWood, Andrew, R1 aLiang, Liming1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aDermitzakis, Emmanouil, T1 aDimas, Antigone, S1 aKarpe, Fredrik1 aMin, Josine, L1 aNicholson, George1 aClegg, Deborah, J1 aPerson, Thomas1 aKrohn, Jon, P1 aBauer, Sabrina1 aBuechler, Christa1 aEisinger, Kristina1 aBonnefond, Amélie1 aFroguel, Philippe1 aHottenga, Jouke-Jan1 aProkopenko, Inga1 aWaite, Lindsay, L1 aHarris, Tamara, B1 aSmith, Albert, Vernon1 aShuldiner, Alan, R1 aMcArdle, Wendy, L1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aGrönberg, Henrik1 aChen, Yii-Der Ida1 aLi, Guo1 aBeckmann, Jacques, S1 aJohnson, Toby1 aThorsteinsdottir, Unnur1 aTeder-Laving, Maris1 aKhaw, Kay-Tee1 aWareham, Nicholas, J1 aZhao, Jing Hua1 aAmin, Najaf1 aOostra, Ben, A1 aKraja, Aldi, T1 aProvince, Michael, A1 aCupples, Adrienne, L1 aHeard-Costa, Nancy, L1 aKaprio, Jaakko1 aRipatti, Samuli1 aSurakka, Ida1 aCollins, Francis, S1 aSaramies, Jouko1 aTuomilehto, Jaakko1 aJula, Antti1 aSalomaa, Veikko1 aErdmann, Jeanette1 aHengstenberg, Christian1 aLoley, Christina1 aSchunkert, Heribert1 aLamina, Claudia1 aWichmann, Erich, H1 aAlbrecht, Eva1 aGieger, Christian1 aHicks, Andrew, A1 aJohansson, Asa1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aSpeliotes, Elizabeth, K1 aPenninx, Brenda1 aHartikainen, Anna-Liisa1 aJarvelin, Marjo-Riitta1 aGyllensten, Ulf1 aBoomsma, Dorret, I1 aCampbell, Harry1 aWilson, James, F1 aChanock, Stephen, J1 aFarrall, Martin1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aRivadeneira, Fernando1 aEstrada, Karol1 aUitterlinden, André, G1 aHofman, Albert1 aZillikens, Carola, M1 aHeijer, Martin, den1 aKiemeney, Lambertus, A1 aMaschio, Andrea1 aHall, Per1 aTyrer, Jonathan1 aTeumer, Alexander1 aVölzke, Henry1 aKovacs, Peter1 aTönjes, Anke1 aMangino, Massimo1 aSpector, Tim, D1 aHayward, Caroline1 aRudan, Igor1 aHall, Alistair, S1 aSamani, Nilesh, J1 aAttwood, Antony, Paul1 aSambrook, Jennifer, G1 aHung, Joseph1 aPalmer, Lyle, J1 aLokki, Marja-Liisa1 aSinisalo, Juha1 aBoucher, Gabrielle1 aHuikuri, Heikki1 aLorentzon, Mattias1 aOhlsson, Claes1 aEklund, Niina1 aEriksson, Johan, G1 aBarlassina, Cristina1 aRivolta, Carlo1 aNolte, Ilja, M1 aSnieder, Harold1 avan der Klauw, Melanie, M1 avan Vliet-Ostaptchouk, Jana, V1 aGejman, Pablo, V1 aShi, Jianxin1 aJacobs, Kevin, B1 aWang, Zhaoming1 aBakker, Stephan, J L1 aLeach, Irene, Mateo1 aNavis, Gerjan1 aHarst, Pim1 aMartin, Nicholas, G1 aMedland, Sarah, E1 aMontgomery, Grant, W1 aYang, Jian1 aChasman, Daniel, I1 aRidker, Paul, M1 aRose, Lynda, M1 aLehtimäki, Terho1 aRaitakari, Olli1 aAbsher, Devin1 aIribarren, Carlos1 aBasart, Hanneke1 aHovingh, Kees, G1 aHyppönen, Elina1 aPower, Chris1 aAnderson, Denise1 aBeilby, John, P1 aHui, Jennie1 aJolley, Jennifer1 aSager, Hendrik1 aBornstein, Stefan, R1 aSchwarz, Peter, E H1 aKristiansson, Kati1 aPerola, Markus1 aLindström, Jaana1 aSwift, Amy, J1 aUusitupa, Matti1 aAtalay, Mustafa1 aLakka, Timo, A1 aRauramaa, Rainer1 aBolton, Jennifer, L1 aFowkes, Gerry1 aFraser, Ross, M1 aPrice, Jackie, F1 aFischer, Krista1 aKov, Kaarel, Krjutå1 aMetspalu, Andres1 aMihailov, Evelin1 aLangenberg, Claudia1 aLuan, Jian'an1 aOng, Ken, K1 aChines, Peter, S1 aKeinanen-Kiukaanniemi, Sirkka, M1 aSaaristo, Timo, E1 aEdkins, Sarah1 aFranks, Paul, W1 aHallmans, Göran1 aShungin, Dmitry1 aMorris, Andrew, David1 aPalmer, Colin, N A1 aErbel, Raimund1 aMoebus, Susanne1 aNöthen, Markus, M1 aPechlivanis, Sonali1 aHveem, Kristian1 aNarisu, Narisu1 aHamsten, Anders1 aHumphries, Steve, E1 aStrawbridge, Rona, J1 aTremoli, Elena1 aGrallert, Harald1 aThorand, Barbara1 aIllig, Thomas1 aKoenig, Wolfgang1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aBoehm, Bernhard, O1 aKleber, Marcus, E1 aMärz, Winfried1 aWinkelmann, Bernhard, R1 aKuusisto, Johanna1 aLaakso, Markku1 aArveiler, Dominique1 aCesana, Giancarlo1 aKuulasmaa, Kari1 aVirtamo, Jarmo1 aYarnell, John, W G1 aKuh, Diana1 aWong, Andrew1 aLind, Lars1 ade Faire, Ulf1 aGigante, Bruna1 aMagnusson, Patrik, K E1 aPedersen, Nancy, L1 aDedoussis, George1 aDimitriou, Maria1 aKolovou, Genovefa1 aKanoni, Stavroula1 aStirrups, Kathleen1 aBonnycastle, Lori, L1 aNjølstad, Inger1 aWilsgaard, Tom1 aGanna, Andrea1 aRehnberg, Emil1 aHingorani, Aroon1 aKivimaki, Mika1 aKumari, Meena1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David1 aIngelsson, Erik1 aKaplan, Robert1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aStrachan, David, P1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAbecasis, Goncalo, R1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aQi, Lu1 aLoos, Ruth, J F1 aLindgren, Cecilia, M1 aNorth, Kari, E1 aHeid, Iris, M1 aDIAGRAM Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/602805870nas a2201489 4500008004100000022001400041245013500055210006900190260001600259300001000275490000700285520175700292653001502049653001002064653001602074653000902090653001902099653001902118653001102137653001602148653001602164100002202180700001402202700001902216700002302235700002002258700001702278700001702295700002002312700002002332700002102352700002602373700003102399700001702430700001502447700002002462700001802482700002302500700001502523700001802538700002202556700002602578700001802604700002802622700001902650700001702669700001702686700002702703700001802730700001902748700001602767700002102783700002102804700001902825700002402844700002002868700002102888700002202909700002202931700002002953700001902973700001902992700002303011700002003034700001803054700002103072700002203093700002203115700001203137700001703149700001503166700002403181700001803205700002303223700002703246700002303273700002003296700002203316700002303338700001803361700002603379700001903405700001803424700002103442700002403463700002103487700002803508700002203536700003003558700002703588700003203615700001703647700001903664700001803683700002003701700001403721700002103735700002003756700002603776700001603802700002303818700002203841700002003863700001703883700002003900700002003920700001903940700002003959700001903979700001803998700001504016700002504031700002004056700002004076700002004096700002404116700001704140700001904157700002004176700002204196700002304218700003004241700002604271700002004297710002704317856003604344 2014 eng d a1537-660500aGene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.0 aGeneage interactions in blood pressure regulation a largescale i c2014 Jul 03 a24-380 v953 aAlthough age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.
10aAdolescent10aAdult10aAge Factors10aAged10aBlood Pressure10aCohort Studies10aHumans10aMiddle Aged10aYoung Adult1 aSimino, Jeannette1 aShi, Gang1 aBis, Joshua, C1 aChasman, Daniel, I1 aEhret, Georg, B1 aGu, Xiangjun1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aSijbrands, Eric1 aSmith, Albert, V1 aVerwoert, Germaine, C1 aBragg-Gresham, Jennifer, L1 aCadby, Gemma1 aChen, Peng1 aCheng, Ching-Yu1 aCorre, Tanguy1 ade Boer, Rudolf, A1 aGoel, Anuj1 aJohnson, Toby1 aKhor, Chiea-Chuen1 aLluís-Ganella, Carla1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aSim, Xueling1 aSõber, Siim1 avan der Most, Peter, J1 aVerweij, Niek1 aZhao, Jing Hua1 aAmin, Najaf1 aBoerwinkle, Eric1 aBouchard, Claude1 aDehghan, Abbas1 aEiriksdottir, Gudny1 aElosua, Roberto1 aFranco, Oscar, H1 aGieger, Christian1 aHarris, Tamara, B1 aHercberg, Serge1 aHofman, Albert1 aJames, Alan, L1 aJohnson, Andrew, D1 aKähönen, Mika1 aKhaw, Kay-Tee1 aKutalik, Zoltán1 aLarson, Martin, G1 aLauner, Lenore, J1 aLi, Guo1 aLiu, Jianjun1 aLiu, Kiang1 aMorrison, Alanna, C1 aNavis, Gerjan1 aOng, Rick Twee-Hee1 aPapanicolau, George, J1 aPenninx, Brenda, W1 aPsaty, Bruce, M1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRice, Kenneth1 aRivadeneira, Fernando1 aRose, Lynda, M1 aSanna, Serena1 aScott, Robert, A1 aSiscovick, David, S1 aStolk, Ronald, P1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Klauw, Melanie, M1 aVasan, Ramachandran, S1 aVithana, Eranga, Nishanthie1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Hugh1 aYoung, Terri, L1 aAung, Tin1 aBochud, Murielle1 aFarrall, Martin1 aHartman, Catharina, A1 aLaan, Maris1 aLakatta, Edward, G1 aLehtimäki, Terho1 aLoos, Ruth, J F1 aLucas, Gavin1 aMeneton, Pierre1 aPalmer, Lyle, J1 aRettig, Rainer1 aSnieder, Harold1 aTai, Shyong, E1 aTeo, Yik-Ying1 aHarst, Pim1 aWareham, Nicholas, J1 aWijmenga, Cisca1 aWong, Tien, Yin1 aFornage, Myriam1 aGudnason, Vilmundur1 aLevy, Daniel1 aPalmas, Walter1 aRidker, Paul, M1 aRotter, Jerome, I1 aDuijn, Cornelia, M1 aWitteman, Jacqueline, C M1 aChakravarti, Aravinda1 aRao, Dabeeru, C1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/659907147nas a2202257 4500008004100000022001400041245010000055210006900155260001300224300001100237490000700248520092000255653001901175653002301194653002201217653002901239653001701268653003801285653001801323653003401341653001101375653001801386653002701404653003601431653001401467653002801481653003101509653001501540653001901555100001801574700002601592700002001618700002001638700002301658700001601681700002301697700002601720700001501746700002101761700002001782700002301802700001901825700002501844700002201869700002601891700002501917700001901942700001801961700001901979700002001998700002202018700001802040700002002058700001702078700002402095700003102119700001902150700001902169700002002188700001502208700001802223700002202241700002002263700002002283700001202303700001902315700001602334700002102350700001902371700002202390700001902412700002402431700001602455700001702471700001902488700002002507700002402527700002002551700001802571700001802589700002102607700002702628700001702655700001702672700002702689700001902716700002202735700001702757700002002774700002102794700001802815700001902833700001902852700002002871700002602891700001902917700001902936700002402955700002402979700002203003700001303025700002203038700002003060700002103080700001903101700001903120700001803139700002003157700002003177700001703197700002503214700002803239700002003267700002303287700002203310700001503332700001803347700002303365700001603388700002603404700001703430700001603447700001703463700001903480700002303499700001903522700002003541700002403561700002003585700002103605700002103626700002103647700002203668700001903690700002003709700002103729700002203750700001903772700002003791700002003811700002203831700001803853700002803871700002403899700001703923700002803940700002403968700002103992700001904013700001904032700002204051700001804073700002204091700001904113700001804132700002304150700002504173700002004198700001904218700002404237700001904261700001604280700001904296700002204315700001804337700001904355700001704374700002704391700002104418700001504439700002304454700002204477700002404499700001704523700002504540700002104565700001704586700001904603700002204622700001704644700002404661700002504685700001704710700002204727700001904749700001704768700002204785700002104807700002504828856003604853 2014 eng d a1546-171800aGenome-wide association analysis identifies six new loci associated with forced vital capacity.0 aGenomewide association analysis identifies six new loci associat c2014 Jul a669-770 v463 aForced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
10aCohort Studies10aDatabases, Genetic10aFollow-Up Studies10aForced Expiratory Volume10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLung Diseases10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aPrognosis10aQuantitative Trait Loci10aRespiratory Function Tests10aSpirometry10aVital Capacity1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aWain, Louise, V1 aFranceschini, Nora1 aKoch, Beate1 aPottinger, Tess, D1 aSmith, Albert, Vernon1 aDuan, Qing1 aOldmeadow, Chris1 aLee, Mi, Kyeong1 aStrachan, David, P1 aJames, Alan, L1 aHuffman, Jennifer, E1 aVitart, Veronique1 aRamasamy, Adaikalavan1 aWareham, Nicholas, J1 aKaprio, Jaakko1 aWang, Xin-Qun1 aTrochet, Holly1 aKähönen, Mika1 aFlexeder, Claudia1 aAlbrecht, Eva1 aLopez, Lorna, M1 ade Jong, Kim1 aThyagarajan, Bharat1 aAlves, Alexessander, Couto1 aEnroth, Stefan1 aOmenaas, Ernst1 aJoshi, Peter, K1 aFall, Tove1 aViñuela, Ana1 aLauner, Lenore, J1 aLoehr, Laura, R1 aFornage, Myriam1 aLi, Guo1 aWilk, Jemma, B1 aTang, Wenbo1 aManichaikul, Ani1 aLahousse, Lies1 aHarris, Tamara, B1 aNorth, Kari, E1 aRudnicka, Alicja, R1 aHui, Jennie1 aGu, Xiangjun1 aLumley, Thomas1 aWright, Alan, F1 aHastie, Nicholas, D1 aCampbell, Susan1 aKumar, Rajesh1 aPin, Isabelle1 aScott, Robert, A1 aPietiläinen, Kirsi, H1 aSurakka, Ida1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aSchulz, Holger1 aHeinrich, Joachim1 aDavies, Gail1 aVonk, Judith, M1 aWojczynski, Mary1 aPouta, Anneli1 aJohansson, Asa1 aWild, Sarah, H1 aIngelsson, Erik1 aRivadeneira, Fernando1 aVölzke, Henry1 aHysi, Pirro, G1 aEiriksdottir, Gudny1 aMorrison, Alanna, C1 aRotter, Jerome, I1 aGao, Wei1 aPostma, Dirkje, S1 aWhite, Wendy, B1 aRich, Stephen, S1 aHofman, Albert1 aAspelund, Thor1 aCouper, David1 aSmith, Lewis, J1 aPsaty, Bruce, M1 aLohman, Kurt1 aBurchard, Esteban, G1 aUitterlinden, André, G1 aGarcia, Melissa1 aJoubert, Bonnie, R1 aMcArdle, Wendy, L1 aMusk, Bill1 aHansel, Nadia1 aHeckbert, Susan, R1 aZgaga, Lina1 avan Meurs, Joyce, B J1 aNavarro, Pau1 aRudan, Igor1 aOh, Yeon-Mok1 aRedline, Susan1 aJarvis, Deborah, L1 aZhao, Jing Hua1 aRantanen, Taina1 aO'Connor, George, T1 aRipatti, Samuli1 aScott, Rodney, J1 aKarrasch, Stefan1 aGrallert, Harald1 aGaddis, Nathan, C1 aStarr, John, M1 aWijmenga, Cisca1 aMinster, Ryan, L1 aLederer, David, J1 aPekkanen, Juha1 aGyllensten, Ulf1 aCampbell, Harry1 aMorris, Andrew, P1 aGläser, Sven1 aHammond, Christopher, J1 aBurkart, Kristin, M1 aBeilby, John1 aKritchevsky, Stephen, B1 aGudnason, Vilmundur1 aHancock, Dana, B1 aWilliams, Dale1 aPolasek, Ozren1 aZemunik, Tatijana1 aKolcic, Ivana1 aPetrini, Marcy, F1 aWjst, Matthias1 aKim, Woo, Jin1 aPorteous, David, J1 aScotland, Generation1 aSmith, Blair, H1 aViljanen, Anne1 aHeliövaara, Markku1 aAttia, John, R1 aSayers, Ian1 aHampel, Regina1 aGieger, Christian1 aDeary, Ian, J1 aBoezen, Marike1 aNewman, Anne1 aJarvelin, Marjo-Riitta1 aWilson, James, F1 aLind, Lars1 aStricker, Bruno, H1 aTeumer, Alexander1 aSpector, Timothy, D1 aMelén, Erik1 aPeters, Marjolein, J1 aLange, Leslie, A1 aBarr, Graham1 aBracke, Ken, R1 aVerhamme, Fien, M1 aSung, Joohon1 aHiemstra, Pieter, S1 aCassano, Patricia, A1 aSood, Akshay1 aHayward, Caroline1 aDupuis, Josée1 aHall, Ian, P1 aBrusselle, Guy, G1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/658206926nas a2201669 4500008004100000022001400041245011700055210006900172260001300241300001300254490000700267520222800274653001902502653001702521653003402538653001902572653002202591653001102613653002202624653001702646653002802663653001602691100001802707700002002725700002002745700002202765700002202787700002302809700001802832700001902850700002302869700002302892700001602915700002502931700002802956700002302984700002503007700002003032700001803052700001703070700001803087700002303105700002403128700001703152700001703169700002003186700001903206700002203225700001803247700001903265700002003284700001903304700001903323700002603342700002203368700002403390700001203414700001803426700001803444700002203462700002003484700002403504700002003528700002503548700001503573700001803588700002503606700002603631700001803657700002503675700002303700700002503723700001503748700001703763700002203780700001603802700002503818700002603843700002403869700002003893700002103913700001903934700002203953700001603975700001603991700002104007700001604028700002104044700002504065700001904090700001904109700002504128700002304153700002204176700002304198700001804221700002104239700002804260700001604288700002304304700001904327700001804346700001804364700002304382700002304405700002204428700001904450700001804469700002004487700002004507700001904527700001904546700002404565700002504589700002004614700002404634700002704658700002704685700002404712700003904736700002504775700002304800700002104823700002304844700002404867700002704891700002604918700002804944700001904972700002304991700002405014700002005038700002405058700002105082700001905103700001805122700002105140700001805161700001905179700002205198856003605220 2014 eng d a1553-740400aIdentification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.0 aIdentification of novel genetic Loci associated with thyroid per c2014 Feb ae10041230 v103 aAutoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
10aAutoantibodies10aGenetic Loci10aGenome-Wide Association Study10aGraves Disease10aHashimoto Disease10aHumans10aIodide Peroxidase10aRisk Factors10aThyroiditis, Autoimmune10aThyrotropin1 aMedici, Marco1 aPorcu, Eleonora1 aPistis, Giorgio1 aTeumer, Alexander1 aBrown, Suzanne, J1 aJensen, Richard, A1 aRawal, Rajesh1 aRoef, Greet, L1 aPlantinga, Theo, S1 aVermeulen, Sita, H1 aLahti, Jari1 aSimmonds, Matthew, J1 aHusemoen, Lise, Lotte N1 aFreathy, Rachel, M1 aShields, Beverley, M1 aPietzner, Diana1 aNagy, Rebecca1 aBroer, Linda1 aChaker, Layal1 aKorevaar, Tim, I M1 aPlia, Maria, Grazia1 aSala, Cinzia1 aVölker, Uwe1 aRichards, Brent1 aSweep, Fred, C1 aGieger, Christian1 aCorre, Tanguy1 aKajantie, Eero1 aThuesen, Betina1 aTaes, Youri, E1 aVisser, Edward1 aHattersley, Andrew, T1 aKratzsch, Jürgen1 aHamilton, Alexander1 aLi, Wei1 aHomuth, Georg1 aLobina, Monia1 aMariotti, Stefano1 aSoranzo, Nicole1 aCocca, Massimiliano1 aNauck, Matthias1 aSpielhagen, Christin1 aRoss, Alec1 aArnold, Alice1 avan de Bunt, Martijn1 aLiyanarachchi, Sandya1 aHeier, Margit1 aGrabe, Hans, Jörgen1 aMasciullo, Corrado1 aGalesloot, Tessel, E1 aLim, Ee, M1 aReischl, Eva1 aLeedman, Peter, J1 aLai, Sandra1 aDelitala, Alessandro1 aBremner, Alexandra, P1 aPhilips, David, I W1 aBeilby, John, P1 aMulas, Antonella1 aVocale, Matteo1 aAbecasis, Goncalo1 aForsen, Tom1 aJames, Alan1 aWiden, Elisabeth1 aHui, Jennie1 aProkisch, Holger1 aRietzschel, Ernst, E1 aPalotie, Aarno1 aFeddema, Peter1 aFletcher, Stephen, J1 aSchramm, Katharina1 aRotter, Jerome, I1 aKluttig, Alexander1 aRadke, Dörte1 aTraglia, Michela1 aSurdulescu, Gabriela, L1 aHe, Huiling1 aFranklyn, Jayne, A1 aTiller, Daniel1 aVaidya, Bijay1 aDe Meyer, Tim1 aJørgensen, Torben1 aEriksson, Johan, G1 aO'Leary, Peter, C1 aWichmann, Eric1 aHermus, Ad, R1 aPsaty, Bruce, M1 aIttermann, Till1 aHofman, Albert1 aBosi, Emanuele1 aSchlessinger, David1 aWallaschofski, Henri1 aPirastu, Nicola1 aAulchenko, Yurii, S1 ade la Chapelle, Albert1 aNetea-Maier, Romana, T1 aGough, Stephen, C L1 aSchwabedissen, Henriette, Meyer Zu1 aFrayling, Timothy, M1 aKaufman, Jean-Marc1 aLinneberg, Allan1 aRäikkönen, Katri1 aSmit, Johannes, W A1 aKiemeney, Lambertus, A1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWalsh, John, P1 aMeisinger, Christa1 aHeijer, Martin, den1 aVisser, Theo, J1 aSpector, Timothy, D1 aWilson, Scott, G1 aVölzke, Henry1 aCappola, Anne1 aToniolo, Daniela1 aSanna, Serena1 aNaitza, Silvia1 aPeeters, Robin, P uhttps://chs-nhlbi.org/node/629405294nas a2201225 4500008004100000022001400041245011300055210006900168260000900237300001200246490000600258520192600264653001002190653003202200653001102232653003102243653001702274653003402291653001102325653002502336653000902361653001602370100001602386700002102402700001802423700002602441700002302467700001702490700002002507700002102527700002002548700002402568700002302592700002202615700002102637700002202658700002402680700002302704700001802727700002402745700002302769700001702792700002202809700002102831700001902852700001702871700001802888700001902906700001502925700001902940700002302959700001302982700001802995700001703013700002103030700002203051700001903073700001903092700002003111700001603131700002103147700001603168700002803184700001803212700001903230700001203249700001503261700002203276700001703298700001703315700001903332700002203351700001903373700002203392700002403414700001503438700001903453700002003472700002903492700002003521700002603541700002203567700001903589700002003608700001703628700001903645700002303664700002203687700002803709700001903737700001903756700002003775700002103795700001903816700001903835700002303854700002303877700002503900700002003925700002103945700002403966700001703990700002504007856003604032 2014 eng d a1932-620300aLarge-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.0 aLargescale genomewide association studies and metaanalyses of lo c2014 ae1007760 v93 aBACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
10aAdult10aChromosomes, Human, Pair 1110aFemale10aGene Expression Regulation10aGenetic Loci10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aMale10aRespiration1 aTang, Wenbo1 aKowgier, Matthew1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aJoubert, Bonnie, R1 aHodge, Emily1 aGharib, Sina, A1 aSmith, Albert, V1 aRuczinski, Ingo1 aGudnason, Vilmundur1 aMathias, Rasika, A1 aHarris, Tamara, B1 aHansel, Nadia, N1 aLauner, Lenore, J1 aBarnes, Kathleen, C1 aHansen, Joyanna, G1 aAlbrecht, Eva1 aAldrich, Melinda, C1 aAllerhand, Michael1 aBarr, Graham1 aBrusselle, Guy, G1 aCouper, David, J1 aCurjuric, Ivan1 aDavies, Gail1 aDeary, Ian, J1 aDupuis, Josée1 aFall, Tove1 aFoy, Millennia1 aFranceschini, Nora1 aGao, Wei1 aGläser, Sven1 aGu, Xiangjun1 aHancock, Dana, B1 aHeinrich, Joachim1 aHofman, Albert1 aImboden, Medea1 aIngelsson, Erik1 aJames, Alan1 aKarrasch, Stefan1 aKoch, Beate1 aKritchevsky, Stephen, B1 aKumar, Ashish1 aLahousse, Lies1 aLi, Guo1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLohman, Kurt1 aLumley, Thomas1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMusk, Bill1 aNorth, Kari, E1 aPalmer, Lyle, J1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchulz, Holger1 aSmith, Lewis, J1 aSood, Akshay1 aStarr, John, M1 aStrachan, David, P1 aTeumer, Alexander1 aUitterlinden, André, G1 aVölzke, Henry1 aVoorman, Arend1 aWain, Louise, V1 aWells, Martin, T1 aWilk, Jemma, B1 aWilliams, Dale1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aLondon, Stephanie, J1 aFornage, Myriam1 aTobin, Martin, D1 aO'Connor, George, T1 aHall, Ian, P1 aCassano, Patricia, A uhttps://chs-nhlbi.org/node/660405936nas a2201453 4500008004100000022001400041245016600055210006900221260000900290300001200299490000600311520182200317653002102139653002002160653001502180653003302195653001302228653001102241653001202252100001802264700001502282700002202297700002502319700002202344700001902366700002002385700002002405700002002425700002202445700001802467700002402485700002302509700002402532700002002556700001602576700002002592700002202612700002502634700002902659700001902688700001702707700001602724700002002740700002402760700002502784700001802809700001802827700001902845700001802864700002102882700002002903700001502923700001802938700003002956700002102986700001703007700002003024700001903044700001903063700003003082700002503112700001903137700001703156700002403173700001803197700001903215700001803234700002203252700001403274700001903288700002403307700002103331700002703352700001803379700002603397700001903423700002403442700002303466700002803489700002603517700002303543700002303566700002103589700002003610700002603630700002003656700002103676700002503697700002503722700001703747700002103764700001903785700002403804700002203828700002103850700002103871700001903892700001503911700002003926700001903946700002103965700002803986700002004014700001704034700002504051700002004076700002304096700001904119700001904138700002004157700002104177700001904198700001904217700002004236700001904256700001804275700002504293700003204318700003004350700002304380700002004403700002304423856003604446 2014 eng d a1932-620300aNo evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.0 aNo evidence for genomewide interactions on plasma fibrinogen by c2014 ae1111560 v93 aPlasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
10aAlcohol Drinking10aBody Mass Index10aFibrinogen10aGene-Environment Interaction10aGenomics10aHumans10aSmoking1 aBaumert, Jens1 aHuang, Jie1 aMcKnight, Barbara1 aSabater-Lleal, Maria1 aSteri, Maristella1 aChu, Audrey, Y1 aTrompet, Stella1 aLopez, Lorna, M1 aFornage, Myriam1 aTeumer, Alexander1 aTang, Weihong1 aRudnicka, Alicja, R1 aMälarstig, Anders1 aHottenga, Jouke-Jan1 aKavousi, Maryam1 aLahti, Jari1 aTanaka, Toshiko1 aHayward, Caroline1 aHuffman, Jennifer, E1 aMorange, Pierre-Emmanuel1 aRose, Lynda, M1 aBasu, Saonli1 aRumley, Ann1 aStott, David, J1 aBuckley, Brendan, M1 ade Craen, Anton, J M1 aSanna, Serena1 aMasala, Marco1 aBiffar, Reiner1 aHomuth, Georg1 aSilveira, Angela1 aSennblad, Bengt1 aGoel, Anuj1 aWatkins, Hugh1 aMüller-Nurasyid, Martina1 aRückerl, Regina1 aTaylor, Kent1 aChen, Ming-Huei1 aGeus, Eco, J C1 aHofman, Albert1 aWitteman, Jacqueline, C M1 ade Maat, Moniek, P M1 aPalotie, Aarno1 aDavies, Gail1 aSiscovick, David, S1 aKolcic, Ivana1 aWild, Sarah, H1 aSong, Jaejoon1 aMcArdle, Wendy, L1 aFord, Ian1 aSattar, Naveed1 aSchlessinger, David1 aGrotevendt, Anne1 aFranzosi, Maria Grazia1 aIllig, Thomas1 aWaldenberger, Melanie1 aLumley, Thomas1 aTofler, Geoffrey, H1 aWillemsen, Gonneke1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aRäikkönen, Katri1 aChasman, Daniel, I1 aFolsom, Aaron, R1 aLowe, Gordon, D1 aWestendorp, Rudi, G J1 aSlagboom, Eline1 aCucca, Francesco1 aWallaschofski, Henri1 aStrawbridge, Rona, J1 aSeedorf, Udo1 aKoenig, Wolfgang1 aBis, Joshua, C1 aMukamal, Kenneth, J1 avan Dongen, Jenny1 aWiden, Elisabeth1 aFranco, Oscar, H1 aStarr, John, M1 aLiu, Kiang1 aFerrucci, Luigi1 aPolasek, Ozren1 aWilson, James, F1 aOudot-Mellakh, Tiphaine1 aCampbell, Harry1 aNavarro, Pau1 aBandinelli, Stefania1 aEriksson, Johan1 aBoomsma, Dorret, I1 aDehghan, Abbas1 aClarke, Robert1 aHamsten, Anders1 aBoerwinkle, Eric1 aJukema, Wouter1 aNaitza, Silvia1 aRidker, Paul, M1 aVölzke, Henry1 aDeary, Ian, J1 aReiner, Alexander, P1 aTrégouët, David-Alexandre1 aO'Donnell, Christopher, J1 aStrachan, David, P1 aPeters, Annette1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/666704953nas a2201105 4500008004100000022001400041245009300055210006900148260001500217300001200232490000700244520183400251653001002085653000902095653002202104653003702126653002402163653002302187653003102210653001102241653004002252653001102292653002002303653003802323653002502361653001102386653001002397653000902407653001602416653003602432653002602468100002202494700002402516700001902540700001902559700002002578700001202598700002202610700002302632700001802655700002202673700001802695700001902713700002102732700003002753700001902783700002202802700001902824700002302843700001702866700002402883700001402907700002102921700002202942700001902964700001902983700001903002700002203021700001903043700002203062700002503084700002203109700002203131700002203153700002003175700002003195700001903215700002203234700002603256700002303282700002203305700002003327700002003347700002403367700002303391700002803414700002603442700001703468700001903485700002403504700002203528700002403550700002203574700002003596700001603616700002503632700002303657700002203680700002303702700001903725700001903744700002403763700002403787856003603811 2014 eng d a1558-359700aNovel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.0 aNovel genetic markers associate with atrial fibrillation risk in c2014 Apr 1 a1200-100 v633 aOBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factors1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aLin, Honghuang1 aArking, Dan, E1 aTrompet, Stella1 aLi, Guo1 aKrijthe, Bouwe, P1 aChasman, Daniel, I1 aBarnard, John1 aKleber, Marcus, E1 aDörr, Marcus1 aOzaki, Kouichi1 aSmith, Albert, V1 aMüller-Nurasyid, Martina1 aWalter, Stefan1 aAgarwal, Sunil, K1 aBis, Joshua, C1 aBrody, Jennifer, A1 aChen, Lin, Y1 aEverett, Brendan, M1 aFord, Ian1 aFranco, Oscar, H1 aHarris, Tamara, B1 aHofman, Albert1 aKääb, Stefan1 aMahida, Saagar1 aKathiresan, Sekar1 aKubo, Michiaki1 aLauner, Lenore, J1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aMcKnight, Barbara1 aMcManus, David, D1 aPeters, Annette1 aPsaty, Bruce, M1 aRose, Lynda, M1 aRotter, Jerome, I1 aSilbernagel, Guenther1 aSmith, Jonathan, D1 aSotoodehnia, Nona1 aStott, David, J1 aTaylor, Kent, D1 aTomaschitz, Andreas1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aMurabito, Joanne, M1 aSinner, Moritz, F1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aMärz, Winfried1 aChung, Mina1 aAlbert, Christine, M1 aStricker, Bruno, H1 aTanaka, Toshihiro1 aHeckbert, Susan, R1 aJukema, Wouter1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/682003608nas a2200601 4500008004100000022001400041245013800055210006900193260001300262300001200275490000700287520190900294653001002203653000902213653002202222653001902244653002102263653001102284653001102295653001902306653001402325653000902339653001602348653001502364653001402379653001702393653003002410653003002440653001602470100002102486700002202507700002102529700002202550700001902572700002202591700002402613700002302637700002602660700002102686700002602707700002002733700001802753700002502771700002002796700002102816700001802837700001902855700001902874700002202893700002102915710003402936856003602970 2014 eng d a1945-719700aThyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.0 aThyroid antibody status subclinical hypothyroidism and the risk c2014 Sep a3353-620 v993 aCONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk.
OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs).
DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes.
DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events.
DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status.
CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.
10aAdult10aAged10aAged, 80 and over10aAutoantibodies10aCoronary Disease10aFemale10aHumans10aHypothyroidism10aIncidence10aMale10aMiddle Aged10aPrevalence10aPrognosis10aRisk Factors10aSeroepidemiologic Studies10aSeverity of Illness Index10aYoung Adult1 aCollet, Tinh-Hai1 aBauer, Douglas, C1 aCappola, Anne, R1 aAsvold, Bjørn, O1 aWeiler, Stefan1 aVittinghoff, Eric1 aGussekloo, Jacobijn1 aBremner, Alexandra1 aElzen, Wendy, P J den1 aMaciel, Rui, M B1 aVanderpump, Mark, P J1 aCornuz, Jacques1 aDörr, Marcus1 aWallaschofski, Henri1 aNewman, Anne, B1 aSgarbi, José, A1 aRazvi, Salman1 aVölzke, Henry1 aWalsh, John, P1 aAujesky, Drahomir1 aRodondi, Nicolas1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/655303870nas a2200721 4500008004100000022001400041245012000055210006900175260001300244300001200257490000800269520185000277653001002127653002602137653001102163653001102174653001902185653001402204653000902218653001702227653001102244653001602255100001802271700002702289700002602316700002002342700002002362700002102382700002502403700001902428700002602447700002102473700001902494700002902513700001802542700002102560700002002581700001402601700002302615700002202638700002002660700002002680700002302700700002102723700002302744700002102767700002402788700001902812700001902831700002302850700002202873700001902895700001802914700001802932700002102950700001902971700002102990700002403011700002103035700002203056710003403078856003603112 2015 eng d a1945-719700aSubclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis.0 aSubclinical Hypothyroidism and the Risk of Stroke Events and Fat c2015 Jun a2181-910 v1003 aOBJECTIVE: The objective was to determine the risk of stroke associated with subclinical hypothyroidism.
DATA SOURCES AND STUDY SELECTION: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels.
DATA EXTRACTION AND SYNTHESIS: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations.
CONCLUSIONS: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.
10aAdult10aAsymptomatic Diseases10aFemale10aHumans10aHypothyroidism10aIncidence10aMale10aRisk Factors10aStroke10aThyrotropin1 aChaker, Layal1 aBaumgartner, Christine1 aElzen, Wendy, P J den1 aIkram, Arfan, M1 aBlum, Manuel, R1 aCollet, Tinh-Hai1 aBakker, Stephan, J L1 aDehghan, Abbas1 aDrechsler, Christiane1 aLuben, Robert, N1 aHofman, Albert1 aPortegies, Marileen, L P1 aMedici, Marco1 aIervasi, Giorgio1 aStott, David, J1 aFord, Ian1 aBremner, Alexandra1 aWanner, Christoph1 aFerrucci, Luigi1 aNewman, Anne, B1 aDullaart, Robin, P1 aSgarbi, José, A1 aCeresini, Graziano1 aMaciel, Rui, M B1 aWestendorp, Rudi, G1 aJukema, Wouter1 aImaizumi, Misa1 aFranklyn, Jayne, A1 aBauer, Douglas, C1 aWalsh, John, P1 aRazvi, Salman1 aKhaw, Kay-Tee1 aCappola, Anne, R1 aVölzke, Henry1 aFranco, Oscar, H1 aGussekloo, Jacobijn1 aRodondi, Nicolas1 aPeeters, Robin, P1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/680004076nas a2200553 4500008004100000022001400041245013600055210006900191260001300260300001200273490000800285520245400293653001902747653002102766653001102787653001902798653001602817100002202833700002002855700001802875700002202893700002302915700002102938700002302959700002602982700002003008700002103028700002303049700002403072700002103096700001903117700002503136700001803161700002103179700002003200700002203220700002003242700001803262700002103280700002003301700002003321700002603341700001903367700001903386700002603405700002103431710003403452856003603486 2015 eng d a2168-611400aThyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts.0 aThyroid function within the normal range and risk of coronary he c2015 Jun a1037-470 v1753 aIMPORTANCE: Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD).
OBJECTIVE: To assess the association between differences in thyroid function within the reference range and CHD risk.
DESIGN, SETTING, AND PARTICIPANTS: Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline.
EXPOSURES: Thyroid function as expressed by serum thyrotropin levels at baseline.
MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status.
RESULTS: Among 55,412 individuals, 1813 people (3.3%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results.
CONCLUSIONS AND RELEVANCE: Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.
10aCohort Studies10aCoronary Disease10aHumans10aHypothyroidism10aThyrotropin1 aAsvold, Bjørn, O1 aVatten, Lars, J1 aBjøro, Trine1 aBauer, Douglas, C1 aBremner, Alexandra1 aCappola, Anne, R1 aCeresini, Graziano1 aElzen, Wendy, P J den1 aFerrucci, Luigi1 aFranco, Oscar, H1 aFranklyn, Jayne, A1 aGussekloo, Jacobijn1 aIervasi, Giorgio1 aImaizumi, Misa1 aKearney, Patricia, M1 aKhaw, Kay-Tee1 aMaciel, Rui, M B1 aNewman, Anne, B1 aPeeters, Robin, P1 aPsaty, Bruce, M1 aRazvi, Salman1 aSgarbi, José, A1 aStott, David, J1 aTrompet, Stella1 aVanderpump, Mark, P J1 aVölzke, Henry1 aWalsh, John, P1 aWestendorp, Rudi, G J1 aRodondi, Nicolas1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/679805079nas a2201093 4500008004100000022001400041245015000055210006900205260000900274300001300283490000700296520193900303653000902242653001902251653002502270653002802295653001102323653003802334653003402372653001102406653000902417653001602426653002602442653003602468653002402504100001902528700001902547700002202566700002602588700002402614700002502638700002002663700002302683700001902706700001702725700002402742700002002766700002202786700002102808700002802829700002302857700001402880700001802894700002002912700002802932700002402960700002702984700002303011700001903034700001903053700002303072700002203095700002403117700002303141700002003164700002403184700002303208700001803231700002403249700002103273700002403294700002003318700001603338700001503354700002203369700001903391700002003410700001903430700001703449700002203466700001903488700002603507700001903533700002003552700001803572700002403590700001703614700002003631700002603651700002203677700001703699700001703716700001803733700001903751700001903770700002003789700002403809700002103833700002403854700002003878700002103898700003003919856003603949 2016 eng d a1932-620300aGenome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.0 aGenomeWide Association Study for Incident Myocardial Infarction c2016 ae01449970 v113 aBACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).
CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
10aAged10aCohort Studies10aCooperative Behavior10aCoronary Artery Disease10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies1 aDehghan, Abbas1 aBis, Joshua, C1 aWhite, Charles, C1 aSmith, Albert, Vernon1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aTrompet, Stella1 aChasman, Daniel, I1 aLumley, Thomas1 aVölker, Uwe1 aBuckley, Brendan, M1 aDing, Jingzhong1 aJensen, Majken, K1 aFolsom, Aaron, R1 aKritchevsky, Stephen, B1 aGirman, Cynthia, J1 aFord, Ian1 aDörr, Marcus1 aSalomaa, Veikko1 aUitterlinden, André, G1 aEiriksdottir, Gudny1 aVasan, Ramachandran, S1 aFranceschini, Nora1 aCarty, Cara, L1 aVirtamo, Jarmo1 aDemissie, Serkalem1 aAmouyel, Philippe1 aArveiler, Dominique1 aHeckbert, Susan, R1 aFerrieres, Jean1 aDucimetiere, Pierre1 aSmith, Nicholas, L1 aWang, Ying, A1 aSiscovick, David, S1 aRice, Kenneth, M1 aWiklund, Per-Gunnar1 aTaylor, Kent, D1 aEvans, Alun1 aKee, Frank1 aRotter, Jerome, I1 aKarvanen, Juha1 aKuulasmaa, Kari1 aHeiss, Gerardo1 aKraft, Peter1 aLauner, Lenore, J1 aHofman, Albert1 aMarkus, Marcello, R P1 aRose, Lynda, M1 aSilander, Kaisa1 aWagner, Peter1 aBenjamin, Emelia, J1 aLohman, Kurt1 aStott, David, J1 aRivadeneira, Fernando1 aHarris, Tamara, B1 aLevy, Daniel1 aLiu, Yongmei1 aRimm, Eric, B1 aJukema, Wouter1 aVölzke, Henry1 aRidker, Paul, M1 aBlankenberg, Stefan1 aFranco, Oscar, H1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/700404458nas a2200937 4500008004100000022001400041245009600055210006900151260001300220300001200233490000700245520181500252100002102067700002002088700001902108700001602127700001802143700002002161700002302181700002102204700002602225700001702251700002102268700002202289700001702311700002402328700002102352700002102373700002302394700002202417700001202439700001902451700002102470700002202491700002402513700002002537700002102557700002302578700002702601700002402628700001902652700001902671700002002690700001902710700002202729700001702751700001702768700002602785700002202811700002802833700001902861700002102880700002302901700002802924700001702952700001902969700001902988700002003007700001403027700002403041700002103065700002203086700002403108700001803132700002003150700002203170700002403192700001903216700002803235700002003263700002003283700002403303700002603327700001803353700002503371700002003396700002303416700002103439700002403460856003603484 2016 eng d a1474-972600aGWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.0 aGWAS analysis of handgrip and lower body strength in older adult c2016 Oct a792-8000 v153 aDecline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
1 aMatteini, Amy, M1 aTanaka, Toshiko1 aKarasik, David1 aAtzmon, Gil1 aChou, Wen-Chi1 aEicher, John, D1 aJohnson, Andrew, D1 aArnold, Alice, M1 aCallisaya, Michele, L1 aDavies, Gail1 aEvans, Daniel, S1 aHoltfreter, Birte1 aLohman, Kurt1 aLunetta, Kathryn, L1 aMangino, Massimo1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTeumer, Alexander1 aYu, Lei1 aArking, Dan, E1 aBuchman, Aron, S1 aChibinik, Lori, B1 aDe Jager, Philip, L1 aEvans, Denis, A1 aFaul, Jessica, D1 aGarcia, Melissa, E1 aGillham-Nasenya, Irina1 aGudnason, Vilmundur1 aHofman, Albert1 aHsu, Yi-Hsiang1 aIttermann, Till1 aLahousse, Lies1 aLiewald, David, C1 aLiu, Yongmei1 aLopez, Lorna1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSiggeirsdottir, Kristin1 aStarr, John, M1 aThomson, Russell1 aTranah, Gregory, J1 aUitterlinden, André, G1 aVölker, Uwe1 aVölzke, Henry1 aWeir, David, R1 aYaffe, Kristine1 aZhao, Wei1 aZhuang, Wei, Vivian1 aZmuda, Joseph, M1 aBennett, David, A1 aCummings, Steven, R1 aDeary, Ian, J1 aFerrucci, Luigi1 aHarris, Tamara, B1 aKardia, Sharon, L R1 aKocher, Thomas1 aKritchevsky, Stephen, B1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aSpector, Timothy, D1 aSrikanth, Velandai, K1 aWindham, Gwen1 aZillikens, Carola, M1 aNewman, Anne, B1 aWalston, Jeremy, D1 aKiel, Douglas, P1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/714204416nas a2200793 4500008004100000022001400041245018200055210006900237260001300306300001200319490000700331520209900338100001902437700002302456700002002479700002302499700001802522700002602540700002102566700001902587700002602606700002002632700002102652700002302673700002202696700002002718700001502738700001402753700002602767700002402793700002202817700002702839700002002866700002102886700002002907700002002927700001502947700001802962700002302980700002103003700002103024700001903045700002103064700001803085700001603103700002403119700001703143700002103160700001903181700002003200700002503220700002203245700001903267700002303286700002003309700001903329700001703348700002303365700002603388700002303414700002103437700002203458700002003480700002003500700002403520700001703544710002503561856003603586 2016 eng d a2047-488100aInflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration.0 aInflammatory markers and extent and progression of early atheros c2016 Jan a194-2050 v233 aBACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.
METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.
RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015).
CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.
1 aWilleit, Peter1 aThompson, Simon, G1 aAgewall, Stefan1 aBergström, Göran1 aBickel, Horst1 aCatapano, Alberico, L1 aChien, Kuo-Liong1 ade Groot, Eric1 aEmpana, Jean-Philippe1 aEtgen, Thorleif1 aFranco, Oscar, H1 aIglseder, Bernhard1 aJohnsen, Stein, H1 aKavousi, Maryam1 aLind, Lars1 aLiu, Jing1 aMathiesen, Ellisiv, B1 aNorata, Giuseppe, D1 aOlsen, Michael, H1 aPapagianni, Aikaterini1 aPoppert, Holger1 aPrice, Jackie, F1 aSacco, Ralph, L1 aYanez, David, N1 aZhao, Dong1 aSchminke, Ulf1 aBülbül, Alpaslan1 aPolak, Joseph, F1 aSitzer, Matthias1 aHofman, Albert1 aGrigore, Liliana1 aDörr, Marcus1 aSu, Ta-Chen1 aDucimetiere, Pierre1 aXie, Wuxiang1 aRonkainen, Kimmo1 aKiechl, Stefan1 aRundek, Tatjana1 aRobertson, Christine1 aFagerberg, Björn1 aBokemark, Lena1 aSteinmetz, Helmuth1 aIkram, Arfan, M1 aVölzke, Henry1 aLin, Hung-Ju1 aPlichart, Matthieu1 aTuomainen, Tomi-Pekka1 aDesvarieux, Moïse1 aMcLachlan, Stela1 aSchmidt, Caroline1 aKauhanen, Jussi1 aWilleit, Johann1 aLorenz, Matthias, W1 aSander, Dirk1 aPROG-IMT Study Group uhttps://chs-nhlbi.org/node/661204937nas a2201345 4500008004100000022001400041245012400055210006900179260001300248300001200261490000700273520113500280100001601415700001901431700002301450700002301473700002301496700001901519700001801538700002401556700001801580700001801598700001701616700001901633700002001652700002201672700002301694700001901717700001901736700001801755700001901773700001601792700001401808700002601822700001501848700002601863700001601889700001301905700001301918700001901931700002201950700002001972700002101992700002002013700001402033700001902047700001802066700002402084700002202108700001902130700002402149700002002173700001202193700002702205700002202232700002002254700002402274700002802298700002402326700002102350700002402371700002102395700002202416700002802438700002102466700002702487700003002514700002002544700001502564700002402579700002002603700001702623700002302640700001902663700001902682700002202701700002202723700001802745700002202763700001902785700001902804700001402823700001802837700001402855700002102869700002302890700002802913700001702941700001902958700001902977700001702996700002003013700002103033700002403054700002503078700002303103700002303126700002103149700002603170700002203196700002003218700002003238700002003258700002003278700002903298700001703327700002303344710002603367710002303393710002603416710002503442710006603467710002203533856003603555 2016 eng d a1546-171800aMeta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.0 aMetaanalysis identifies common and rare variants influencing blo c2016 Oct a1162-700 v483 aMeta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
1 aLiu, Chunyu1 aKraja, Aldi, T1 aSmith, Jennifer, A1 aBrody, Jennifer, A1 aFranceschini, Nora1 aBis, Joshua, C1 aRice, Kenneth1 aMorrison, Alanna, C1 aLu, Yingchang1 aWeiss, Stefan1 aGuo, Xiuqing1 aPalmas, Walter1 aMartin, Lisa, W1 aChen, Yii-Der Ida1 aSurendran, Praveen1 aDrenos, Fotios1 aCook, James, P1 aAuer, Paul, L1 aChu, Audrey, Y1 aGiri, Ayush1 aZhao, Wei1 aJakobsdottir, Johanna1 aLin, Li-An1 aStafford, Jeanette, M1 aAmin, Najaf1 aMei, Hao1 aYao, Jie1 aVoorman, Arend1 aLarson, Martin, G1 aGrove, Megan, L1 aSmith, Albert, V1 aHwang, Shih-Jen1 aChen, Han1 aHuan, Tianxiao1 aKosova, Gulum1 aStitziel, Nathan, O1 aKathiresan, Sekar1 aSamani, Nilesh1 aSchunkert, Heribert1 aDeloukas, Panos1 aLi, Man1 aFuchsberger, Christian1 aPattaro, Cristian1 aGorski, Mathias1 aKooperberg, Charles1 aPapanicolaou, George, J1 aRossouw, Jacques, E1 aFaul, Jessica, D1 aKardia, Sharon, L R1 aBouchard, Claude1 aRaffel, Leslie, J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aVasan, Ramachandran, S1 aO'Donnell, Christopher, J1 aTaylor, Kent, D1 aLiu, Kiang1 aBottinger, Erwin, P1 aGottesman, Omri1 aDaw, Warwick1 aGiulianini, Franco1 aGanesh, Santhi1 aSalfati, Elias1 aHarris, Tamara, B1 aLauner, Lenore, J1 aDörr, Marcus1 aFelix, Stephan, B1 aRettig, Rainer1 aVölzke, Henry1 aKim, Eric1 aLee, Wen-Jane1 aLee, I-Te1 aSheu, Wayne, H-H1 aTsosie, Krystal, S1 aEdwards, Digna, R Velez1 aLiu, Yongmei1 aCorrea, Adolfo1 aWeir, David, R1 aVölker, Uwe1 aRidker, Paul, M1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aReiner, Alexander, P1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aEdwards, Todd, L1 aChakravarti, Aravinda1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aLoos, Ruth, J F1 aFornage, Myriam1 aEhret, Georg, B1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aChasman, Daniel, I1 aCHD Exome+ Consortium1 aExomeBP Consortium1 aGoT2DGenes Consortium1 aT2D-GENES Consortium1 aMyocardial Infarction Genetics and CARDIoGRAM Exome Consortia1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/726405480nas a2201321 4500008004100000022001400041245007700055210006900132260001600201520175400217100002301971700001901994700002402013700001902037700001802056700002102074700002302095700001702118700002002135700001802155700001702173700002002190700002002210700002802230700002502258700001802283700002402301700001702325700002402342700002102366700002002387700001902407700001302426700003102439700001602470700001702486700002302503700001802526700002202544700002502566700002002591700002102611700001902632700001902651700002102670700002102691700002202712700002202734700002302756700001902779700001802798700001902816700001802835700001902853700002002872700002402892700001902916700002202935700002002957700001902977700002502996700002203021700002303043700002003066700002303086700001903109700002603128700002203154700002103176700002003197700001603217700002503233700002303258700002303281700002203304700002603326700002103352700002203373700002003395700002203415700002003437700002303457700002803480700002203508700002203530700001703552700002303569700002503592700001803617700002403635700002103659700002103680700002103701700002203722700001803744700001903762700002203781700002403803700002203827700002003849700002903869700002003898700002103918700002203939700002103961700002303982700001904005700002204024700002404046700003004070710002204100856003604122 2016 eng d a1942-326800aMultiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.0 aMultiethnic ExomeWide Association Study of Subclinical Atheroscl c2016 Nov 213 aBACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.
METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).
CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.
1 aNatarajan, Pradeep1 aBis, Joshua, C1 aBielak, Lawrence, F1 aCox, Amanda, J1 aDörr, Marcus1 aFeitosa, Mary, F1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aIsaacs, Aaron1 aJhun, Min, A1 aKavousi, Maryam1 aLi-Gao, Ruifang1 aLyytikäinen, Leo-Pekka1 aMarioni, Riccardo, E1 aSchminke, Ulf1 aStitziel, Nathan, O1 aTada, Hayato1 avan Setten, Jessica1 aSmith, Albert, V1 aVojinovic, Dina1 aYanek, Lisa, R1 aYao, Jie1 aYerges-Armstrong, Laura, M1 aAmin, Najaf1 aBaber, Usman1 aBorecki, Ingrid, B1 aCarr, Jeffrey1 aChen, Yii-Der Ida1 aCupples, Adrienne, L1 ade Jong, Pim, A1 ade Koning, Harry1 ade Vos, Bob, D1 aDemirkan, Ayse1 aFuster, Valentin1 aFranco, Oscar, H1 aGoodarzi, Mark, O1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHoffmann, Udo1 aHofman, Albert1 aIšgum, Ivana1 aJukema, Wouter1 aKähönen, Mika1 aKardia, Sharon, L R1 aKral, Brian, G1 aLauner, Lenore, J1 aMassaro, Joseph1 aMehran, Roxana1 aMitchell, Braxton, D1 aMosley, Thomas, H1 ade Mutsert, Renée1 aNewman, Anne, B1 aNguyen, Khanh-Dung1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aOudkerk, Matthijs1 aPankow, James, S1 aPeloso, Gina, M1 aPost, Wendy1 aProvince, Michael, A1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRivadeneira, Fernando1 aRosendaal, Frits1 aSartori, Samantha1 aTaylor, Kent, D1 aTeumer, Alexander1 aTrompet, Stella1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Lugt, Aad1 aVölker, Uwe1 aWardlaw, Joanna, M1 aWassel, Christina, L1 aWeiss, Stefan1 aWojczynski, Mary, K1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBowden, Donald, W1 aDeary, Ian, J1 aDehghan, Abbas1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aLehtimäki, Terho1 aMathias, Rasika1 aMook-Kanamori, Dennis, O1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRotter, Jerome, I1 aWilson, James, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aKathiresan, Sekar1 aPeyser, Patricia, A1 aO'Donnell, Christopher, J1 aCHARGE Consortium uhttps://chs-nhlbi.org/node/725706109nas a2201525 4500008004100000022001400041245009200055210006900147260001500216300001000231490000700241520179700248100002002045700002002065700002002085700002002105700002002125700001902145700002402164700002202188700002202210700002102232700001802253700002302271700001602294700002302310700002102333700002102354700001602375700001702391700001702408700002502425700002102450700001202471700002602483700002302509700002102532700002102553700001602574700002302590700002802613700001702641700002302658700002002681700002102701700001802722700002302740700002202763700001802785700001902803700002602822700002302848700002102871700002302892700002002915700002502935700002002960700002002980700002203000700002403022700002203046700002003068700002103088700002403109700001903133700002403152700002003176700001803196700002403214700002003238700002603258700002203284700002203306700002403328700002803352700002403380700001703404700002203421700002203443700002103465700002503486700002103511700001203532700001703544700002103561700002103582700001803603700002103621700002103642700001603663700002703679700001903706700002303725700002203748700002203770700002503792700001903817700002803836700002403864700002003888700002103908700002003929700002003949700002103969700002003990700001604010700002404026700002204050700001804072700002404090700001704114700001904131700001904150700002604169700002804195700002104223700001904244700002104263700002204284700002204306700002004328700001804348700002004366700002204386700002304408710003804431710003204469710004604501856003604547 2016 eng d a1537-660500aPlatelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.0 aPlateletRelated Variants Identified by Exomechip Metaanalysis in c2016 Jul 7 a40-550 v993 aPlatelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
1 aEicher, John, D1 aChami, Nathalie1 aKacprowski, Tim1 aNomura, Akihiro1 aChen, Ming-Huei1 aYanek, Lisa, R1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aSlater, Andrew, J1 aPankratz, Nathan1 aPolfus, Linda1 aSchurmann, Claudia1 aGiri, Ayush1 aBrody, Jennifer, A1 aLange, Leslie, A1 aManichaikul, Ani1 aHill, David1 aPazoki, Raha1 aElliot, Paul1 aEvangelou, Evangelos1 aTzoulaki, Ioanna1 aGao, He1 aVergnaud, Anne-Claire1 aMathias, Rasika, A1 aBecker, Diane, M1 aBecker, Lewis, C1 aBurt, Amber1 aCrosslin, David, R1 aLyytikäinen, Leo-Pekka1 aNikus, Kjell1 aHernesniemi, Jussi1 aKähönen, Mika1 aRaitoharju, Emma1 aMononen, Nina1 aRaitakari, Olli, T1 aLehtimäki, Terho1 aCushman, Mary1 aZakai, Neil, A1 aNickerson, Deborah, A1 aRaffield, Laura, M1 aQuarells, Rakale1 aWiller, Cristen, J1 aPeloso, Gina, M1 aAbecasis, Goncalo, R1 aLiu, Dajiang, J1 aDeloukas, Panos1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aErdmann, Jeanette1 aFornage, Myriam1 aRichard, Melissa1 aTardif, Jean-Claude1 aRioux, John, D1 aDubé, Marie-Pierre1 ade Denus, Simon1 aLu, Yingchang1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSmith, Albert, Vernon1 aHarris, Tamara, B1 aLauner, Lenore, J1 aGudnason, Vilmundur1 aEdwards, Digna, R Velez1 aTorstenson, Eric, S1 aLiu, Yongmei1 aTracy, Russell, P1 aRotter, Jerome, I1 aRich, Stephen, S1 aHighland, Heather, M1 aBoerwinkle, Eric1 aLi, Jin1 aLange, Ethan1 aWilson, James, G1 aMihailov, Evelin1 aMägi, Reedik1 aHirschhorn, Joel1 aMetspalu, Andres1 aEsko, Tõnu1 aVacchi-Suzzi, Caterina1 aNalls, Mike, A1 aZonderman, Alan, B1 aEvans, Michele, K1 aEngström, Gunnar1 aOrho-Melander, Marju1 aMelander, Olle1 aO'Donoghue, Michelle, L1 aWaterworth, Dawn, M1 aWallentin, Lars1 aWhite, Harvey, D1 aFloyd, James, S1 aBartz, Traci, M1 aRice, Kenneth, M1 aPsaty, Bruce, M1 aStarr, J, M1 aLiewald, David, C M1 aHayward, Caroline1 aDeary, Ian, J1 aGreinacher, Andreas1 aVölker, Uwe1 aThiele, Thomas1 aVölzke, Henry1 avan Rooij, Frank, J A1 aUitterlinden, André, G1 aFranco, Oscar, H1 aDehghan, Abbas1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aKathiresan, Sekar1 aFaraday, Nauder1 aAuer, Paul, L1 aReiner, Alex, P1 aLettre, Guillaume1 aJohnson, Andrew, D1 aGlobal Lipids Genetics Consortium1 aCARDIoGRAM Exome Consortium1 aMyocardial Infarction Genetics Consortium uhttps://chs-nhlbi.org/node/713906988nas a2201993 4500008004100000022001400041245011600055210006900171260001600240520137500256100001201631700001301643700001801656700002201674700002201696700002501718700001801743700002701761700002001788700002801808700001901836700002001855700002101875700001801896700001601914700002801930700001901958700002501977700002302002700002302025700002302048700002502071700001902096700002102115700002102136700002202157700002102179700002302200700001502223700001802238700001902256700002102275700001702296700001702313700001602330700002002346700002802366700001802394700001902412700002002431700001702451700001802468700001802486700002202504700002102526700002102547700002902568700002302597700002202620700001702642700002202659700003202681700002102713700002302734700002102757700003102778700001402809700002202823700001902845700001602864700002102880700002102901700002302922700002302945700002402968700001902992700002103011700002303032700002103055700002003076700002403096700001803120700001703138700002003155700001803175700002003193700002403213700002103237700002103258700002503279700002203304700001603326700002103342700001703363700002203380700002303402700002003425700001803445700002403463700002203487700002203509700001903531700001903550700001703569700002803586700002403614700002303638700002503661700002003686700002403706700002103730700002403751700002203775700002203797700002303819700002203842700001703864700002103881700002103902700001703923700002003940700001803960700002503978700001904003700002104022700001904043700002004062700002104082700002504103700001804128700001904146700002004165700001904185700001904204700002004223700002904243700002004272700001104292700002304303700002004326700001904346700002004365700002604385700002404411700001904435700002104454700002004475700002404495700002104519700002304540700002804563700001804591700002304609700001704632700001904649700002604668700001904694700001904713700001804732700002304750700002104773700002304794700002304817700001904840700001904859710003904878710004104917856003604958 2016 eng d a1533-345000aSOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.0 aSOS2 and ACP1 Loci Identified through LargeScale Exome Chip Anal c2016 Dec 053 aGenome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
1 aLi, Man1 aLi, Yong1 aWeeks, Olivia1 aMijatovic, Vladan1 aTeumer, Alexander1 aHuffman, Jennifer, E1 aTromp, Gerard1 aFuchsberger, Christian1 aGorski, Mathias1 aLyytikäinen, Leo-Pekka1 aNutile, Teresa1 aSedaghat, Sanaz1 aSorice, Rossella1 aTin, Adrienne1 aYang, Qiong1 aAhluwalia, Tarunveer, S1 aArking, Dan, E1 aBihlmeyer, Nathan, A1 aBöger, Carsten, A1 aCarroll, Robert, J1 aChasman, Daniel, I1 aCornelis, Marilyn, C1 aDehghan, Abbas1 aFaul, Jessica, D1 aFeitosa, Mary, F1 aGambaro, Giovanni1 aGasparini, Paolo1 aGiulianini, Franco1 aHeid, Iris1 aHuang, Jinyan1 aImboden, Medea1 aJackson, Anne, U1 aJeff, Janina1 aJhun, Min, A1 aKatz, Ronit1 aKifley, Annette1 aKilpeläinen, Tuomas, O1 aKumar, Ashish1 aLaakso, Markku1 aLi-Gao, Ruifang1 aLohman, Kurt1 aLu, Yingchang1 aMägi, Reedik1 aMalerba, Giovanni1 aMihailov, Evelin1 aMohlke, Karen, L1 aMook-Kanamori, Dennis, O1 aRobino, Antonietta1 aRuderfer, Douglas1 aSalvi, Erika1 aSchick, Ursula, M1 aSchulz, Christina-Alexandra1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTraglia, Michela1 aYerges-Armstrong, Laura, M1 aZhao, Wei1 aGoodarzi, Mark, O1 aKraja, Aldi, T1 aLiu, Chunyu1 aWessel, Jennifer1 aBoerwinkle, Eric1 aBorecki, Ingrid, B1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBraga, Daniele1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarey, David, J1 aChristensen, Cramer1 aCoresh, Josef1 aCrook, Errol1 aCurhan, Gary, C1 aCusi, Daniele1 ade Boer, Ian, H1 ade Vries, Aiko, P J1 aDenny, Joshua, C1 aDevuyst, Olivier1 aDreisbach, Albert, W1 aEndlich, Karlhans1 aEsko, Tõnu1 aFranco, Oscar, H1 aFulop, Tibor1 aGerhard, Glenn, S1 aGlümer, Charlotte1 aGottesman, Omri1 aGrarup, Niels1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHayward, Caroline1 aHocking, Lynne1 aHofman, Albert1 aHu, Frank, B1 aHusemoen, Lise, Lotte N1 aJackson, Rebecca, D1 aJørgensen, Torben1 aJørgensen, Marit, E1 aKähönen, Mika1 aKardia, Sharon, L R1 aKönig, Wolfgang1 aKooperberg, Charles1 aKriebel, Jennifer1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLehtimäki, Terho1 aLevy, Daniel1 aLinksted, Pamela1 aLinneberg, Allan1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLupo, Antonio1 aMeisinger, Christine1 aMelander, Olle1 aMetspalu, Andres1 aMitchell, Paul1 aNauck, Matthias1 aNürnberg, Peter1 aOrho-Melander, Marju1 aParsa, Afshin1 aPedersen, Oluf1 aPeters, Annette1 aPeters, Ulrike1 aPolasek, Ozren1 aPorteous, David1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aQi, Lu1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRettig, Rainer1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRossouw, Jacques, E1 aSchmidt, Frank1 aSiscovick, David1 aSoranzo, Nicole1 aStrauch, Konstantin1 aToniolo, Daniela1 aTurner, Stephen, T1 aUitterlinden, André, G1 aUlivi, Sheila1 aVelayutham, Dinesh1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWang, Jie, Jin1 aWeir, David, R1 aWitte, Daniel1 aKuivaniemi, Helena1 aFox, Caroline, S1 aFranceschini, Nora1 aGoessling, Wolfram1 aKöttgen, Anna1 aChu, Audrey, Y1 aCHARGE Glycemic-T2D Working Group,1 aCHARGE Blood Pressure Working Group, uhttps://chs-nhlbi.org/node/725503627nas a2200637 4500008004100000022001400041245011300055210006900168260001300237300001400250490000800264520178200272100001802054700002702072700002602099700002102125700002002146700002002166700001902186700002602205700002102231700002902252700002102281700001802302700002002320700002302340700001402363700002302377700002002400700002202420700002102442700001802463700002002481700002002501700002002521700002102541700002402562700001902586700002302605700001902628700001902647700002502666700002302691700001802714700002202732700001902754700001802773700002402791700001902815700002102834700002102855700002102876700002202897710003402919856003602953 2016 eng d a1945-719700aThyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis.0 aThyroid Function Within the Reference Range and the Risk of Stro c2016 Nov a4270-42820 v1013 aCONTEXT: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously.
DESIGN AND SETTING: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L.
RESULTS: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes.
CONCLUSION: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.
1 aChaker, Layal1 aBaumgartner, Christine1 aElzen, Wendy, P J den1 aCollet, Tinh-Hai1 aIkram, Arfan, M1 aBlum, Manuel, R1 aDehghan, Abbas1 aDrechsler, Christiane1 aLuben, Robert, N1 aPortegies, Marileen, L P1 aIervasi, Giorgio1 aMedici, Marco1 aStott, David, J1 aDullaart, Robin, P1 aFord, Ian1 aBremner, Alexandra1 aNewman, Anne, B1 aWanner, Christoph1 aSgarbi, José, A1 aDörr, Marcus1 aLongstreth, W T1 aPsaty, Bruce, M1 aFerrucci, Luigi1 aMaciel, Rui, M B1 aWestendorp, Rudi, G1 aJukema, Wouter1 aCeresini, Graziano1 aImaizumi, Misa1 aHofman, Albert1 aBakker, Stephan, J L1 aFranklyn, Jayne, A1 aKhaw, Kay-Tee1 aBauer, Douglas, C1 aWalsh, John, P1 aRazvi, Salman1 aGussekloo, Jacobijn1 aVölzke, Henry1 aFranco, Oscar, H1 aCappola, Anne, R1 aRodondi, Nicolas1 aPeeters, Robin, P1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/723808180nas a2202449 4500008004100000022001400041245010000055210006900155260001600224300000700240490000600247520139100253100002501644700002301669700001901692700003101711700001801742700001901760700002201779700001701801700001801818700002201836700002101858700001801879700001601897700002001913700002101933700002501954700002401979700002002003700001802023700001802041700002302059700001602082700002102098700001902119700002202138700001802160700001902178700002102197700002102218700002302239700002102262700001802283700002002301700002802321700002002349700002202369700002102391700001502412700001602427700002102443700002502464700002102489700002402510700002402534700001702558700003502575700002102610700002402631700002102655700001602676700002302692700001902715700001902734700002102753700002102774700001202795700002002807700002202827700001802849700002202867700002102889700001902910700001802929700002202947700002202969700001902991700002103010700001803031700001903049700002103068700001803089700002003107700002003127700001803147700002003165700002003185700002303205700002203228700001603250700002103266700001803287700002803305700001803333700002703351700002503378700002203403700002503425700002103450700002203471700001903493700001603512700001703528700002303545700002203568700002003590700002103610700002103631700001503652700002203667700001703689700001403706700001703720700002103737700002303758700002103781700002103802700002303823700002803846700002203874700001903896700002003915700001703935700002303952700002503975700002204000700002004022700001704042700002304059700002604082700001904108700002004127700001904147700002504166700001904191700001904210700002004229700001904249700002304268700002304291700002304314700002004337700002104357700002204378700001604400700002004416700002504436700002004461700001904481700001704500700001704517700001504534700002004549700002304569700001604592700002004608700002504628700003504653700002704688700002604715700002204741700002004763700002504783700002304808700002404831700002804855700001904883700002304902700002304925700002704948700001704975700002404992700001905016700002605035700001705061700002305078700001605101700002205117700002105139700002705160700002105187700002205208700001605230700001205246700001705258700002205275700002005297700002305317700002205340700002405362700002205386700002005408700002405428700002105452700002605473700002805499700002505527700002005552700002105572700002005593700001905613700002205632700001905654700002105673856003605694 2017 eng d a2041-172300aLarge meta-analysis of genome-wide association studies identifies five loci for lean body mass.0 aLarge metaanalysis of genomewide association studies identifies c2017 Jul 19 a800 v83 aLean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.
1 aZillikens, Carola, M1 aDemissie, Serkalem1 aHsu, Yi-Hsiang1 aYerges-Armstrong, Laura, M1 aChou, Wen-Chi1 aStolk, Lisette1 aLivshits, Gregory1 aBroer, Linda1 aJohnson, Toby1 aKoller, Daniel, L1 aKutalik, Zoltán1 aLuan, Jian'an1 aMalkin, Ida1 aRied, Janina, S1 aSmith, Albert, V1 aThorleifsson, Gudmar1 aVandenput, Liesbeth1 aZhao, Jing, Hua1 aZhang, Weihua1 aAghdassi, Ali1 aÅkesson, Kristina1 aAmin, Najaf1 aBaier, Leslie, J1 aBarroso, Inês1 aBennett, David, A1 aBertram, Lars1 aBiffar, Rainer1 aBochud, Murielle1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aBuchman, Aron, S1 aByberg, Liisa1 aCampbell, Harry1 aObanda, Natalia, Campos1 aCauley, Jane, A1 aCawthon, Peggy, M1 aCederberg, Henna1 aChen, Zhao1 aCho, Nam, H1 aChoi, Hyung, Jin1 aClaussnitzer, Melina1 aCollins, Francis1 aCummings, Steven, R1 aDe Jager, Philip, L1 aDemuth, Ilja1 aDhonukshe-Rutten, Rosalie, A M1 aDiatchenko, Luda1 aEiriksdottir, Gudny1 aEnneman, Anke, W1 aErdos, Mike1 aEriksson, Johan, G1 aEriksson, Joel1 aEstrada, Karol1 aEvans, Daniel, S1 aFeitosa, Mary, F1 aFu, Mao1 aGarcia, Melissa1 aGieger, Christian1 aGirke, Thomas1 aGlazer, Nicole, L1 aGrallert, Harald1 aGrewal, Jagvir1 aHan, Bok-Ghee1 aHanson, Robert, L1 aHayward, Caroline1 aHofman, Albert1 aHoffman, Eric, P1 aHomuth, Georg1 aHsueh, Wen-Chi1 aHubal, Monica, J1 aHubbard, Alan1 aHuffman, Kim, M1 aHusted, Lise, B1 aIllig, Thomas1 aIngelsson, Erik1 aIttermann, Till1 aJansson, John-Olov1 aJordan, Joanne, M1 aJula, Antti1 aKarlsson, Magnus1 aKhaw, Kay-Tee1 aKilpeläinen, Tuomas, O1 aKlopp, Norman1 aKloth, Jacqueline, S L1 aKoistinen, Heikki, A1 aKraus, William, E1 aKritchevsky, Stephen1 aKuulasmaa, Teemu1 aKuusisto, Johanna1 aLaakso, Markku1 aLahti, Jari1 aLang, Thomas1 aLangdahl, Bente, L1 aLauner, Lenore, J1 aLee, Jong-Young1 aLerch, Markus, M1 aLewis, Joshua, R1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLiu, Tian1 aLiu, Youfang1 aLjunggren, Osten1 aLorentzon, Mattias1 aLuben, Robert, N1 aMaixner, William1 aMcGuigan, Fiona, E1 aMedina-Gómez, Carolina1 aMeitinger, Thomas1 aMelhus, Håkan1 aMellström, Dan1 aMelov, Simon1 aMichaëlsson, Karl1 aMitchell, Braxton, D1 aMorris, Andrew, P1 aMosekilde, Leif1 aNewman, Anne1 aNielson, Carrie, M1 aO'Connell, Jeffrey, R1 aOostra, Ben, A1 aOrwoll, Eric, S1 aPalotie, Aarno1 aParker, Stephen, C J1 aPeacock, Munro1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPrince, Richard, L1 aRäikkönen, Katri1 aRalston, Stuart, H1 aRipatti, Samuli1 aRobbins, John, A1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSatterfield, Suzanne1 aSchadt, Eric, E1 aSchipf, Sabine1 aScott, Laura1 aSehmi, Joban1 aShen, Jian1 aShin, Chan, Soo1 aSigurdsson, Gunnar1 aSmith, Shad1 aSoranzo, Nicole1 aStančáková, Alena1 aSteinhagen-Thiessen, Elisabeth1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aSwart, Karin, M A1 aTan, Sian-Tsung1 aTarnopolsky, Mark, A1 aThompson, Patricia1 aThomson, Cynthia, A1 aThorsteinsdottir, Unnur1 aTikkanen, Emmi1 aTranah, Gregory, J1 aTuomilehto, Jaakko1 avan Schoor, Natasja, M1 aVerma, Arjun1 aVollenweider, Peter1 aVölzke, Henry1 aWactawski-Wende, Jean1 aWalker, Mark1 aWeedon, Michael, N1 aWelch, Ryan1 aWichmann, H-Erich1 aWiden, Elisabeth1 aWilliams, Frances, M K1 aWilson, James, F1 aWright, Nicole, C1 aXie, Weijia1 aYu, Lei1 aZhou, Yanhua1 aChambers, John, C1 aDöring, Angela1 aDuijn, Cornelia, M1 aEcons, Michael, J1 aGudnason, Vilmundur1 aKooner, Jaspal, S1 aPsaty, Bruce, M1 aSpector, Timothy, D1 aStefansson, Kari1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aOssowski, Vicky1 aWaterworth, Dawn1 aLoos, Ruth, J F1 aKarasik, David1 aHarris, Tamara, B1 aOhlsson, Claes1 aKiel, Douglas, P uhttps://chs-nhlbi.org/node/760006419nas a2201621 4500008004100000022001400041245011300055210006900168260001600237300001400253490000800267520184900275100002102124700002102145700002002166700002202186700002002208700002602228700001702254700002002271700002302291700002502314700002002339700001902359700001902378700002202397700002202419700002102441700002602462700002202488700002102510700002202531700002802553700001902581700001802600700002202618700002402640700002302664700002402687700001802711700002002729700002202749700002102771700002402792700001902816700002002835700002102855700001702876700002102893700002602914700002002940700002002960700001702980700002002997700002203017700001703039700001903056700001503075700002003090700002003110700002403130700001903154700002103173700001903194700002203213700002203235700002503257700001903282700002503301700002103326700002103347700002403368700001703392700002203409700002203431700002303453700003003476700002003506700002203526700002203548700001903570700002003589700001803609700002003627700002603647700002303673700002103696700002603717700002203743700002203765700002003787700002503807700002003832700002303852700002203875700002103897700002203918700002303940700002303963700001603986700002404002700002804026700001804054700001904072700002104091700002004112700002004132700002304152700002404175700002204199700002304221700001804244700002204262700002504284700001904309700001704328700002204345700001904367700002104386700001504407700002404422700002004446700002304466700002004489700002404509700002004533700001504553700002104568700002004589700002404609700002204633700002204655700002104677700001804698700002704716700001804743856003604761 2017 eng d a1558-823800aLarge-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.0 aLargescale genomewide analysis identifies genetic variants assoc c2017 May 01 a1798-18120 v1273 aBACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.
METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.
RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.
CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.
FUNDING: For detailed information per study, see Acknowledgments.
1 aWild, Philipp, S1 aFelix, Janine, F1 aSchillert, Arne1 aTeumer, Alexander1 aChen, Ming-Huei1 aLeening, Maarten, J G1 aVölker, Uwe1 aGroßmann, Vera1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aShah, Sanjiv, J1 aPramana, Setia1 aLieb, Wolfgang1 aSchmidt, Reinhold1 aStanton, Alice, V1 aMalzahn, Dörthe1 aSmith, Albert, Vernon1 aSundström, Johan1 aMinelli, Cosetta1 aRuggiero, Daniela1 aLyytikäinen, Leo-Pekka1 aTiller, Daniel1 aSmith, Gustav1 aMonnereau, Claire1 aDi Tullio, Marco, R1 aMusani, Solomon, K1 aMorrison, Alanna, C1 aPers, Tune, H1 aMorley, Michael1 aKleber, Marcus, E1 aAragam, Jayashri1 aBenjamin, Emelia, J1 aBis, Joshua, C1 aBisping, Egbert1 aBroeckel, Ulrich1 aCheng, Susan1 aDeckers, Jaap, W1 aM, Fabiola, del Greco1 aEdelmann, Frank1 aFornage, Myriam1 aFranke, Lude1 aFriedrich, Nele1 aHarris, Tamara, B1 aHofer, Edith1 aHofman, Albert1 aHuang, Jie1 aHughes, Alun, D1 aKähönen, Mika1 aInvestigators, Knhi1 aKruppa, Jochen1 aLackner, Karl, J1 aLannfelt, Lars1 aLaskowski, Rafael1 aLauner, Lenore, J1 aLeosdottir, Margrét1 aLin, Honghuang1 aLindgren, Cecilia, M1 aLoley, Christina1 aMacRae, Calum, A1 aMascalzoni, Deborah1 aMayet, Jamil1 aMedenwald, Daniel1 aMorris, Andrew, P1 aMüller, Christian1 aMüller-Nurasyid, Martina1 aNappo, Stefania1 aNilsson, Peter, M1 aNuding, Sebastian1 aNutile, Teresa1 aPeters, Annette1 aPfeufer, Arne1 aPietzner, Diana1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aRuohonen, Saku, T1 aSacco, Ralph, L1 aSamdarshi, Tandaw, E1 aSchmidt, Helena1 aSharp, Andrew, S P1 aShields, Denis, C1 aSorice, Rossella1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSurendran, Praveen1 aThom, Simon1 aTöglhofer, Anna, M1 aUitterlinden, André, G1 aWachter, Rolf1 aVölzke, Henry1 aZiegler, Andreas1 aMünzel, Thomas1 aMärz, Winfried1 aCappola, Thomas, P1 aHirschhorn, Joel, N1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aFox, Ervin, R1 aDueker, Nicole, D1 aJaddoe, Vincent, W V1 aMelander, Olle1 aRuss, Martin1 aLehtimäki, Terho1 aCiullo, Marina1 aHicks, Andrew, A1 aLind, Lars1 aGudnason, Vilmundur1 aPieske, Burkert1 aBarron, Anthony, J1 aZweiker, Robert1 aSchunkert, Heribert1 aIngelsson, Erik1 aLiu, Kiang1 aArnett, Donna, K1 aPsaty, Bruce, M1 aBlankenberg, Stefan1 aLarson, Martin, G1 aFelix, Stephan, B1 aFranco, Oscar, H1 aZeller, Tanja1 aVasan, Ramachandran, S1 aDörr, Marcus uhttps://chs-nhlbi.org/node/737303467nas a2200673 4500008004100000022001400041245015500055210006900210260001600279520146600295100001701761700002101778700001901799700002201818700001901840700003001859700002401889700002801913700002001941700001901961700001801980700001801998700002202016700002102038700002802059700002102087700002402108700002002132700002402152700002402176700001902200700002402219700002002243700001602263700003502279700001902314700001902333700002002352700002302372700001802395700002502413700002102438700002002459700002002479700001902499700001802518700002102536700002202557700002002579700002002599700002202619700002002641700002102661700001802682700001702700700002302717700001702740856003602757 2017 eng d a1476-625600aREPEATED MEASUREMENTS OF BLOOD PRESSURE AND CHOLESTEROL IMPROVES CARDIOVASCULAR DISEASE RISK PREDICTION: AN INDIVIDUAL-PARTICIPANT-DATA META-ANALYSIS.0 aREPEATED MEASUREMENTS OF BLOOD PRESSURE AND CHOLESTEROL IMPROVES c2017 May 263 aThe added value of incorporating information from repeated measurements of blood pressure and cholesterol for cardiovascular disease (CVD) risk prediction has not been rigorously assessed. We used data from the Emerging Risk Factors Collaboration on 191,445 adults (38 cohorts from across 17 countries with data from 1962-2014) with > 1 million measurements of systolic blood pressure, total cholesterol and high-density lipoprotein cholesterol; over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative means of repeated measurements and summary measures from longitudinal modelling of the repeated measurements were compared to models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analysed across studies. Compared to the single time point model, the cumulative means and the longitudinal models increased the C-index by 0.0040 (95% CI: 0.0023, 0.0057) and 0.0023 (0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared to the single time point model, overall net reclassification improvements were 0.0369 (0.0303, 0.0436) for the cumulative means model and 0.0177 (0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.
1 aPaige, Ellie1 aBarrett, Jessica1 aPennells, Lisa1 aSweeting, Michael1 aWilleit, Peter1 aDi Angelantonio, Emanuele1 aGudnason, Vilmundur1 aNordestgaard, Børge, G1 aPsaty, Bruce, M1 aGoldbourt, Uri1 aBest, Lyle, G1 aAssmann, Gerd1 aSalonen, Jukka, T1 aNietert, Paul, J1 aVerschuren, Wm, Monique1 aBrunner, Eric, J1 aKronmal, Richard, A1 aSalomaa, Veikko1 aBakker, Stephan, Jl1 aDagenais, Gilles, R1 aSato, Shinichi1 aJansson, Jan-Håkan1 aWilleit, Johann1 aOnat, Altan1 ade la Cámara, Agustin, Gómez1 aRoussel, Ronan1 aVölzke, Henry1 aDankner, Rachel1 aTipping, Robert, W1 aMeade, Tom, W1 aDonfrancesco, Chiara1 aKuller, Lewis, H1 aPeters, Annette1 aGallacher, John1 aKromhout, Daan1 aIso, Hiroyasu1 aKnuiman, Matthew1 aCasiglia, Edoardo1 aKavousi, Maryam1 aPalmieri, Luigi1 aSundström, Johan1 aDavis, Barry, R1 aNjølstad, Inger1 aCouper, David1 aDanesh, John1 aThompson, Simon, G1 aWood, Angela uhttps://chs-nhlbi.org/node/745104137nas a2200745 4500008004100000022001400041245011100055210006900166260001600235300001400251490000800265520205100273653001002324653000902334653002202343653002602365653002402391653001502415653002802430653001102458653001102469653001902480653001402499653000902513653001602522653003002538653001402568653003202582653002002614653001702634653002702651653001802678653001602696653001402712653001702726653001602743100002702759700002302786700002102809700001902830700002102849700002202870700002102892700002302913700002302936700002402959700002602983700002203009700001803031700001903049700001803068700001903086700002303105700002403128700002203152700001803174700002003192700002603212700001803238700002203256700002203278700002103300710003403321856003603355 2017 eng d a1524-453900aThyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation.0 aThyroid Function Within the Normal Range Subclinical Hypothyroid c2017 Nov 28 a2100-21160 v1363 aBACKGROUND: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF.
METHODS: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF.
RESULTS: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease.
CONCLUSIONS: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.
10aAdult10aAged10aAged, 80 and over10aAsymptomatic Diseases10aAtrial Fibrillation10aBiomarkers10aChi-Square Distribution10aFemale10aHumans10aHypothyroidism10aIncidence10aMale10aMiddle Aged10aPredictive Value of Tests10aPrognosis10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aThyroid Function Tests10aThyroid Gland10aThyrotropin10aThyroxine10aTime Factors10aYoung Adult1 aBaumgartner, Christine1 ada Costa, Bruno, R1 aCollet, Tinh-Hai1 aFeller, Martin1 aFloriani, Carmen1 aBauer, Douglas, C1 aCappola, Anne, R1 aHeckbert, Susan, R1 aCeresini, Graziano1 aGussekloo, Jacobijn1 aElzen, Wendy, P J den1 aPeeters, Robin, P1 aLuben, Robert1 aVölzke, Henry1 aDörr, Marcus1 aWalsh, John, P1 aBremner, Alexandra1 aIacoviello, Massimo1 aMacfarlane, Peter1 aHeeringa, Jan1 aStott, David, J1 aWestendorp, Rudi, G J1 aKhaw, Kay-Tee1 aMagnani, Jared, W1 aAujesky, Drahomir1 aRodondi, Nicolas1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/755005196nas a2201345 4500008004100000022001400041245009400055210006900149260001300218300001200231490000700243520143500250100001901685700002401704700002101728700002501749700002101774700002301795700002101818700001701839700001801856700003001874700002001904700001801924700001801942700002001960700002801980700002102008700001802029700001902047700002202066700002802088700001302116700002202129700002202151700001202173700001902185700002402204700002102228700001902249700001802268700002402286700002002310700001702330700002202347700002202369700001902391700002102410700002402431700001702455700001602472700001902488700002202507700002702529700002402556700002202580700002402602700002002626700002602646700002202672700002302694700001902717700002102736700001602757700002302773700002402796700001302820700001702833700002002850700002202870700002202892700002902914700002002943700002602963700002402989700002203013700002503035700002003060700001903080700002203099700001803121700001703139700002103156700002403177700002103201700001703222700002003239700002303259700002403282700001903306700002403325700002003349700002303369700002403392700002103416700002203437700001903459700001903478700001903497700001503516700002303531700001903554700002303573700002203596700001803618700002003636700002703656700002403683700002203707700002103729700002403750700002203774700001803796856003603814 2018 eng d a2574-830000aCommon and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.0 aCommon and Rare Coding Genetic Variation Underlying the Electroc c2018 May ae0020370 v113 aBACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.
METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.
RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.
CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
1 aLin, Honghuang1 avan Setten, Jessica1 aSmith, Albert, V1 aBihlmeyer, Nathan, A1 aWarren, Helen, R1 aBrody, Jennifer, A1 aRadmanesh, Farid1 aHall, Leanne1 aGrarup, Niels1 aMüller-Nurasyid, Martina1 aBoutin, Thibaud1 aVerweij, Niek1 aLin, Henry, J1 aLi-Gao, Ruifang1 avan den Berg, Marten, E1 aMarten, Jonathan1 aWeiss, Stefan1 aPrins, Bram, P1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aMei, Hao1 aHarris, Tamara, B1 aLauner, Lenore, J1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aConnell, John, M1 aHuang, Paul, L1 aWeng, Lu-Chen1 aJameson, Heather, S1 aHucker, William1 aHanley, Alan1 aTucker, Nathan, R1 aChen, Yii-Der Ida1 aBis, Joshua, C1 aRice, Kenneth, M1 aSitlani, Colleen, M1 aKors, Jan, A1 aXie, Zhijun1 aWen, Chengping1 aMagnani, Jared, W1 aNelson, Christopher, P1 aKanters, Jørgen, K1 aSinner, Moritz, F1 aStrauch, Konstantin1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aBork-Jensen, Jette1 aPedersen, Oluf1 aLinneberg, Allan1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aYao, Jie1 aGuo, Xiuqing1 aTaylor, Kent, D1 aSotoodehnia, Nona1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aTrompet, Stella1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aEijgelsheim, Mark1 aPadmanabhan, Sandosh1 aSmith, Blair, H1 aVölzke, Henry1 aFelix, Stephan, B1 aHomuth, Georg1 aVölker, Uwe1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aKähönen, Mika1 aRaitakari, Olli, T1 aGudnason, Vilmundur1 aArking, Dan, E1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aBenjamin, Emelia, J1 aRosand, Jonathan1 aSamani, Nilesh, J1 aHansen, Torben1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aJukema, Wouter1 aStricker, Bruno, H1 aHayward, Caroline1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aWilson, James, G1 aEllinor, Patrick, T1 aLubitz, Steven, A1 aIsaacs, Aaron uhttps://chs-nhlbi.org/node/780105662nas a2201321 4500008004100000022001400041245015200055210006900207260001600276520185700292100001902149700002102168700001702189700001902206700001802225700001502243700002102258700001902279700001902298700002202317700002202339700001802361700001802379700002402397700001802421700002202439700002002461700001902481700002802500700002202528700002102550700002102571700002302592700002302615700001402638700002402652700002202676700002202698700001902720700001802739700003102757700002202788700002002810700002202830700002302852700002202875700003002897700002002927700002102947700002402968700002302992700001903015700002503034700002503059700002403084700002203108700002003130700001603150700002203166700002303188700002403211700002303235700002203258700002203280700001803302700002203320700001903342700001903361700001903380700002103399700003503420700001903455700002203474700001603496700002003512700002003532700002103552700002003573700002603593700002003619700001703639700002303656700001903679700002103698700002103719700002003740700002103760700002303781700002003804700001903824700002503843700002003868700002103888700001903909700002903928700002503957700001603982700001703998700002204015700001904037700001804056700002004074700001904094700001704113700002004130700001904150700002504169700002304194700001704217700003004234710004004264856003604304 2018 eng d a1522-964500aEqualization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.0 aEqualization of four cardiovascular risk algorithms after system c2018 Nov 223 aAims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.
Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.
Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
1 aPennells, Lisa1 aKaptoge, Stephen1 aWood, Angela1 aSweeting, Mike1 aZhao, Xiaohui1 aWhite, Ian1 aBurgess, Stephen1 aWilleit, Peter1 aBolton, Thomas1 aMoons, Karel, G M1 aSchouw, Yvonne, T1 aSelmer, Randi1 aKhaw, Kay-Tee1 aGudnason, Vilmundur1 aAssmann, Gerd1 aAmouyel, Philippe1 aSalomaa, Veikko1 aKivimaki, Mika1 aNordestgaard, Børge, G1 aBlaha, Michael, J1 aKuller, Lewis, H1 aBrenner, Hermann1 aGillum, Richard, F1 aMeisinger, Christa1 aFord, Ian1 aKnuiman, Matthew, W1 aRosengren, Annika1 aLawlor, Debbie, A1 aVölzke, Henry1 aCooper, Cyrus1 aIbañez, Alejandro, Marín1 aCasiglia, Edoardo1 aKauhanen, Jussi1 aCooper, Jackie, A1 aRodriguez, Beatriz1 aSundström, Johan1 aBarrett-Connor, Elizabeth1 aDankner, Rachel1 aNietert, Paul, J1 aDavidson, Karina, W1 aWallace, Robert, B1 aBlazer, Dan, G1 aBjörkelund, Cecilia1 aDonfrancesco, Chiara1 aKrumholz, Harlan, M1 aNissinen, Aulikki1 aDavis, Barry, R1 aCoady, Sean1 aWhincup, Peter, H1 aJørgensen, Torben1 aDucimetiere, Pierre1 aTrevisan, Maurizio1 aEngström, Gunnar1 aCrespo, Carlos, J1 aMeade, Tom, W1 aVisser, Marjolein1 aKromhout, Daan1 aKiechl, Stefan1 aDaimon, Makoto1 aPrice, Jackie, F1 ade la Cámara, Agustin, Gómez1 aJukema, Wouter1 aLamarche, Benoît1 aOnat, Altan1 aSimons, Leon, A1 aKavousi, Maryam1 aBen-Shlomo, Yoav1 aGallacher, John1 aDekker, Jacqueline, M1 aArima, Hisatomi1 aShara, Nawar1 aTipping, Robert, W1 aRoussel, Ronan1 aBrunner, Eric, J1 aKoenig, Wolfgang1 aSakurai, Masaru1 aPavlovic, Jelena1 aGansevoort, Ron, T1 aNagel, Dorothea1 aGoldbourt, Uri1 aBarr, Elizabeth, L M1 aPalmieri, Luigi1 aNjølstad, Inger1 aSato, Shinichi1 aVerschuren, W, M Monique1 aVarghese, Cherian, V1 aGraham, Ian1 aOnuma, Oyere1 aGreenland, Philip1 aWoodward, Mark1 aEzzati, Majid1 aPsaty, Bruce, M1 aSattar, Naveed1 aJackson, Rod1 aRidker, Paul, M1 aCook, Nancy, R1 aD'Agostino, Ralph, B1 aThompson, Simon, G1 aDanesh, John1 aDi Angelantonio, Emanuele1 aEmerging Risk Factors Collaboration uhttps://chs-nhlbi.org/node/792305658nas a2201489 4500008004100000022001400041245010600055210006900161260001500230300000700245490000700252520146500259100001901724700002101743700002301764700002701787700001901814700002501833700002501858700002301883700002501906700002901931700002201960700002301982700001702005700001702022700001802039700002202057700002002079700002102099700001802120700002002138700001902158700001802177700002802195700002102223700001302244700003002257700001902287700002502306700002102331700001902352700002302371700002002394700002402414700002102438700001802459700002102477700001802498700001902516700002002535700002102555700002302576700002402599700002202623700002402645700001702669700002202686700002202708700002202730700002302752700001902775700001702794700002002811700001702831700002202848700002202870700001202892700002102904700002702925700001902952700001702971700002002988700001903008700002003027700002303047700002103070700002203091700002203113700002403135700002003159700002403179700002803203700001903231700002003250700002403270700002103294700002403315700001703339700001903356700002603375700002103401700001603422700002703438700001803465700002303483700002103506700002803527700002403555700001903579700001903598700002403617700002403641700002203665700001803687700002203705700002903727700002403756700003203780700002103812700001603833700002203849700002403871700002003895700001603915700002303931700001803954700002203972700002003994700001504014700002104029700002404050700001904074700001904093700002004112856003604132 2018 eng d a1474-760X00aExome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.0 aExomechip metaanalysis identifies novel loci associated with car c2018 07 17 a870 v193 aBACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.
RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.
CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
1 aPrins, Bram, P1 aMead, Timothy, J1 aBrody, Jennifer, A1 aSveinbjornsson, Gardar1 aNtalla, Ioanna1 aBihlmeyer, Nathan, A1 avan den Berg, Marten1 aBork-Jensen, Jette1 aCappellani, Stefania1 aVan Duijvenboden, Stefan1 aKlena, Nikolai, T1 aGabriel, George, C1 aLiu, Xiaoqin1 aGulec, Cagri1 aGrarup, Niels1 aHaessler, Jeffrey1 aHall, Leanne, M1 aIorio, Annamaria1 aIsaacs, Aaron1 aLi-Gao, Ruifang1 aLin, Honghuang1 aLiu, Ching-Ti1 aLyytikäinen, Leo-Pekka1 aMarten, Jonathan1 aMei, Hao1 aMüller-Nurasyid, Martina1 aOrini, Michele1 aPadmanabhan, Sandosh1 aRadmanesh, Farid1 aRamirez, Julia1 aRobino, Antonietta1 aSchwartz, Molly1 avan Setten, Jessica1 aSmith, Albert, V1 aVerweij, Niek1 aWarren, Helen, R1 aWeiss, Stefan1 aAlonso, Alvaro1 aArnar, David, O1 aBots, Michiel, L1 ade Boer, Rudolf, A1 aDominiczak, Anna, F1 aEijgelsheim, Mark1 aEllinor, Patrick, T1 aGuo, Xiuqing1 aFelix, Stephan, B1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHuang, Paul, L1 aJukema, J, W1 aKähönen, Mika1 aKors, Jan, A1 aLambiase, Pier, D1 aLauner, Lenore, J1 aLi, Man1 aLinneberg, Allan1 aNelson, Christopher, P1 aPedersen, Oluf1 aPerez, Marco1 aPeters, Annette1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRotter, Jerome, I1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Tim, D1 aStrauch, Konstantin1 aThorsteinsdottir, Unnur1 aTinker, Andrew1 aTrompet, Stella1 aUitterlinden, Andre1 aVaartjes, Ilonca1 avan der Meer, Peter1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWilson, James, G1 aXie, Zhijun1 aAsselbergs, Folkert, W1 aDörr, Marcus1 aDuijn, Cornelia, M1 aGasparini, Paolo1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHansen, Torben1 aKääb, Stefan1 aKanters, Jørgen, K1 aKooperberg, Charles1 aLehtimäki, Terho1 aLin, Henry, J1 aLubitz, Steven, A1 aMook-Kanamori, Dennis, O1 aConti, Francesco, J1 aNewton-Cheh, Christopher, H1 aRosand, Jonathan1 aRudan, Igor1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aSmith, Blair, H1 aHolm, Hilma1 aStricker, Bruno, H1 aUlivi, Sheila1 aSotoodehnia, Nona1 aApte, Suneel, S1 aHarst, Pim1 aStefansson, Kari1 aMunroe, Patricia, B1 aArking, Dan, E1 aLo, Cecilia, W1 aJamshidi, Yalda uhttps://chs-nhlbi.org/node/780905298nas a2201333 4500008004100000022001400041245011200055210006900167260001300236300001200249490000700261520154600268100002501814700002301839700002601862700002101888700001901909700001801928700001801946700002101964700002101985700002002006700001802026700001302044700003002057700002502087700001802112700001702130700001302147700002002160700002502180700001802205700001902223700002402242700002202266700002802288700001202316700001902328700002402347700001902371700001602390700002202406700002002428700002302448700002202471700002502493700002102518700001902539700001602558700002402574700001702598700002102615700002202636700002702658700002102685700002302706700001902729700001902748700002102767700002202788700002002810700002602830700002202856700002002878700001802898700001602916700002302932700002402955700001802979700002002997700002303017700002003040700001903060700001803079700002503097700002603122700002403148700001703172700001803189700001903207700002203226700002103248700002403269700002103293700001703314700002303331700002003354700001803374700002403392700002403416700002203440700002303462700003203485700002203517700002103539700002203560700002403582700002103606700001903627700001903646700001503665700002303680700002203703700002903725700002203754700001803776700002003794700002703814700002403841700002203865700001903887700002203906856003603928 2018 eng d a2574-830000aExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.0 aExomeChipWide Analysis of 95 626 Individuals Identifies 10 Novel c2018 Jan ae0017580 v113 aBACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.
METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.
CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
1 aBihlmeyer, Nathan, A1 aBrody, Jennifer, A1 aSmith, Albert, Vernon1 aWarren, Helen, R1 aLin, Honghuang1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aMarten, Jonathan1 aRadmanesh, Farid1 aHall, Leanne, M1 aGrarup, Niels1 aMei, Hao1 aMüller-Nurasyid, Martina1 aHuffman, Jennifer, E1 aVerweij, Niek1 aGuo, Xiuqing1 aYao, Jie1 aLi-Gao, Ruifang1 avan den Berg, Marten1 aWeiss, Stefan1 aPrins, Bram, P1 avan Setten, Jessica1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aBis, Joshua, C1 aAustin, Tom1 aChen, Yii-Der Ida1 aPsaty, Bruce, M1 aHarrris, Tamara, B1 aLauner, Lenore, J1 aPadmanabhan, Sandosh1 aDominiczak, Anna1 aHuang, Paul, L1 aXie, Zhijun1 aEllinor, Patrick, T1 aKors, Jan, A1 aCampbell, Archie1 aMurray, Alison, D1 aNelson, Christopher, P1 aTobin, Martin, D1 aBork-Jensen, Jette1 aHansen, Torben1 aPedersen, Oluf1 aLinneberg, Allan1 aSinner, Moritz, F1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aPerz, Siegfried1 aKolcic, Ivana1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aLin, Henry, J1 aTaylor, Kent, D1 ade Mutsert, Renée1 aTrompet, Stella1 aJukema, Wouter1 aMaan, Arie, C1 aStricker, Bruno, H C1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aVölker, Uwe1 aHomuth, Georg1 aVölzke, Henry1 aFelix, Stephan, B1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aRaitakari, Olli, T1 aKähönen, Mika1 aMononen, Nina1 aGudnason, Vilmundur1 aMunroe, Patricia, B1 aLubitz, Steven, A1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher, H1 aHayward, Caroline1 aRosand, Jonathan1 aSamani, Nilesh, J1 aKanters, Jørgen, K1 aWilson, James, G1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aEijgelsheim, Mark1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aArking, Dan, E1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/778405787nas a2201681 4500008004100000022001400041245009400055210006900149260001500218300000900233490000600242520110000248100002201348700001801370700002201388700001301410700002001423700002301443700002501466700002101491700002801512700002001540700002701560700001901587700001801606700001701624700002001641700002001661700001901681700002101700700002201721700002101743700002401764700002301788700002501811700002101836700001801857700001801875700002101893700001901914700002301933700002101956700001501977700002201992700001402014700002102028700002702049700002502076700002202101700002002123700002602143700001802169700002702187700001802214700001902232700002102251700002202272700002402294700002102318700002702339700001802366700001602384700002002400700002002420700002302440700001902463700001902482700001902501700002302520700001902543700002302562700002702585700002602612700002402638700001902662700001602681700001802697700001302715700002402728700001702752700002102769700002002790700002402810700002002834700002202854700002302876700002302899700001802922700004102940700002402981700001903005700002703024700001903051700002003070700001603090700002203106700001903128700002303147700002003170700001803190700002603208700002003234700002403254700001803278700001803296700002003314700002503334700002603359700001603385700002203401700002003423700002403443700002203467700002003489700002003509700002903529700002403558700001903582700002003601700001603621700001903637700002003656700002003676700001903696700002103715700002803736700001903764700001903783700002103802700003003823700001603853700002003869700001803889700002203907700001903929700001903948700001803967700001903985700002004004700001804024710002704042856003604069 2018 eng d a2041-172300aGenome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.0 aGenomewide analyses identify a role for SLC17A4 and AADAT in thy c2018 10 26 a44550 v93 aThyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
1 aTeumer, Alexander1 aChaker, Layal1 aGroeneweg, Stefan1 aLi, Yong1 aDi Munno, Celia1 aBarbieri, Caterina1 aSchultheiss, Ulla, T1 aTraglia, Michela1 aAhluwalia, Tarunveer, S1 aAkiyama, Masato1 aAppel, Emil, Vincent R1 aArking, Dan, E1 aArnold, Alice1 aAstrup, Arne1 aBeekman, Marian1 aBeilby, John, P1 aBekaert, Sofie1 aBoerwinkle, Eric1 aBrown, Suzanne, J1 aDe Buyzere, Marc1 aCampbell, Purdey, J1 aCeresini, Graziano1 aCerqueira, Charlotte1 aCucca, Francesco1 aDeary, Ian, J1 aDeelen, Joris1 aEckardt, Kai-Uwe1 aEkici, Arif, B1 aEriksson, Johan, G1 aFerrrucci, Luigi1 aFiers, Tom1 aFiorillo, Edoardo1 aFord, Ian1 aFox, Caroline, S1 aFuchsberger, Christian1 aGalesloot, Tessel, E1 aGieger, Christian1 aGögele, Martin1 aDe Grandi, Alessandro1 aGrarup, Niels1 aGreiser, Karin, Halina1 aHaljas, Kadri1 aHansen, Torben1 aHarris, Sarah, E1 avan Heemst, Diana1 aHeijer, Martin, den1 aHicks, Andrew, A1 aHollander, Wouter, den1 aHomuth, Georg1 aHui, Jennie1 aIkram, Arfan, M1 aIttermann, Till1 aJensen, Richard, A1 aJing, Jiaojiao1 aJukema, Wouter1 aKajantie, Eero1 aKamatani, Yoichiro1 aKasbohm, Elisa1 aKaufman, Jean-Marc1 aKiemeney, Lambertus, A1 aKloppenburg, Margreet1 aKronenberg, Florian1 aKubo, Michiaki1 aLahti, Jari1 aLapauw, Bruno1 aLi, Shuo1 aLiewald, David, C M1 aLim, Ee, Mun1 aLinneberg, Allan1 aMarina, Michela1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMedenwald, Daniel1 aMeisinger, Christa1 aMeulenbelt, Ingrid1 aDe Meyer, Tim1 aMeyer zu Schwabedissen, Henriette, E1 aMikolajczyk, Rafael1 aMoed, Matthijs1 aNetea-Maier, Romana, T1 aNolte, Ilja, M1 aOkada, Yukinori1 aPala, Mauro1 aPattaro, Cristian1 aPedersen, Oluf1 aPetersmann, Astrid1 aPorcu, Eleonora1 aPostmus, Iris1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aRamos, Yolande, F M1 aRawal, Rajesh1 aRedmond, Paul1 aRichards, Brent1 aRietzschel, Ernst, R1 aRivadeneira, Fernando1 aRoef, Greet1 aRotter, Jerome, I1 aSala, Cinzia, F1 aSchlessinger, David1 aSelvin, Elizabeth1 aSlagboom, Eline1 aSoranzo, Nicole1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStarr, John, M1 aStott, David, J1 aTaes, Youri1 aTaliun, Daniel1 aTanaka, Toshiko1 aThuesen, Betina1 aTiller, Daniel1 aToniolo, Daniela1 aUitterlinden, André, G1 aVisser, Edward1 aWalsh, John, P1 aWilson, Scott, G1 aWolffenbuttel, Bruce, H R1 aYang, Qiong1 aZheng, Hou-Feng1 aCappola, Anne1 aPeeters, Robin, P1 aNaitza, Silvia1 aVölzke, Henry1 aSanna, Serena1 aKöttgen, Anna1 aVisser, Theo, J1 aMedici, Marco1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/792705033nas a2201381 4500008004100000022001400041245013800055210006900193260001600262300000800278490000600286520112300292100001501415700002201430700002001452700001901472700002001491700001901511700002001530700001901550700001701569700001701586700002201603700001901625700001701644700002501661700002701686700002301713700002201736700001201758700001801770700002201788700002501810700001901835700001401854700001701868700002201885700002001907700002101927700002801948700002201976700001801998700002702016700002802043700003102071700001802102700002502120700002002145700002702165700001802192700001702210700002002227700001902247700002402266700002302290700002302313700001502336700002302351700002802374700001702402700002002419700002002439700001902459700002202478700002002500700002002520700001802540700002202558700002202580700002002602700002002622700002002642700002202662700002102684700003002705700002402735700002702759700002002786700002002806700002102826700002202847700001502869700002302884700002002907700002502927700002802952700002602980700001703006700001603023700002003039700002403059700002503083700002103108700002303129700001903152700001903171700002203190700002803212700002003240700002303260700001903283700002003302700001903322700001903341700002503360700002403385700002103409700002503430700001803455700002503473700001703498700002103515700002003536700002103556700001703577700002103594856003603615 2018 eng d a2041-172300aGenome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.0 aGenomewide association study in 79366 Europeanancestry individua c2018 Jan 17 a2600 v93 aVitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
1 aJiang, Xia1 aO'Reilly, Paul, F1 aAschard, Hugues1 aHsu, Yi-Hsiang1 aRichards, Brent1 aDupuis, Josée1 aIngelsson, Erik1 aKarasik, David1 aPilz, Stefan1 aBerry, Diane1 aKestenbaum, Bryan1 aZheng, Jusheng1 aLuan, Jianan1 aSofianopoulou, Eleni1 aStreeten, Elizabeth, A1 aAlbanes, Demetrius1 aLutsey, Pamela, L1 aYao, Lu1 aTang, Weihong1 aEcons, Michael, J1 aWallaschofski, Henri1 aVölzke, Henry1 aZhou, Ang1 aPower, Chris1 aMcCarthy, Mark, I1 aMichos, Erin, D1 aBoerwinkle, Eric1 aWeinstein, Stephanie, J1 aFreedman, Neal, D1 aHuang, Wen-Yi1 avan Schoor, Natasja, M1 avan der Velde, Nathalie1 ade Groot, Lisette, C P G M1 aEnneman, Anke1 aCupples, Adrienne, L1 aBooth, Sarah, L1 aVasan, Ramachandran, S1 aLiu, Ching-Ti1 aZhou, Yanhua1 aRipatti, Samuli1 aOhlsson, Claes1 aVandenput, Liesbeth1 aLorentzon, Mattias1 aEriksson, Johan, G1 aShea, Kyla1 aHouston, Denise, K1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aLohman, Kurt, K1 aFerrucci, Luigi1 aPeacock, Munro1 aGieger, Christian1 aBeekman, Marian1 aSlagboom, Eline1 aDeelen, Joris1 avan Heemst, Diana1 aKleber, Marcus, E1 aMärz, Winfried1 ade Boer, Ian, H1 aWood, Alexis, C1 aRotter, Jerome, I1 aRich, Stephen, S1 aRobinson-Cohen, Cassianne1 aHeijer, Martin, den1 aJarvelin, Marjo-Riitta1 aCavadino, Alana1 aJoshi, Peter, K1 aWilson, James, F1 aHayward, Caroline1 aLind, Lars1 aMichaëlsson, Karl1 aTrompet, Stella1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aBroer, Linda1 aZgaga, Lina1 aCampbell, Harry1 aTheodoratou, Evropi1 aFarrington, Susan, M1 aTimofeeva, Maria1 aDunlop, Malcolm, G1 aValdes, Ana, M1 aTikkanen, Emmi1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aKähönen, Mika1 aRaitakari, Olli, T1 aMikkilä, Vera1 aIkram, Arfan, M1 aSattar, Naveed1 aJukema, Wouter1 aWareham, Nicholas, J1 aLangenberg, Claudia1 aForouhi, Nita, G1 aGundersen, Thomas, E1 aKhaw, Kay-Tee1 aButterworth, Adam, S1 aDanesh, John1 aSpector, Timothy1 aWang, Thomas, J1 aHyppönen, Elina1 aKraft, Peter1 aKiel, Douglas, P uhttps://chs-nhlbi.org/node/766707247nas a2202185 4500008004100000022001400041245013000055210006900185260001500254300000900269490000600278520110800284653002001392653003101412653003501443653002101478653003801499653003401537653001101571653001401582653002801596653003601624653002801660653001701688100002301705700002801728700002201756700001701778700001901795700002401814700002201838700002401860700002301884700001601907700002001923700001901943700002101962700001701983700003002000700001902030700001502049700001902064700003302083700002102116700002002137700002002157700002102177700002502198700002002223700002302243700001802266700001902284700001802303700001902321700002302340700001902363700002202382700001902404700002802423700001702451700002102468700002002489700001902509700002002528700002002548700001602568700002102584700002302605700002302628700002502651700002402676700002002700700002502720700002302745700002002768700001502788700001902803700002002822700001702842700002102859700002002880700002002900700002102920700002602941700001902967700002002986700001903006700002003025700002003045700001903065700002003084700001803104700001903122700002503141700002203166700001603188700002303204700002003227700002003247700002003267700001703287700001803304700002003322700001903342700003103361700001503392700002303407700002203430700002003452700001803472700002103490700002103511700002103532700001803553700001903571700001903590700001903609700002003628700002103648700002603669700001903695700002203714700002203736700002003758700001803778700001703796700001803813700002103831700002103852700001903873700002203892700002303914700002303937700002503960700002203985700001604007700001604023700002104039700002004060700002004080700001704100700002304117700001604140700002204156700002204178700002504200700001504225700001804240700002104258700002304279700001604302700001804318700002004336700001704356700001804373700001904391700002204410700002404432700002004456700002004476700002304496700002304519700002904542700002204571700002004593700002104613700002104634700002204655700002304677700002004700700001904720700002804739700002104767700002204788700002304810700002404833700001704857700002404874700002404898700002804922700001904950700003004969710002604999856003605025 2018 eng d a2041-172300aGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.0 aGWAS and colocalization analyses implicate carotid intimamedia t c2018 12 03 a51410 v93 aCarotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
10aADAMTS9 Protein10aAmino Acid Oxidoreductases10aCarotid Intima-Media Thickness10aCoronary Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLod Score10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors1 aFranceschini, Nora1 aGiambartolomei, Claudia1 ade Vries, Paul, S1 aFinan, Chris1 aBis, Joshua, C1 aHuntley, Rachael, P1 aLovering, Ruth, C1 aTajuddin, Salman, M1 aWinkler, Thomas, W1 aGraff, Misa1 aKavousi, Maryam1 aDale, Caroline1 aSmith, Albert, V1 aHofer, Edith1 avan Leeuwen, Elisabeth, M1 aNolte, Ilja, M1 aLu, Lingyi1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aPitkänen, Niina1 aFranzén, Oscar1 aJoshi, Peter, K1 aNoordam, Raymond1 aMarioni, Riccardo, E1 aHwang, Shih-Jen1 aMusani, Solomon, K1 aSchminke, Ulf1 aPalmas, Walter1 aIsaacs, Aaron1 aCorrea, Adolfo1 aZonderman, Alan, B1 aHofman, Albert1 aTeumer, Alexander1 aCox, Amanda, J1 aUitterlinden, André, G1 aWong, Andrew1 aSmit, Andries, J1 aNewman, Anne, B1 aBritton, Annie1 aRuusalepp, Arno1 aSennblad, Bengt1 aHedblad, Bo1 aPasaniuc, Bogdan1 aPenninx, Brenda, W1 aLangefeld, Carl, D1 aWassel, Christina, L1 aTzourio, Christophe1 aFava, Cristiano1 aBaldassarre, Damiano1 aO'Leary, Daniel, H1 aTeupser, Daniel1 aKuh, Diana1 aTremoli, Elena1 aMannarino, Elmo1 aGrossi, Enzo1 aBoerwinkle, Eric1 aSchadt, Eric, E1 aIngelsson, Erik1 aVeglia, Fabrizio1 aRivadeneira, Fernando1 aBeutner, Frank1 aChauhan, Ganesh1 aHeiss, Gerardo1 aSnieder, Harold1 aCampbell, Harry1 aVölzke, Henry1 aMarkus, Hugh, S1 aDeary, Ian, J1 aJukema, Wouter1 ade Graaf, Jacqueline1 aPrice, Jacqueline1 aPott, Janne1 aHopewell, Jemma, C1 aLiang, Jingjing1 aThiery, Joachim1 aEngmann, Jorgen1 aGertow, Karl1 aRice, Kenneth1 aTaylor, Kent, D1 aDhana, Klodian1 aKiemeney, Lambertus, A L M1 aLind, Lars1 aRaffield, Laura, M1 aLauner, Lenore, J1 aHoldt, Lesca, M1 aDörr, Marcus1 aDichgans, Martin1 aTraylor, Matthew1 aSitzer, Matthias1 aKumari, Meena1 aKivimaki, Mika1 aNalls, Mike, A1 aMelander, Olle1 aRaitakari, Olli1 aFranco, Oscar, H1 aRueda-Ochoa, Oscar, L1 aRoussos, Panos1 aWhincup, Peter, H1 aAmouyel, Philippe1 aGiral, Philippe1 aAnugu, Pramod1 aWong, Quenna1 aMalik, Rainer1 aRauramaa, Rainer1 aBurkhardt, Ralph1 aHardy, Rebecca1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aMorris, Richard, W1 aStrawbridge, Rona, J1 aWannamethee, Goya1 aHägg, Sara1 aShah, Sonia1 aMcLachlan, Stela1 aTrompet, Stella1 aSeshadri, Sudha1 aKurl, Sudhir1 aHeckbert, Susan, R1 aRing, Susan1 aHarris, Tamara, B1 aLehtimäki, Terho1 aGalesloot, Tessel, E1 aShah, Tina1 ade Faire, Ulf1 aPlagnol, Vincent1 aRosamond, Wayne, D1 aPost, Wendy1 aZhu, Xiaofeng1 aZhang, Xiaoling1 aGuo, Xiuqing1 aSaba, Yasaman1 aDehghan, Abbas1 aSeldenrijk, Adrie1 aMorrison, Alanna, C1 aHamsten, Anders1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLawlor, Deborah, A1 aMook-Kanamori, Dennis, O1 aBowden, Donald, W1 aSchmidt, Helena1 aWilson, James, F1 aWilson, James, G1 aRotter, Jerome, I1 aWardlaw, Joanna, M1 aDeanfield, John1 aHalcox, Julian1 aLyytikäinen, Leo-Pekka1 aLoeffler, Markus1 aEvans, Michele, K1 aDebette, Stephanie1 aHumphries, Steve, E1 aVölker, Uwe1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aBjörkegren, Johan, L M1 aCasas, Juan, P1 aO'Donnell, Christopher, J1 aMEGASTROKE Consortium uhttps://chs-nhlbi.org/node/791303623nas a2200589 4500008004100000022001400041245009600055210006900151260001600220520189500236100002702131700002202158700002102180700002002201700002402221700002202245700002002267700002402287700001502311700001802326700001802344700002102362700002202383700001802405700002002423700002502443700002002468700002102488700002202509700002302531700002002554700002502574700002502599700001902624700002502643700002002668700002202688700002102710700001902731700001902750700002302769700002102792700002102813700001902834700001702853700002202870700002102892700002402913700002602937710003402963856003602997 2018 eng d a1460-238500aLow thyroid function is not associated with an accelerated deterioration in renal function.0 aLow thyroid function is not associated with an accelerated deter c2018 Apr 183 aBackground: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.
Methods: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.
Results: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.
Conclusions: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.
1 aMeuwese, Christiaan, L1 avan Diepen, Merel1 aCappola, Anne, R1 aSarnak, Mark, J1 aShlipak, Michael, G1 aBauer, Douglas, C1 aFried, Linda, P1 aIacoviello, Massimo1 aVaes, Bert1 aDegryse, Jean1 aKhaw, Kay-Tee1 aLuben, Robert, N1 aAsvold, Bjørn, O1 aBjøro, Trine1 aVatten, Lars, J1 ade Craen, Anton, J M1 aTrompet, Stella1 aIervasi, Giorgio1 aMolinaro, Sabrina1 aCeresini, Graziano1 aFerrucci, Luigi1 aDullaart, Robin, P F1 aBakker, Stephan, J L1 aJukema, Wouter1 aKearney, Patricia, M1 aStott, David, J1 aPeeters, Robin, P1 aFranco, Oscar, H1 aVölzke, Henry1 aWalsh, John, P1 aBremner, Alexandra1 aSgarbi, José, A1 aMaciel, Rui, M B1 aImaizumi, Misa1 aOhishi, Waka1 aDekker, Friedo, W1 aRodondi, Nicolas1 aGussekloo, Jacobijn1 aElzen, Wendy, P J den1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/780516401nas 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/768305872nas a2201645 4500008004100000022001400041245013800055210006900193260001600262300000900278490000600287520118400293100002401477700002301501700002001524700002401544700002001568700002001588700002601608700002101634700001901655700002801674700002201702700002201724700002801746700002301774700003001797700001901827700002501846700002401871700002301895700002101918700002201939700002001961700002201981700002002003700001802023700001802041700001702059700002002076700002702096700001902123700001802142700001402160700002402174700002102198700001902219700002402238700001902262700001902281700002202300700001902322700002402341700002002365700002202385700002402407700002202431700002102453700001702474700002202491700001602513700001902529700002102548700002002569700001802589700001702607700002302624700002202647700001902669700001802688700002002706700002202726700002502748700002202773700002402795700002202819700002502841700002002866700002802886700002002914700001802934700002602952700002302978700002203001700001603023700002203039700002403061700002903085700002203114700002303136700002003159700002403179700002403203700002003227700002403247700002303271700002803294700002803322700002603350700001703376700001903393700002603412700002203438700002103460700001803481700001903499700002203518700002503540700002403565700002103589700001803610700002003628700002103648700002403669700002203693700002303715700002103738700001903759700001903778700002203797700001703819700002403836700001803860700001903878700002003897700001803917700002403935700002403959700002103983700002304004700001504027700002304042700002104065700002004086700002504106700001804131700001904149700002204168856003604190 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/781505160nas a2201237 4500008004100000022001400041245019700055210006900252260000900321300001300330490000700343520163700350653000901987653002801996653003502024653001102059653001102070653003202081653000902113653001602122653001402138653001702152100002402169700001202193700002502205700002902230700002702259700002302286700001702309700002102326700001902347700002102366700001702387700001802404700002802422700001502450700002002465700002502485700001902510700002102529700002302550700001702573700002002590700002302610700002002633700002702653700001802680700002302698700002302721700001902744700002202763700002002785700002102805700001702826700001902843700002102862700002302883700002402906700001602930700002202946700002602968700002102994700001903015700001803034700002003052700002003072700002103092700001803113700001603131700001903147700001903166700001503185700002203200700002303222700002403245700003003269700002103299700002103320700002303341700002003364700001903384700001803403700002103421700002003442700002603462700001903488700002103507700001803528700002003546700001903566700002603585700002503611700002403636700001903660700002003679700002003699700001403719700002503733700002003758700001903778700002103797700002003818700002303838710002503861856003603886 2018 eng d a1932-620300aPredictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.0 aPredictive value for cardiovascular events of common carotid int c2018 ae01911720 v133 aAIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.
METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C.
CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
10aAged10aCardiovascular Diseases10aCarotid Intima-Media Thickness10aFemale10aHumans10aIntersectoral Collaboration10aMale10aMiddle Aged10aPrognosis10aRisk Factors1 aLorenz, Matthias, W1 aGao, Lu1 aZiegelbauer, Kathrin1 aNorata, Giuseppe, Danilo1 aEmpana, Jean, Philippe1 aSchmidtmann, Irene1 aLin, Hung-Ju1 aMcLachlan, Stela1 aBokemark, Lena1 aRonkainen, Kimmo1 aAmato, Mauro1 aSchminke, Ulf1 aSrinivasan, Sathanur, R1 aLind, Lars1 aOkazaki, Shuhei1 aStehouwer, Coen, D A1 aWilleit, Peter1 aPolak, Joseph, F1 aSteinmetz, Helmuth1 aSander, Dirk1 aPoppert, Holger1 aDesvarieux, Moïse1 aIkram, Arfan, M1 aJohnsen, Stein, Harald1 aStaub, Daniel1 aSirtori, Cesare, R1 aIglseder, Bernhard1 aBeloqui, Oscar1 aEngström, Gunnar1 aFriera, Alfonso1 aRozza, Francesco1 aXie, Wuxiang1 aParraga, Grace1 aGrigore, Liliana1 aPlichart, Matthieu1 aBlankenberg, Stefan1 aSu, Ta-Chen1 aSchmidt, Caroline1 aTuomainen, Tomi-Pekka1 aVeglia, Fabrizio1 aVölzke, Henry1 aNijpels, Giel1 aWilleit, Johann1 aSacco, Ralph, L1 aFranco, Oscar, H1 aUthoff, Heiko1 aHedblad, Bo1 aSuarez, Carmen1 aIzzo, Raffaele1 aZhao, Dong1 aWannarong, Thapat1 aCatapano, Alberico1 aDucimetiere, Pierre1 aEspinola-Klein, Christine1 aChien, Kuo-Liong1 aPrice, Jackie, F1 aBergström, Göran1 aKauhanen, Jussi1 aTremoli, Elena1 aDörr, Marcus1 aBerenson, Gerald1 aKitagawa, Kazuo1 aDekker, Jacqueline, M1 aKiechl, Stefan1 aSitzer, Matthias1 aBickel, Horst1 aRundek, Tatjana1 aHofman, Albert1 aMathiesen, Ellisiv, B1 aCastelnuovo, Samuela1 aLandecho, Manuel, F1 aRosvall, Maria1 aGabriel, Rafael1 ade Luca, Nicola1 aLiu, Jing1 aBaldassarre, Damiano1 aKavousi, Maryam1 ade Groot, Eric1 aBots, Michiel, L1 aYanez, David, N1 aThompson, Simon, G1 aPROG-IMT Study Group uhttps://chs-nhlbi.org/node/784603682nas a2200577 4500008004100000022001400041245010400055210006900159260001600228520196600244100002302210700002202233700002202255700001902277700002302296700002502319700002202344700002102366700002302387700001802410700002502428700001902453700002002472700002102492700002102513700002402534700002102558700001902579700001902598700001802617700002102635700002202656700002002678700002202698700002202720700002002742700001802762700002502780700002702805700002002832700001502852700002602867700001902893700002602912700002102938700002502959700002402984700002603008710003403034856003603068 2018 eng d a1945-719700aThe relation between thyroid function and anemia: a pooled analysis of individual participant data.0 arelation between thyroid function and anemia a pooled analysis o c2018 Aug 023 aContext: Anemia and thyroid dysfunction often co-occur and both increase with age. Human data on the relationship between thyroid disease and anemia are scarce.
Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia.
Design: Individual participant data meta-analysis.
Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n=42 162).
Main outcome measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women).
Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants (overt hypothyroidism, pooled odds ratio 1.84 [95% CI: 1.35-2.50], subclinical hypothyroidism 1.21 [1.02-1.43], subclinical hyperthyroidism 1.27 [1.03-1.57], overt hyperthyroidism 1.69 [1.00-2.87]). Hemoglobin levels were lower in all groups compared to participants with euthyroidism. In the longitudinal analyses (n=25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 [95% CI: 0.86-2.20] for overt hypothyroidism, 1.18 [1.00-1.38] for subclinical hypothyroidism, 1.15 [0.94-1.42] for subclinical hyperthyroidism and 1.47 [0.91-2.38] for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups.
Conclusion: Higher odds of having anemia were observed in both participants with hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.
1 aWopereis, Daisy, M1 aPuy, Robert, S Du1 avan Heemst, Diana1 aWalsh, John, P1 aBremner, Alexandra1 aBakker, Stephan, J L1 aBauer, Douglas, C1 aCappola, Anne, R1 aCeresini, Graziano1 aDegryse, Jean1 aDullaart, Robin, P F1 aFeller, Martin1 aFerrucci, Luigi1 aFloriani, Carmen1 aFranco, Oscar, H1 aIacoviello, Massimo1 aIervasi, Georgio1 aImaizumi, Misa1 aJukema, Wouter1 aKhaw, Kay-Tee1 aLuben, Robert, N1 aMolinaro, Sabrina1 aNauck, Matthias1 aPatel, Kushang, V1 aPeeters, Robin, P1 aPsaty, Bruce, M1 aRazvi, Salman1 aSchindhelm, Roger, K1 avan Schoor, Natasja, M1 aStott, David, J1 aVaes, Bert1 aVanderpump, Mark, P J1 aVölzke, Henry1 aWestendorp, Rudi, G J1 aRodondi, Nicolas1 aCobbaert, Christa, M1 aGussekloo, Jacobijn1 aElzen, Wendy, P J den1 aThyroid Studies Collaboration uhttps://chs-nhlbi.org/node/781708059nas a2201585 4500008004100000022001400041245015200055210006900207260001500276300001400291490000800305520349800313100002003811700002103831700002503852700001903877700002403896700001903920700001703939700001803956700002203974700002103996700001704017700001904034700001904053700002004072700002104092700002904113700001904142700002104161700001904182700002004201700002804221700001604249700002104265700001904286700002104305700002104326700002004347700002104367700002204388700001804410700001804428700002104446700002104467700002004488700003504508700001904543700002304562700002204585700002504607700002204632700002204654700001804676700002004694700001904714700002404733700002304757700002004780700002304800700002604823700002404849700002104873700002404894700002304918700001804941700002004959700001904979700002104998700001905019700002205038700002005060700001605080700002105096700002605117700002105143700002005164700001905184700003105203700001905234700002405253700001705277700002005294700002105314700001805335700002205353700002205375700002005397700002005417700003305437700002205470700002605492700001805518700002605536700003005562700002405592700001905616700001705635700002005652700001805672700002405690700001805714700002005732700002605752700001805778700002205796700002505818700002005843700002205863700002105885700002005906700002305926700002205949700002105971700002005992700002406012700002106036700001806057700002306075700002306098700001406121700001906135700001806154700002306172700002006195700001906215700002406234700001806258700001706276700001706293700003006310700001706340710008006357856003606437 2018 eng d a1474-547X00aRisk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.0 aRisk thresholds for alcohol consumption combined analysis of ind c2018 04 14 a1513-15230 v3913 aBACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.
METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies.
FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.
INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.
FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.
1 aWood, Angela, M1 aKaptoge, Stephen1 aButterworth, Adam, S1 aWilleit, Peter1 aWarnakula, Samantha1 aBolton, Thomas1 aPaige, Ellie1 aPaul, Dirk, S1 aSweeting, Michael1 aBurgess, Stephen1 aBell, Steven1 aAstle, William1 aStevens, David1 aKoulman, Albert1 aSelmer, Randi, M1 aVerschuren, W, M Monique1 aSato, Shinichi1 aNjølstad, Inger1 aWoodward, Mark1 aSalomaa, Veikko1 aNordestgaard, Børge, G1 aYeap, Bu, B1 aFletcher, Astrid1 aMelander, Olle1 aKuller, Lewis, H1 aBalkau, Beverley1 aMarmot, Michael1 aKoenig, Wolfgang1 aCasiglia, Edoardo1 aCooper, Cyrus1 aArndt, Volker1 aFranco, Oscar, H1 aWennberg, Patrik1 aGallacher, John1 ade la Cámara, Agustin, Gómez1 aVölzke, Henry1 aDahm, Christina, C1 aDale, Caroline, E1 aBergmann, Manuela, M1 aCrespo, Carlos, J1 aSchouw, Yvonne, T1 aKaaks, Rudolf1 aSimons, Leon, A1 aLagiou, Pagona1 aSchoufour, Josje, D1 aBoer, Jolanda, M A1 aKey, Timothy, J1 aRodriguez, Beatriz1 aMoreno-Iribas, Conchi1 aDavidson, Karina, W1 aTaylor, James, O1 aSacerdote, Carlotta1 aWallace, Robert, B1 aQuiros, Ramon1 aTumino, Rosario1 aBlazer, Dan, G1 aLinneberg, Allan1 aDaimon, Makoto1 aPanico, Salvatore1 aHoward, Barbara1 aSkeie, Guri1 aStrandberg, Timo1 aWeiderpass, Elisabete1 aNietert, Paul, J1 aPsaty, Bruce, M1 aKromhout, Daan1 aSalamanca-Fernandez, Elena1 aKiechl, Stefan1 aKrumholz, Harlan, M1 aGrioni, Sara1 aPalli, Domenico1 aHuerta, José, M1 aPrice, Jackie1 aSundström, Johan1 aArriola, Larraitz1 aArima, Hisatomi1 aTravis, Ruth, C1 aPanagiotakos, Demosthenes, B1 aKarakatsani, Anna1 aTrichopoulou, Antonia1 aKühn, Tilman1 aGrobbee, Diederick, E1 aBarrett-Connor, Elizabeth1 avan Schoor, Natasja1 aBoeing, Heiner1 aOvervad, Kim1 aKauhanen, Jussi1 aWareham, Nick1 aLangenberg, Claudia1 aForouhi, Nita1 aWennberg, Maria1 aDesprés, Jean-Pierre1 aCushman, Mary1 aCooper, Jackie, A1 aRodriguez, Carlos, J1 aSakurai, Masaru1 aShaw, Jonathan, E1 aKnuiman, Matthew1 aVoortman, Trudy1 aMeisinger, Christa1 aTjønneland, Anne1 aBrenner, Hermann1 aPalmieri, Luigi1 aDallongeville, Jean1 aBrunner, Eric, J1 aAssmann, Gerd1 aTrevisan, Maurizio1 aGillum, Richard, F1 aFord, Ian1 aSattar, Naveed1 aLazo, Mariana1 aThompson, Simon, G1 aFerrari, Pietro1 aLeon, David, A1 aSmith, George Davey1 aPeto, Richard1 aJackson, Rod1 aBanks, Emily1 aDi Angelantonio, Emanuele1 aDanesh, John1 aEmerging Risk Factors Collaboration/EPIC-CVD/UK Biobank Alcohol Study Group uhttps://chs-nhlbi.org/node/766404940nas 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/797301454nas a2200493 4500008004100000022001400041245010500055210006900160260001300229300001200242490000700254100001800261700002200279700002300301700002300324700002300347700002200370700002200392700001800414700001600432700001500448700002300463700001700486700002400503700002200527700002200549700002000571700002400591700002100615700002000636700001900656700002000675700002200695700002000717700002500737700002200762700002200784700002000806700002800826700002200854700002400876700002400900856003600924 2019 eng d a2574-830000aCommon Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation.0 aCommon Genetic Variation in Relation to Brachial Vascular Dimens c2019 Feb ae0024090 v121 aDörr, Marcus1 aHamburg, Naomi, M1 aMüller, Christian1 aSmith, Nicholas, L1 aGustafsson, Stefan1 aLehtimäki, Terho1 aTeumer, Alexander1 aZeller, Tanja1 aLi, Xiaohui1 aLind, Lars1 aRaitakari, Olli, T1 aVölker, Uwe1 aBlankenberg, Stefan1 aMcKnight, Barbara1 aMorris, Andrew, P1 aKähönen, Mika1 aLemaitre, Rozenn, N1 aWild, Philipp, S1 aNauck, Matthias1 aVölzke, Henry1 aMünzel, Thomas1 aMitchell, Gary, F1 aPsaty, Bruce, M1 aLindgren, Cecilia, M1 aLarson, Martin, G1 aFelix, Stephan, B1 aIngelsson, Erik1 aLyytikäinen, Leo-Pekka1 aHerrington, David1 aBenjamin, Emelia, J1 aSchnabel, Renate, B uhttps://chs-nhlbi.org/node/797207560nas a2202017 4500008004100000022001400041245004500055210004400100260001600144300001200160490000800172520198400180100001902164700002502183700001902208700001802227700002302245700001602268700001902284700002202303700001802325700002102343700002302364700001702387700002102404700001802425700002002443700002702463700002002490700002202510700002202532700001502554700001602569700002102585700001802606700002402624700003102648700002502679700001702704700002102721700002202742700002402764700002102788700001902809700002302828700001902851700002102870700002102891700001202912700002202924700002102946700002402967700002202991700002203013700001903035700001803054700002003072700002003092700001803112700002003130700002003150700002303170700001803193700001903211700002203230700001603252700002103268700001803289700002803307700001803335700002703353700002203380700002203402700002203424700002503446700002103471700002103492700002203513700001903535700001603554700001703570700002303587700002103610700002103631700002003652700001503672700002203687700001703709700002203726700002103748700002003769700002303789700001803812700002103830700001603851700002303867700002803890700002203918700001903940700002003959700002303979700002504002700002204027700002004049700002104069700002004090700002604110700001904136700002004155700001904175700001904194700001904213700002004232700002304252700002004275700002304295700002304318700002004341700002604361700002104387700002204408700001604430700002004446700002504466700001904491700002004510700002104530700001904551700002004570700002404590700002504614700002104639700003504660700001904695700002704714700002604741700002204767700002304789700002404812700002504836700002804861700001904889700002304908700002804931700002304959700002704982700002405009700002405033700001905057700002605076700001705102700002505119700002105144700002305165700002205188700002105210700002705231700002105258700002205279700003105301700001205332700001805344700001905362700001705381700002305398700002205421700002305443700002105466700001905487856003605506 2019 eng d a1938-320700aDisentangling the genetics of lean mass.0 aDisentangling the genetics of lean mass c2019 Feb 01 a276-2870 v1093 aBackground: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.
Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.
Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).
Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.
Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
1 aKarasik, David1 aZillikens, Carola, M1 aHsu, Yi-Hsiang1 aAghdassi, Ali1 aÅkesson, Kristina1 aAmin, Najaf1 aBarroso, Inês1 aBennett, David, A1 aBertram, Lars1 aBochud, Murielle1 aBorecki, Ingrid, B1 aBroer, Linda1 aBuchman, Aron, S1 aByberg, Liisa1 aCampbell, Harry1 aCampos-Obando, Natalia1 aCauley, Jane, A1 aCawthon, Peggy, M1 aChambers, John, C1 aChen, Zhao1 aCho, Nam, H1 aChoi, Hyung, Jin1 aChou, Wen-Chi1 aCummings, Steven, R1 ade Groot, Lisette, C P G M1 aDe Jager, Phillip, L1 aDemuth, Ilja1 aDiatchenko, Luda1 aEcons, Michael, J1 aEiriksdottir, Gudny1 aEnneman, Anke, W1 aEriksson, Joel1 aEriksson, Johan, G1 aEstrada, Karol1 aEvans, Daniel, S1 aFeitosa, Mary, F1 aFu, Mao1 aGieger, Christian1 aGrallert, Harald1 aGudnason, Vilmundur1 aLenore, Launer, J1 aHayward, Caroline1 aHofman, Albert1 aHomuth, Georg1 aHuffman, Kim, M1 aHusted, Lise, B1 aIllig, Thomas1 aIngelsson, Erik1 aIttermann, Till1 aJansson, John-Olov1 aJohnson, Toby1 aBiffar, Reiner1 aJordan, Joanne, M1 aJula, Antti1 aKarlsson, Magnus1 aKhaw, Kay-Tee1 aKilpeläinen, Tuomas, O1 aKlopp, Norman1 aKloth, Jacqueline, S L1 aKoller, Daniel, L1 aKooner, Jaspal, S1 aKraus, William, E1 aKritchevsky, Stephen1 aKutalik, Zoltán1 aKuulasmaa, Teemu1 aKuusisto, Johanna1 aLaakso, Markku1 aLahti, Jari1 aLang, Thomas1 aLangdahl, Bente, L1 aLerch, Markus, M1 aLewis, Joshua, R1 aLill, Christina1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLivshits, Gregory1 aLjunggren, Osten1 aLoos, Ruth, J F1 aLorentzon, Mattias1 aLuan, Jian'an1 aLuben, Robert, N1 aMalkin, Ida1 aMcGuigan, Fiona, E1 aMedina-Gómez, Carolina1 aMeitinger, Thomas1 aMelhus, Håkan1 aMellström, Dan1 aMichaëlsson, Karl1 aMitchell, Braxton, D1 aMorris, Andrew, P1 aMosekilde, Leif1 aNethander, Maria1 aNewman, Anne, B1 aO'Connell, Jeffery, R1 aOostra, Ben, A1 aOrwoll, Eric, S1 aPalotie, Aarno1 aPeacock, Munro1 aPerola, Markus1 aPeters, Annette1 aPrince, Richard, L1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRalston, Stuart, H1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRobbins, John, A1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSatterfield, Suzanne1 aSchipf, Sabine1 aShin, Chan, Soo1 aSmith, Albert, V1 aSmith, Shad, B1 aSoranzo, Nicole1 aSpector, Timothy, D1 aStančáková, Alena1 aStefansson, Kari1 aSteinhagen-Thiessen, Elisabeth1 aStolk, Lisette1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aSwart, Karin, M A1 aThompson, Patricia1 aThomson, Cynthia, A1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTikkanen, Emmi1 aTranah, Gregory, J1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 avan Schoor, Natasja, M1 aVandenput, Liesbeth1 aVollenweider, Peter1 aVölzke, Henry1 aWactawski-Wende, Jean1 aWalker, Mark1 aWareham, Nicholas, J1 aWaterworth, Dawn1 aWeedon, Michael, N1 aWichmann, H-Erich1 aWiden, Elisabeth1 aWilliams, Frances, M K1 aWilson, James, F1 aWright, Nicole, C1 aYerges-Armstrong, Laura, M1 aYu, Lei1 aZhang, Weihua1 aZhao, Jing Hua1 aZhou, Yanhua1 aNielson, Carrie, M1 aHarris, Tamara, B1 aDemissie, Serkalem1 aKiel, Douglas, P1 aOhlsson, Claes uhttps://chs-nhlbi.org/node/797411242nas a2203601 4500008004100000022001400041245008000055210006900135260001300204300001400217490000700231520105900238100002601297700002201323700002101345700002201366700001901388700002001407700001901427700003301446700002001479700002801499700002101527700001901548700001701567700002201584700001701606700002201623700002501645700001801670700001901688700001601707700001301723700001501736700001701751700002001768700002601788700002901814700002001843700002301863700002501886700001701911700001701928700002501945700001601970700002101986700002302007700002202030700002202052700002102074700001802095700002202113700002002135700002102155700002202176700002002198700002002218700002902238700001902267700002102286700002102307700001602328700001802344700002102362700002002383700002302403700002202426700001902448700002002467700002102487700002402508700002202532700002102554700002202575700002502597700001802622700002902640700001602669700001702685700001802702700002902720700002802749700002102777700001602798700002202814700001702836700002302853700002102876700002302897700002602920700002302946700002102969700002602990700002003016700002303036700001903059700001903078700003303097700002203130700001503152700002303167700002003190700002103210700001603231700002103247700001903268700002203287700002203309700002103331700002003352700002703372700002003399700002303419700002003442700002503462700001703487700002503504700002303529700002303552700002203575700002203597700002003619700001703639700001903656700001703675700002703692700002203719700002403741700002303765700002203788700003403810700002103844700002203865700002403887700002203911700002203933700002403955700002703979700002004006700001304026700002404039700001904063700002304082700001904105700001904124700001704143700002504160700002804185700002604213700002404239700002104263700002404284700001904308700002604327700002404353700002104377700002004398700002304418700002104441700003304462700002404495700002304519700002104542700002004563700001804583700001904601700002604620700002004646700001904666700002804685700002104713700001904734700001904753700002504772700001804797700002004815700002004835700002504855700002304880700002304903700002404926700002004950700003004970700001705000700002705017700003405044700001605078700002005094700002105114700002605135700002205161700002905183700001905212700002205231700002405253700002605277700002205303700002205325700001305347700001905360700002005379700001905399700002405418700002505442700002205467700001705489700002205506700003005528700002005558700002205578700002805600700002605628700002005654700002005674700002505694700002105719700001805740700002405758700002705782700001805809700002305827700002405850700002505874700001805899700002205917700002705939700002105966700002305987700002206010700002106032700002106053700002306074700002006097700002106117700002006138700002106158700001806179700002206197700002806219700002306247700002106270700002206291700002306313700002206336700002006358700002306378700002206401700002006423700001806443700002406461700001706485700001806502700001906520700002406539700001706563700001806580700002306598700002006621700001906641700002406660700002406684700002306708700002006731700002206751700002506773700002606798700002406824700002806848700002106876700002106897700001906918700002206937700002106959700002906980700002607009700002407035700002407059700002307083700001907106700002407125700002107149700002007170700002207190700001907212700002307231700002207254700002307276700002007299700002007319700002307339700002207362700002107384700002407405700002107429700002307450700002407473700002207497700002307519700002207542700002007564700002007584856003607604 2019 eng d a1546-171800aGenetic architecture of subcortical brain structures in 38,851 individuals.0 aGenetic architecture of subcortical brain structures in 38851 in c2019 Nov a1624-16360 v513 aSubcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
1 aSatizabal, Claudia, L1 aAdams, Hieab, H H1 aHibar, Derrek, P1 aWhite, Charles, C1 aKnol, Maria, J1 aStein, Jason, L1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aJahanshad, Neda1 aRoshchupkin, Gennady, V1 aSmith, Albert, V1 aBis, Joshua, C1 aJian, Xueqiu1 aLuciano, Michelle1 aHofer, Edith1 aTeumer, Alexander1 avan der Lee, Sven, J1 aYang, Jingyun1 aYanek, Lisa, R1 aLee, Tom, V1 aLi, Shuo1 aHu, Yanhui1 aKoh, Jia, Yu1 aEicher, John, D1 aDesrivières, Sylvane1 aArias-Vasquez, Alejandro1 aChauhan, Ganesh1 aAthanasiu, Lavinia1 aRentería, Miguel, E1 aKim, Sungeun1 aHoehn, David1 aArmstrong, Nicola, J1 aChen, Qiang1 aHolmes, Avram, J1 aBraber, Anouk, den1 aKloszewska, Iwona1 aAndersson, Micael1 aEspeseth, Thomas1 aGrimm, Oliver1 aAbramovic, Lucija1 aAlhusaini, Saud1 aMilaneschi, Yuri1 aPapmeyer, Martina1 aAxelsson, Tomas1 aEhrlich, Stefan1 aRoiz-Santiañez, Roberto1 aKraemer, Bernd1 aHåberg, Asta, K1 aJones, Hannah, J1 aPike, Bruce1 aStein, Dan, J1 aStevens, Allison1 aBralten, Janita1 aVernooij, Meike, W1 aHarris, Tamara, B1 aFilippi, Irina1 aWitte, Veronica1 aGuadalupe, Tulio1 aWittfeld, Katharina1 aMosley, Thomas, H1 aBecker, James, T1 aDoan, Nhat, Trung1 aHagenaars, Saskia, P1 aSaba, Yasaman1 aCuellar-Partida, Gabriel1 aAmin, Najaf1 aHilal, Saima1 aNho, Kwangsik1 aMirza-Schreiber, Nazanin1 aArfanakis, Konstantinos1 aBecker, Diane, M1 aAmes, David1 aGoldman, Aaron, L1 aLee, Phil, H1 aBoomsma, Dorret, I1 aLovestone, Simon1 aGiddaluru, Sudheer1 aLe Hellard, Stephanie1 aMattheisen, Manuel1 aBohlken, Marc, M1 aKasperaviciute, Dalia1 aSchmaal, Lianne1 aLawrie, Stephen, M1 aAgartz, Ingrid1 aWalton, Esther1 aTordesillas-Gutierrez, Diana1 aDavies, Gareth, E1 aShin, Jean1 aIpser, Jonathan, C1 aVinke, Louis, N1 aHoogman, Martine1 aJia, Tianye1 aBurkhardt, Ralph1 aKlein, Marieke1 aCrivello, Fabrice1 aJanowitz, Deborah1 aCarmichael, Owen1 aHaukvik, Unn, K1 aAribisala, Benjamin, S1 aSchmidt, Helena1 aStrike, Lachlan, T1 aCheng, Ching-Yu1 aRisacher, Shannon, L1 aPütz, Benno1 aFleischman, Debra, A1 aAssareh, Amelia, A1 aMattay, Venkata, S1 aBuckner, Randy, L1 aMecocci, Patrizia1 aDale, Anders, M1 aCichon, Sven1 aBoks, Marco, P1 aMatarin, Mar1 aPenninx, Brenda, W J H1 aCalhoun, Vince, D1 aChakravarty, Mallar1 aMarquand, Andre, F1 aMacare, Christine1 aMasouleh, Shahrzad, Kharabian1 aOosterlaan, Jaap1 aAmouyel, Philippe1 aHegenscheid, Katrin1 aRotter, Jerome, I1 aSchork, Andrew, J1 aLiewald, David, C M1 ade Zubicaray, Greig, I1 aWong, Tien, Yin1 aShen, Li1 aSämann, Philipp, G1 aBrodaty, Henry1 aRoffman, Joshua, L1 aGeus, Eco, J C1 aTsolaki, Magda1 aErk, Susanne1 avan Eijk, Kristel, R1 aCavalleri, Gianpiero, L1 avan der Wee, Nic, J A1 aMcIntosh, Andrew, M1 aGollub, Randy, L1 aBulayeva, Kazima, B1 aBernard, Manon1 aRichards, Jennifer, S1 aHimali, Jayandra, J1 aLoeffler, Markus1 aRommelse, Nanda1 aHoffmann, Wolfgang1 aWestlye, Lars, T1 aHernández, Maria, C Valdés1 aHansell, Narelle, K1 avan Erp, Theo, G M1 aWolf, Christiane1 aKwok, John, B J1 aVellas, Bruno1 aHeinz, Andreas1 aLoohuis, Loes, M Olde1 aDelanty, Norman1 aHo, Beng-Choon1 aChing, Christopher, R K1 aShumskaya, Elena1 aSingh, Baljeet1 aHofman, Albert1 avan der Meer, Dennis1 aHomuth, Georg1 aPsaty, Bruce, M1 aBastin, Mark, E1 aMontgomery, Grant, W1 aForoud, Tatiana, M1 aReppermund, Simone1 aHottenga, Jouke-Jan1 aSimmons, Andrew1 aMeyer-Lindenberg, Andreas1 aCahn, Wiepke1 aWhelan, Christopher, D1 avan Donkelaar, Marjolein, M J1 aYang, Qiong1 aHosten, Norbert1 aGreen, Robert, C1 aThalamuthu, Anbupalam1 aMohnke, Sebastian1 aPol, Hilleke, E Hulshoff1 aLin, Honghuang1 aJack, Clifford, R1 aSchofield, Peter, R1 aMühleisen, Thomas, W1 aMaillard, Pauline1 aPotkin, Steven, G1 aWen, Wei1 aFletcher, Evan1 aToga, Arthur, W1 aGruber, Oliver1 aHuentelman, Matthew1 aSmith, George, Davey1 aLauner, Lenore, J1 aNyberg, Lars1 aJönsson, Erik, G1 aCrespo-Facorro, Benedicto1 aKoen, Nastassja1 aGreve, Douglas, N1 aUitterlinden, André, G1 aWeinberger, Daniel, R1 aSteen, Vidar, M1 aFedko, Iryna, O1 aGroenewold, Nynke, A1 aNiessen, Wiro, J1 aToro, Roberto1 aTzourio, Christophe1 aLongstreth, William, T1 aIkram, Kamran1 aSmoller, Jordan, W1 avan Tol, Marie-Jose1 aSussmann, Jessika, E1 aPaus, Tomáš1 aLemaître, Hervé1 aSchroeter, Matthias, L1 aMazoyer, Bernard1 aAndreassen, Ole, A1 aHolsboer, Florian1 aDepondt, Chantal1 aVeltman, Dick, J1 aTurner, Jessica, A1 aPausova, Zdenka1 aSchumann, Gunter1 avan Rooij, Daan1 aDjurovic, Srdjan1 aDeary, Ian, J1 aMcMahon, Katie, L1 aMüller-Myhsok, Bertram1 aBrouwer, Rachel, M1 aSoininen, Hilkka1 aPandolfo, Massimo1 aWassink, Thomas, H1 aCheung, Joshua, W1 aWolfers, Thomas1 aMartinot, Jean-Luc1 aZwiers, Marcel, P1 aNauck, Matthias1 aMelle, Ingrid1 aMartin, Nicholas, G1 aKanai, Ryota1 aWestman, Eric1 aKahn, René, S1 aSisodiya, Sanjay, M1 aWhite, Tonya1 aSaremi, Arvin1 avan Bokhoven, Hans1 aBrunner, Han, G1 aVölzke, Henry1 aWright, Margaret, J1 aEnt, Dennis, van 't1 aNöthen, Markus, M1 aOphoff, Roel, A1 aBuitelaar, Jan, K1 aFernández, Guillén1 aSachdev, Perminder, S1 aRietschel, Marcella1 avan Haren, Neeltje, E M1 aFisher, Simon, E1 aBeiser, Alexa, S1 aFrancks, Clyde1 aSaykin, Andrew, J1 aMather, Karen, A1 aRomanczuk-Seiferth, Nina1 aHartman, Catharina, A1 aDeStefano, Anita, L1 aHeslenfeld, Dirk, J1 aWeiner, Michael, W1 aWalter, Henrik1 aHoekstra, Pieter, J1 aNyquist, Paul, A1 aFranke, Barbara1 aBennett, David, A1 aGrabe, Hans, J1 aJohnson, Andrew, D1 aChen, Christopher1 aDuijn, Cornelia, M1 aLopez, Oscar, L1 aFornage, Myriam1 aWardlaw, Joanna, M1 aSchmidt, Reinhold1 aDeCarli, Charles1 aDe Jager, Philip, L1 aVillringer, Arno1 aDebette, Stephanie1 aGudnason, Vilmundur1 aMedland, Sarah, E1 aShulman, Joshua, M1 aThompson, Paul, M1 aSeshadri, Sudha1 aIkram, Arfan, M uhttps://chs-nhlbi.org/node/820606391nas a2201909 4500008004100000022001400041245012500055210006900180260001600249300000900265490000700274520109900281100002101380700001901401700001701420700002301437700002001460700002801480700002201508700001801530700002101548700001901569700001901588700002001607700002201627700001401649700002301663700002301686700002101709700002001730700002301750700002001773700002601793700001801819700002401837700001801861700001701879700001601896700001701912700001501929700001701944700002901961700002001990700002402010700002502034700001402059700002102073700002102094700001702115700002502132700002002157700001402177700002102191700002802212700002502240700001902265700002602284700002102310700001702331700002002348700001802368700001702386700001902403700001902422700002502441700001802466700002402484700002102508700001602529700002402545700001502569700002002584700002402604700002202628700002202650700002002672700002102692700002102713700001802734700002002752700002202772700002102794700001502815700001702830700002002847700002302867700001802890700002002908700002202928700002102950700002102971700001902992700002003011700002003031700002103051700002303072700002003095700002503115700001903140700002103159700002103180700002203201700002503223700001903248700002303267700001603290700002403306700001703330700002403347700002203371700002003393700002803413700002303441700001903464700002603483700002403509700002103533700001703554700002303571700002103594700001803615700001603633700002203649700001903671700001903690700002203709700001903731700002703750700002403777700002603801700001703827700002103844700001503865700002103880700002103901700002203922700002403944700001903968700002103987700002804008700002004036700002604056700001904082700002004101700002004121700001804141700001604159700002504175700002004200700001804220700001704238700002104255700001804276700002404294700002404318700001804342700002404360700002004384700002204404700001904426856003604445 2019 eng d a2041-172300aMulti-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.0 aMultiancestry sleepbySNP interaction analysis in 126926 individu c2019 Nov 12 a51210 v103 aBoth short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
1 aNoordam, Raymond1 aBos, Maxime, M1 aWang, Heming1 aWinkler, Thomas, W1 aBentley, Amy, R1 aKilpeläinen, Tuomas, O1 ade Vries, Paul, S1 aSung, Yun, Ju1 aSchwander, Karen1 aCade, Brian, E1 aManning, Alisa1 aAschard, Hugues1 aBrown, Michael, R1 aChen, Han1 aFranceschini, Nora1 aMusani, Solomon, K1 aRichard, Melissa1 aVojinovic, Dina1 aAslibekyan, Stella1 aBartz, Traci, M1 aFuentes, Lisa, de Las1 aFeitosa, Mary1 aHorimoto, Andrea, R1 aIlkov, Marjan1 aKho, Minjung1 aKraja, Aldi1 aLi, Changwei1 aLim, Elise1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aRankinen, Tuomo1 aTajuddin, Salman, M1 avan der Spek, Ashley1 aWang, Zhe1 aMarten, Jonathan1 aLaville, Vincent1 aAlver, Maris1 aEvangelou, Evangelos1 aGraff, Maria, E1 aHe, Meian1 aKuhnel, Brigitte1 aLyytikäinen, Leo-Pekka1 aMarques-Vidal, Pedro1 aNolte, Ilja, M1 aPalmer, Nicholette, D1 aRauramaa, Rainer1 aShu, Xiao-Ou1 aSnieder, Harold1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aAdolfo, Correa1 aBallantyne, Christie1 aBielak, Larry1 aBiermasz, Nienke, R1 aBoerwinkle, Eric1 aDimou, Niki1 aEiriksdottir, Gudny1 aGao, Chuan1 aGharib, Sina, A1 aGottlieb, Daniel, J1 aHaba-Rubio, José1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeinzer, Raphael1 aHixson, James, E1 aHomuth, Georg1 aIkram, Arfan, M1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aLee, Jiwon1 aLiu, Jingmin1 aLohman, Kurt, K1 aLuik, Annemarie, I1 aMägi, Reedik1 aMartin, Lisa, W1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aNalls, Mike, A1 aO'Connell, Jeff1 aPeters, Annette1 aPeyser, Patricia1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRensen, Patrick, C N1 aRice, Treva, K1 aRich, Stephen, S1 aRoenneberg, Till1 aRotter, Jerome, I1 aSchreiner, Pamela, J1 aShikany, James1 aSidney, Stephen, S1 aSims, Mario1 aSitlani, Colleen, M1 aSofer, Tamar1 aStrauch, Konstantin1 aSwertz, Morris, A1 aTaylor, Kent, D1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aWaldenberger, Melanie1 aWallance, Robert, B1 aDijk, Ko Willems1 aYu, Caizheng1 aZonderman, Alan, B1 aBecker, Diane, M1 aElliott, Paul1 aEsko, Tõnu1 aGieger, Christian1 aGrabe, Hans, J1 aLakka, Timo, A1 aLehtimäki, Terho1 aNorth, Kari, E1 aPenninx, Brenda, W J H1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWu, Tangchun1 aXiang, Yong-Bing1 aZheng, Wei1 aArnett, Donna, K1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon1 aKelly, Tanika, N1 aKritchevsky, Stephen, B1 aLoos, Ruth, J F1 aPereira, Alexandre, C1 aProvince, Mike1 aPsaty, Bruce, M1 aRotimi, Charles1 aZhu, Xiaofeng1 aAmin, Najaf1 aCupples, Adrienne, L1 aFornage, Myriam1 aFox, Ervin, F1 aGuo, Xiuqing1 aGauderman, James1 aRice, Kenneth1 aKooperberg, Charles1 aMunroe, Patricia, B1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 avan Heemst, Diana1 aRedline, Susan uhttps://chs-nhlbi.org/node/820213215nas a2204525 4500008004100000022001400041245005800055210005400113260001600167300001300183490000800196100002400204700002000228700002300248700002600271700002000297700002200317700002300339700002500362700003000387700002800417700002400445700002400469700002800493700002000521700002400541700001900565700002000584700002700604700001600631700002100647700002200668700001500690700002600705700002500731700002300756700001900779700002400798700002900822700001800851700002300869700002100892700002400913700001600937700002300953700002900976700002101005700002101026700002601047700002801073700002801101700002301129700002201152700002001174700002001194700002901214700001701243700002101260700002101281700002101302700002101323700002101344700002501365700001301390700002301403700002301426700002301449700002601472700002301498700002301521700002201544700002501566700002301591700002301614700002601637700002001663700001801683700002501701700001701726700001701743700001801760700002201778700002101800700002401821700001901845700002201864700002101886700001601907700002501923700001701948700001901965700002601984700002102010700001802031700002202049700001902071700001902090700002302109700001902132700001302151700002602164700001802190700002302208700002302231700002402254700002202278700002102300700002402321700002402345700002202369700002102391700002902412700002502441700002702466700002802493700001602521700002302537700001802560700002702578700003302605700002202638700002202660700001702682700001702699700003102716700002302747700002202770700001902792700002602811700002102837700002402858700002602882700002602908700002502934700002102959700002102980700001803001700002303019700001803042700002003060700002503080700002103105700002503126700001303151700001503164700002103179700002303200700001903223700002603242700002203268700002603290700003303316700002403349700001803373700003303391700002503424700003603449700001903485700002503504700003003529700002003559700002403579700002103603700001903624700001903643700001903662700001803681700002403699700001303723700002203736700002803758700002403786700002403810700002103834700002003855700001803875700002503893700001903918700001503937700002303952700001803975700002403993700002404017700002004041700002604061700002304087700001704110700002304127700002304150700002604173700002504199700002004224700002104244700002304265700001904288700001904307700001704326700002304343700002204366700002804388700002004416700001904436700002704455700002204482700001804504700002004522700002304542700001704565700002004582700002404602700001904626700001704645700001504662700002004677700002204697700002504719700002204744700002404766700002004790700003204810700002204842700001804864700002204882700002304904700002004927700002104947700002404968700002604992700001505018700003705033700001605070700001805086700002205104700002105126700002005147700002305167700002105190700002105211700002305232700002205255700002405277700001905301700001705320700002305337700002405360700002005384700002305404700002105427700002005448700002405468700001705492700001705509700001905526700002305545700002105568700002105589700002305610700002905633700002705662700002205689700002005711700001605731700002505747700001605772700002205788700002405810700002905834700002105863700002405884700002205908700001905930700002405949700001905973700002105992700002306013700002306036700002306059700001706082700002306099700001906122700002206141700002006163700002006183700002906203700002106232700001806253700003006271700003106301700002006332700002406352700001906376700002006395700002106415700002606436700001806462700002106480700002506501700002206526700001606548700002606564700001906590700002006609700002106629700002206650700002006672700001906692700002206711700002206733700002706755700002106782700001906803700002406822700002806846700002506874700002206899700001706921700002506938700002906963700002406992700002307016700002007039700002407059700002507083700002007108700002207128700002607150700002607176700002507202700002307227700001907250700002307269700003007292700002507322700002407347700001707371700001707388700002107405700002107426700002307447700001807470700002007488700003007508700002807538700002307566700002407589700002407613700002307637700002707660700002507687700001907712700002107731700002207752700001407774700002507788700002407813700002107837700002307858700001907881700002107900700002407921700002807945700002607973700001907999700001908018700001708037700002708054700002508081700001508106700002108121700002308142700002308165710005208188710002408240710002408264710002408288710002108312710005108333710010308384856020208487 2020 eng d a0036-807500aThe genetic architecture of the human cerebral cortex0 agenetic architecture of the human cerebral cortex cAug-03-2021 aeaay66900 v3671 aGrasby, Katrina, L.1 aJahanshad, Neda1 aPainter, Jodie, N.1 aColodro-Conde, Lucía1 aBralten, Janita1 aHibar, Derrek, P.1 aLind, Penelope, A.1 aPizzagalli, Fabrizio1 aChing, Christopher, R. K.1 aMcMahon, Mary, Agnes B.1 aShatokhina, Natalia1 aZsembik, Leo, C. P.1 aThomopoulos, Sophia, I.1 aZhu, Alyssa, H.1 aStrike, Lachlan, T.1 aAgartz, Ingrid1 aAlhusaini, Saud1 aAlmeida, Marcio, A. A.1 aAlnæs, Dag1 aAmlien, Inge, K.1 aAndersson, Micael1 aArd, Tyler1 aArmstrong, Nicola, J.1 aAshley-Koch, Allison1 aAtkins, Joshua, R.1 aBernard, Manon1 aBrouwer, Rachel, M.1 aBuimer, Elizabeth, E. L.1 aBülow, Robin1 aBürger, Christian1 aCannon, Dara, M.1 aChakravarty, Mallar1 aChen, Qiang1 aCheung, Joshua, W.1 aCouvy-Duchesne, Baptiste1 aDale, Anders, M.1 aDalvie, Shareefa1 ade Araujo, Tânia, K.1 ade Zubicaray, Greig, I.1 ade Zwarte, Sonja, M. C.1 aBraber, Anouk, den1 aDoan, Nhat, Trung1 aDohm, Katharina1 aEhrlich, Stefan1 aEngelbrecht, Hannah-Ruth1 aErk, Susanne1 aFan, Chun, Chieh1 aFedko, Iryna, O.1 aFoley, Sonya, F.1 aFord, Judith, M.1 aFukunaga, Masaki1 aGarrett, Melanie, E.1 aGe, Tian1 aGiddaluru, Sudheer1 aGoldman, Aaron, L.1 aGreen, Melissa, J.1 aGroenewold, Nynke, A.1 aGrotegerd, Dominik1 aGurholt, Tiril, P.1 aGutman, Boris, A.1 aHansell, Narelle, K.1 aHarris, Mathew, A.1 aHarrison, Marc, B.1 aHaswell, Courtney, C.1 aHauser, Michael1 aHerms, Stefan1 aHeslenfeld, Dirk, J.1 aHo, New, Fei1 aHoehn, David1 aHoffmann, Per1 aHolleran, Laurena1 aHoogman, Martine1 aHottenga, Jouke-Jan1 aIkeda, Masashi1 aJanowitz, Deborah1 aJansen, Iris, E.1 aJia, Tianye1 aJockwitz, Christiane1 aKanai, Ryota1 aKarama, Sherif1 aKasperaviciute, Dalia1 aKaufmann, Tobias1 aKelly, Sinead1 aKikuchi, Masataka1 aKlein, Marieke1 aKnapp, Michael1 aKnodt, Annchen, R.1 aKrämer, Bernd1 aLam, Max1 aLancaster, Thomas, M.1 aLee, Phil, H.1 aLett, Tristram, A.1 aLewis, Lindsay, B.1 aLopes-Cendes, Iscia1 aLuciano, Michelle1 aMacciardi, Fabio1 aMarquand, Andre, F.1 aMathias, Samuel, R.1 aMelzer, Tracy, R.1 aMilaneschi, Yuri1 aMirza-Schreiber, Nazanin1 aMoreira, Jose, C. V.1 aMühleisen, Thomas, W.1 aMüller-Myhsok, Bertram1 aNajt, Pablo1 aNakahara, Soichiro1 aNho, Kwangsik1 aLoohuis, Loes, M. Olde1 aOrfanos, Dimitri, Papadopoul1 aPearson, John, F.1 aPitcher, Toni, L.1 aPütz, Benno1 aQuidé, Yann1 aRagothaman, Anjanibhargavi1 aRashid, Faisal, M.1 aReay, William, R.1 aRedlich, Ronny1 aReinbold, Céline, S.1 aRepple, Jonathan1 aRichard, Geneviève1 aRiedel, Brandalyn, C.1 aRisacher, Shannon, L.1 aRocha, Cristiane, S.1 aMota, Nina, Roth1 aSalminen, Lauren1 aSaremi, Arvin1 aSaykin, Andrew, J.1 aSchlag, Fenja1 aSchmaal, Lianne1 aSchofield, Peter, R.1 aSecolin, Rodrigo1 aShapland, Chin, Yang1 aShen, Li1 aShin, Jean1 aShumskaya, Elena1 aSønderby, Ida, E.1 aSprooten, Emma1 aTansey, Katherine, E.1 aTeumer, Alexander1 aThalamuthu, Anbupalam1 aTordesillas-Gutierrez, Diana1 aTurner, Jessica, A.1 aUhlmann, Anne1 aVallerga, Costanza, Ludovica1 avan der Meer, Dennis1 avan Donkelaar, Marjolein, M. J.1 avan Eijk, Liza1 avan Erp, Theo, G. M.1 avan Haren, Neeltje, E. M.1 avan Rooij, Daan1 avan Tol, Marie-Jose1 aVeldink, Jan, H.1 aVerhoef, Ellen1 aWalton, Esther1 aWang, Mingyuan1 aWang, Yunpeng1 aWardlaw, Joanna, M.1 aWen, Wei1 aWestlye, Lars, T.1 aWhelan, Christopher, D.1 aWitt, Stephanie, H.1 aWittfeld, Katharina1 aWolf, Christiane1 aWolfers, Thomas1 aWu, Jing, Qin1 aYasuda, Clarissa, L.1 aZaremba, Dario1 aZhang, Zuo1 aZwiers, Marcel, P.1 aArtiges, Eric1 aAssareh, Amelia, A.1 aAyesa-Arriola, Rosa1 aBelger, Aysenil1 aBrandt, Christine, L.1 aBrown, Gregory, G.1 aCichon, Sven1 aCurran, Joanne, E.1 aDavies, Gareth, E.1 aDegenhardt, Franziska1 aDennis, Michelle, F.1 aDietsche, Bruno1 aDjurovic, Srdjan1 aDoherty, Colin, P.1 aEspiritu, Ryan1 aGarijo, Daniel1 aGil, Yolanda1 aGowland, Penny, A.1 aGreen, Robert, C.1 aHäusler, Alexander, N.1 aHeindel, Walter1 aHo, Beng-Choon1 aHoffmann, Wolfgang, U.1 aHolsboer, Florian1 aHomuth, Georg1 aHosten, Norbert1 aJack, Clifford, R.1 aJang, MiHyun1 aJansen, Andreas1 aKimbrel, Nathan, A.1 aKolskår, Knut1 aKoops, Sanne1 aKrug, Axel1 aLim, Kelvin, O.1 aLuykx, Jurjen, J.1 aMathalon, Daniel, H.1 aMather, Karen, A.1 aMattay, Venkata, S.1 aMatthews, Sarah1 aVan Son, Jaqueline, Mayoral1 aMcEwen, Sarah, C.1 aMelle, Ingrid1 aMorris, Derek, W.1 aMueller, Bryon, A.1 aNauck, Matthias1 aNordvik, Jan, E.1 aNöthen, Markus, M.1 aO’Leary, Daniel, S.1 aOpel, Nils1 aMartinot, Marie-Laure, Paillère1 aPike, Bruce1 aPreda, Adrian1 aQuinlan, Erin, B.1 aRasser, Paul, E.1 aRatnakar, Varun1 aReppermund, Simone1 aSteen, Vidar, M.1 aTooney, Paul, A.1 aTorres, Fábio, R.1 aVeltman, Dick, J.1 aVoyvodic, James, T.1 aWhelan, Robert1 aWhite, Tonya1 aYamamori, Hidenaga1 aAdams, Hieab, H. H.1 aBis, Joshua, C.1 aDebette, Stephanie1 aDeCarli, Charles1 aFornage, Myriam1 aGudnason, Vilmundur1 aHofer, Edith1 aIkram, Arfan1 aLauner, Lenore1 aLongstreth, W., T.1 aLopez, Oscar, L.1 aMazoyer, Bernard1 aMosley, Thomas, H.1 aRoshchupkin, Gennady, V.1 aSatizabal, Claudia, L.1 aSchmidt, Reinhold1 aSeshadri, Sudha1 aYang, Qiong1 aAlvim, Marina, K. M.1 aAmes, David1 aAnderson, Tim, J.1 aAndreassen, Ole, A.1 aArias-Vasquez, Alejandro1 aBastin, Mark, E.1 aBaune, Bernhard, T.1 aBeckham, Jean, C.1 aBlangero, John1 aBoomsma, Dorret, I.1 aBrodaty, Henry1 aBrunner, Han, G.1 aBuckner, Randy, L.1 aBuitelaar, Jan, K.1 aBustillo, Juan, R.1 aCahn, Wiepke1 aCairns, Murray, J.1 aCalhoun, Vince1 aCarr, Vaughan, J.1 aCaseras, Xavier1 aCaspers, Svenja1 aCavalleri, Gianpiero, L.1 aCendes, Fernando1 aCorvin, Aiden1 aCrespo-Facorro, Benedicto1 aDalrymple-Alford, John, C.1 aDannlowski, Udo1 ade Geus, Eco, J. C.1 aDeary, Ian, J.1 aDelanty, Norman1 aDepondt, Chantal1 aDesrivières, Sylvane1 aDonohoe, Gary1 aEspeseth, Thomas1 aFernández, Guillén1 aFisher, Simon, E.1 aFlor, Herta1 aForstner, Andreas, J.1 aFrancks, Clyde1 aFranke, Barbara1 aGlahn, David, C.1 aGollub, Randy, L.1 aGrabe, Hans, J.1 aGruber, Oliver1 aHåberg, Asta, K.1 aHariri, Ahmad, R.1 aHartman, Catharina, A.1 aHashimoto, Ryota1 aHeinz, Andreas1 aHenskens, Frans, A.1 aHillegers, Manon, H. J.1 aHoekstra, Pieter, J.1 aHolmes, Avram, J.1 aHong, Elliot1 aHopkins, William, D.1 aPol, Hilleke, E. Hulshof1 aJernigan, Terry, L.1 aJönsson, Erik, G.1 aKahn, René, S.1 aKennedy, Martin, A.1 aKircher, Tilo, T. J.1 aKochunov, Peter1 aKwok, John, B. J.1 aLe Hellard, Stephanie1 aLoughland, Carmel, M.1 aMartin, Nicholas, G.1 aMartinot, Jean-Luc1 aMcDonald, Colm1 aMcMahon, Katie, L.1 aMeyer-Lindenberg, Andreas1 aMichie, Patricia, T.1 aMorey, Rajendra, A.1 aMowry, Bryan1 aNyberg, Lars1 aOosterlaan, Jaap1 aOphoff, Roel, A.1 aPantelis, Christos1 aPaus, Tomáš1 aPausova, Zdenka1 aPenninx, Brenda, W. J. H.1 aPolderman, Tinca, J. C.1 aPosthuma, Danielle1 aRietschel, Marcella1 aRoffman, Joshua, L.1 aRowland, Laura, M.1 aSachdev, Perminder, S.1 aSämann, Philipp, G.1 aSchall, Ulrich1 aSchumann, Gunter1 aScott, Rodney, J.1 aSim, Kang1 aSisodiya, Sanjay, M.1 aSmoller, Jordan, W.1 aSommer, Iris, E.1 aSt Pourcain, Beate1 aStein, Dan, J.1 aToga, Arthur, W.1 aTrollor, Julian, N.1 aVan der Wee, Nic, J. A.1 aEnt, Dennis, van ’t1 aVölzke, Henry1 aWalter, Henrik1 aWeber, Bernd1 aWeinberger, Daniel, R.1 aWright, Margaret, J.1 aZhou, Juan1 aStein, Jason, L.1 aThompson, Paul, M.1 aMedland, Sarah, E.1 aAlzheimer’s Disease Neuroimaging Initiative¶1 aCHARGE Consortium¶1 aEPIGEN Consortium¶1 aIMAGEN Consortium¶1 aSYS Consortium¶1 aParkinson’s Progression Markers Initiative¶1 aEnhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group uhttps://www.sciencemag.org/lookup/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay669004618nas a2200805 4500008004100000022001400041245019400055210006900249260000900318300001300327490000700340520222500347653001002572653002802582653002802610653001102638653004002649653001702689653003402706653001102740653002602751653003602777653002402813100001602837700001602853700002202869700001902891700002202910700002102932700001902953700001802972700002302990700002603013700001703039700002003056700002103076700002103097700002103118700002303139700002203162700002103184700001703205700002203222700001903244700002003263700001903283700002203302700002603324700002103350700002103371700002003392700002603412700002203438700002203460700002003482700002803502700001703530700001903547700001303566700002303579700001803602700002403620700002303644700001603667700002003683700001903703700003003722700002403752856003603776 2020 eng d a1932-620300aGenetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.0 aGenetic loci associated with prevalent and incident myocardial i c2020 ae02300350 v153 aBACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.
METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.
CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
10aAging10aCoronary Artery Disease10aCross-Sectional Studies10aEurope10aEuropean Continental Ancestry Group10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies1 aHahn, Julie1 aFu, Yi-Ping1 aBrown, Michael, R1 aBis, Joshua, C1 ade Vries, Paul, S1 aFeitosa, Mary, F1 aYanek, Lisa, R1 aWeiss, Stefan1 aGiulianini, Franco1 aSmith, Albert, Vernon1 aGuo, Xiuqing1 aBartz, Traci, M1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aChen, Yii-Der Ida1 aFranco, Oscar, H1 aGrove, Megan1 aHarris, Tamara, B1 aHofman, Albert1 aHwang, Shih-Jen1 aKral, Brian, G1 aLauner, Lenore, J1 aMarkus, Marcello, R P1 aRice, Kenneth, M1 aRich, Stephen, S1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aUitterlinden, André, G1 aVölker, Uwe1 aVölzke, Henry1 aYao, Jie1 aChasman, Daniel, I1 aDörr, Marcus1 aGudnason, Vilmundur1 aMathias, Rasika, A1 aPost, Wendy1 aPsaty, Bruce, M1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aMorrison, Alanna, C uhttps://chs-nhlbi.org/node/862505243nas a2201489 4500008004100000022001400041245006800055210006300123260001600186300001800202490000800220520113000228100002201358700001701380700001801397700002101415700001801436700001501454700002001469700002301489700002301512700002501535700002201560700001601582700002201598700002801620700002301648700002201671700001801693700001901711700002201730700001701752700001701769700002001786700002001806700002101826700002001847700002301867700002401890700002301914700002601937700002901963700002301992700002002015700001702035700003002052700001602082700002002098700001802118700001602136700002202152700002202174700002002196700001702216700001802233700002002251700001202271700002402283700001902307700001902326700002402345700001502369700002002384700002002404700002002424700002302444700002002467700002402487700002302511700002102534700002202555700002102577700001702598700002802615700002102643700002002664700002102684700001802705700002402723700002402747700001702771700002102788700001902809700002002828700002002848700002302868700002102891700002902912700002302941700002202964700002002986700002803006700002303034700001403057700002403071700002103095700001703116700001903133700002503152700001803177700001203195700001803207700002103225700002003246700002303266700001503289700001203304700002003316700002203336700002003358700001903378700002503397700002003422700002203442700002003464700002303484700001803507700002203525700002503547700002503572700002403597700002203621700002303643700002003666710003103686856003603717 2020 eng d a1097-417200aThe Polygenic and Monogenic Basis of Blood Traits and Diseases.0 aPolygenic and Monogenic Basis of Blood Traits and Diseases c2020 Sep 03 a1214-1231.e110 v1823 aBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
1 aVuckovic, Dragana1 aBao, Erik, L1 aAkbari, Parsa1 aLareau, Caleb, A1 aMousas, Abdou1 aJiang, Tao1 aChen, Ming-Huei1 aRaffield, Laura, M1 aTardaguila, Manuel1 aHuffman, Jennifer, E1 aRitchie, Scott, C1 aMegy, Karyn1 aPonstingl, Hannes1 aPenkett, Christopher, J1 aAlbers, Patrick, K1 aWigdor, Emilie, M1 aSakaue, Saori1 aMoscati, Arden1 aManansala, Regina1 aLo, Ken, Sin1 aQian, Huijun1 aAkiyama, Masato1 aBartz, Traci, M1 aBen-Shlomo, Yoav1 aBeswick, Andrew1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrody, Jennifer, A1 avan Rooij, Frank, J A1 aChitrala, Kumaraswamy, N1 aWilson, Peter, W F1 aChoquet, Helene1 aDanesh, John1 aDi Angelantonio, Emanuele1 aDimou, Niki1 aDing, Jingzhong1 aElliott, Paul1 aEsko, Tõnu1 aEvans, Michele, K1 aFelix, Stephan, B1 aFloyd, James, S1 aBroer, Linda1 aGrarup, Niels1 aGuo, Michael, H1 aGuo, Qi1 aGreinacher, Andreas1 aHaessler, Jeff1 aHansen, Torben1 aHowson, Joanna, M M1 aHuang, Wei1 aJorgenson, Eric1 aKacprowski, Tim1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKarthikeyan, Savita1 aKoskeridis, Fotios1 aLange, Leslie, A1 aLehtimäki, Terho1 aLinneberg, Allan1 aLiu, Yongmei1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMatsuda, Koichi1 aMohlke, Karen, L1 aMononen, Nina1 aMurakami, Yoshinori1 aNadkarni, Girish, N1 aNikus, Kjell1 aPankratz, Nathan1 aPedersen, Oluf1 aPreuss, Michael1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRich, Stephen, S1 aRodriguez, Benjamin, A T1 aRosen, Jonathan, D1 aRotter, Jerome, I1 aSchubert, Petra1 aSpracklen, Cassandra, N1 aSurendran, Praveen1 aTang, Hua1 aTardif, Jean-Claude1 aGhanbari, Mohsen1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Nicholas, A1 aWeiss, Stefan1 aCai, Na1 aKundu, Kousik1 aWatt, Stephen, B1 aWalter, Klaudia1 aZonderman, Alan, B1 aCho, Kelly1 aLi, Yun1 aLoos, Ruth, J F1 aKnight, Julian, C1 aGeorges, Michel1 aStegle, Oliver1 aEvangelou, Evangelos1 aOkada, Yukinori1 aRoberts, David, J1 aInouye, Michael1 aJohnson, Andrew, D1 aAuer, Paul, L1 aAstle, William, J1 aReiner, Alexander, P1 aButterworth, Adam, S1 aOuwehand, Willem, H1 aLettre, Guillaume1 aSankaran, Vijay, G1 aSoranzo, Nicole1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/849005226nas a2201465 4500008004100000022001400041245010900055210006900164260001600233300001800249490000800267520110800275100002001383700002301403700001801426700001801444700002501462700001901487700001901506700001501525700001801540700002201558700001701580700001501597700002201612700002501634700001701659700001701676700001701693700002101710700002301731700001901754700002001773700002001793700002101813700002001834700002301854700002401877700002301901700002601924700003101950700001501981700002001996700001902016700001702035700003002052700001602082700002002098700001802118700001602136700002202152700002002174700001702194700001802211700002002229700002402249700001902273700001902292700002402311700002002335700001502355700002002370700002002390700002002410700002302430700002002453700002402473700002202497700002102519700002202540700002102562700002102583700001702604700002802621700002102649700002202670700002002692700002102712700001802733700002402751700002402775700002002799700001702819700002402836700002102860700001902881700002002900700002002920700002302940700002202963700002102985700002903006700002303035700002203058700002003080700002803100700002303128700001403151700002403165700002503189700002103214700001703235700001903252700002503271700002303296700002303319700001203342700002503354700002803379700002803407700001703435700002003452700002203472700002503494700002303519700002303542700002003565700002003585700002303605700002503628700001803653700002203671710003103693856003603724 2020 eng d a1097-417200aTrans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.0 aTransethnic and AncestrySpecific BloodCell Genetics in 746667 In c2020 Sep 03 a1198-1213.e140 v1823 aMost loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
1 aChen, Ming-Huei1 aRaffield, Laura, M1 aMousas, Abdou1 aSakaue, Saori1 aHuffman, Jennifer, E1 aMoscati, Arden1 aTrivedi, Bhavi1 aJiang, Tao1 aAkbari, Parsa1 aVuckovic, Dragana1 aBao, Erik, L1 aZhong, Xue1 aManansala, Regina1 aLaplante, Véronique1 aChen, Minhui1 aLo, Ken, Sin1 aQian, Huijun1 aLareau, Caleb, A1 aBeaudoin, Mélissa1 aHunt, Karen, A1 aAkiyama, Masato1 aBartz, Traci, M1 aBen-Shlomo, Yoav1 aBeswick, Andrew1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrody, Jennifer, A1 avan Rooij, Frank, J A1 aChitrala, Kumaraswamynaidu1 aCho, Kelly1 aChoquet, Helene1 aCorrea, Adolfo1 aDanesh, John1 aDi Angelantonio, Emanuele1 aDimou, Niki1 aDing, Jingzhong1 aElliott, Paul1 aEsko, Tõnu1 aEvans, Michele, K1 aFloyd, James, S1 aBroer, Linda1 aGrarup, Niels1 aGuo, Michael, H1 aGreinacher, Andreas1 aHaessler, Jeff1 aHansen, Torben1 aHowson, Joanna, M M1 aHuang, Qin, Qin1 aHuang, Wei1 aJorgenson, Eric1 aKacprowski, Tim1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKarthikeyan, Savita1 aKoskeridis, Fotis1 aLange, Leslie, A1 aLehtimäki, Terho1 aLerch, Markus, M1 aLinneberg, Allan1 aLiu, Yongmei1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMartin, Hilary, C1 aMatsuda, Koichi1 aMohlke, Karen, L1 aMononen, Nina1 aMurakami, Yoshinori1 aNadkarni, Girish, N1 aNauck, Matthias1 aNikus, Kjell1 aOuwehand, Willem, H1 aPankratz, Nathan1 aPedersen, Oluf1 aPreuss, Michael1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRoberts, David, J1 aRich, Stephen, S1 aRodriguez, Benjamin, A T1 aRosen, Jonathan, D1 aRotter, Jerome, I1 aSchubert, Petra1 aSpracklen, Cassandra, N1 aSurendran, Praveen1 aTang, Hua1 aTardif, Jean-Claude1 aTrembath, Richard, C1 aGhanbari, Mohsen1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Nicholas, A1 aZonderman, Alan, B1 aWilson, Peter, W F1 aLi, Yun1 aButterworth, Adam, S1 aGauchat, Jean-François1 aChiang, Charleston, W K1 aLi, Bingshan1 aLoos, Ruth, J F1 aAstle, William, J1 aEvangelou, Evangelos1 avan Heel, David, A1 aSankaran, Vijay, G1 aOkada, Yukinori1 aSoranzo, Nicole1 aJohnson, Andrew, D1 aReiner, Alexander, P1 aAuer, Paul, L1 aLettre, Guillaume1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/848111212nas a2203445 4500008004100000022001400041245008000055210006900135260001300204300001200217490000800229520148100237100002301718700001801741700001901759700002701778700002401805700001601829700002501845700002301870700001801893700002601911700002901937700002401966700002601990700002302016700001902039700002202058700002002080700001802100700002202118700001502140700003102155700001902186700002802205700002302233700002002256700002002276700002302296700002002319700002502339700001502364700002102379700002502400700002202425700002502447700001802472700002302490700002102513700002402534700002602558700002502584700002602609700002302635700001802658700002602676700002802702700001902730700002102749700002102770700002102791700002202812700002302834700002102857700002302878700001702901700002102918700002102939700002002960700002202980700002003002700002403022700002903046700001903075700001803094700002103112700001603133700002003149700002003169700002103189700001803210700002403228700002403252700002303276700002403299700002303323700001603346700002303362700001703385700002103402700001603423700002303439700002103462700002003483700002303503700002503526700002803551700002403579700003103603700002203634700002103656700002103677700002803698700002403726700002003750700002703770700002303797700001403820700002203834700001603856700001203872700001903884700002303903700002003926700002303946700001403969700001803983700002304001700002404024700002704048700002004075700002004095700001904115700002404134700002704158700002104185700002204206700001804228700002404246700001704270700002304287700002104310700002304331700002404354700002404378700002204402700002104424700002304445700002304468700001604491700002104507700002104528700002204549700001804571700001704589700001504606700001804621700001804639700002704657700002104684700002004705700001804725700002104743700002404764700001804788700002204806700002204828700002304850700002204873700002004895700002104915700001704936700002004953700002504973700002904998700002105027700002205048700001905070700001905089700001705108700002105125700001905146700002005165700002205185700001905207700002205226700001905248700002305267700002305290700002005313700001905333700002305352700001905375700002005394700002005414700001805434700001705452700002105469700002005490700001905510700002305529700001905552700002405571700002105595700001605616700001705632700002205649700002005671700002605691700002105717700001805738700002205756700002105778700002405799700002505823700002605848700002605874700002305900700001905923700002305942700002105965700002005986700002306006700002106029700002406050700002006074700002206094700001906116700001906135700002606154700002406180700002606204700002506230700002006255700002106275700002206296700002806318700002506346700002106371700002106392700002506413700002206438700002106460700002806481700001806509700002206527700002206549700001706571700002406588700001906612700001406631700002506645700002506670700001906695700002106714700002106735700002306756700002106779700003006800700001706830700002006847700001406867700001906881700002006900700001506920700001706935700002106952700002006973700001806993700002907011700002707040700001607067700003107083700002207114700002107136700002407157700002207181700002407203700002307227700002307250700002107273700002107294700002507315700001507340700002407355700001607379700002107395700001707416700001707433700002107450710006007471710002307531710002607554710004707580710002607627710002707653710002407680710002607704856003607730 2021 eng d a1476-468700aGenetic insights into biological mechanisms governing human ovarian ageing.0 aGenetic insights into biological mechanisms governing human ovar c2021 Aug a393-3970 v5963 aReproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
1 aRuth, Katherine, S1 aDay, Felix, R1 aHussain, Jazib1 aMartínez-Marchal, Ana1 aAiken, Catherine, E1 aAzad, Ajuna1 aThompson, Deborah, J1 aKnoblochova, Lucie1 aAbe, Hironori1 aTarry-Adkins, Jane, L1 aGonzalez, Javier, Martin1 aFontanillas, Pierre1 aClaringbould, Annique1 aBakker, Olivier, B1 aSulem, Patrick1 aWalters, Robin, G1 aTerao, Chikashi1 aTuron, Sandra1 aHorikoshi, Momoko1 aLin, Kuang1 aOnland-Moret, Charlotte, N1 aSankar, Aditya1 aHertz, Emil, Peter Thra1 aTimshel, Pascal, N1 aShukla, Vallari1 aBorup, Rehannah1 aOlsen, Kristina, W1 aAguilera, Paula1 aFerrer-Roda, Mònica1 aHuang, Yan1 aStankovic, Stasa1 aTimmers, Paul, R H J1 aAhearn, Thomas, U1 aAlizadeh, Behrooz, Z1 aNaderi, Elnaz1 aAndrulis, Irene, L1 aArnold, Alice, M1 aAronson, Kristan, J1 aAugustinsson, Annelie1 aBandinelli, Stefania1 aBarbieri, Caterina, M1 aBeaumont, Robin, N1 aBecher, Heiko1 aBeckmann, Matthias, W1 aBenonisdottir, Stefania1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBojesen, Stig, E1 aBolla, Manjeet, K1 aBoomsma, Dorret, I1 aBowker, Nicholas1 aBrody, Jennifer, A1 aBroer, Linda1 aBuring, Julie, E1 aCampbell, Archie1 aCampbell, Harry1 aCastelao, Jose, E1 aCatamo, Eulalia1 aChanock, Stephen, J1 aChenevix-Trench, Georgia1 aCiullo, Marina1 aCorre, Tanguy1 aCouch, Fergus, J1 aCox, Angela1 aCrisponi, Laura1 aCross, Simon, S1 aCucca, Francesco1 aCzene, Kamila1 aSmith, George Davey1 ade Geus, Eco, J C N1 ade Mutsert, Renée1 aDe Vivo, Immaculata1 aDemerath, Ellen, W1 aDennis, Joe1 aDunning, Alison, M1 aDwek, Miriam1 aEriksson, Mikael1 aEsko, Tõnu1 aFasching, Peter, A1 aFaul, Jessica, D1 aFerrucci, Luigi1 aFranceschini, Nora1 aFrayling, Timothy, M1 aGago-Dominguez, Manuela1 aMezzavilla, Massimo1 aGarcía-Closas, Montserrat1 aGieger, Christian1 aGiles, Graham, G1 aGrallert, Harald1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aGuénel, Pascal1 aHaiman, Christopher, A1 aHåkansson, Niclas1 aHall, Per1 aHayward, Caroline1 aHe, Chunyan1 aHe, Wei1 aHeiss, Gerardo1 aHøffding, Miya, K1 aHopper, John, L1 aHottenga, Jouke, J1 aHu, Frank1 aHunter, David1 aIkram, Mohammad, A1 aJackson, Rebecca, D1 aJoaquim, Micaella, D R1 aJohn, Esther, M1 aJoshi, Peter, K1 aKarasik, David1 aKardia, Sharon, L R1 aKartsonaki, Christiana1 aKarlsson, Robert1 aKitahara, Cari, M1 aKolcic, Ivana1 aKooperberg, Charles1 aKraft, Peter1 aKurian, Allison, W1 aKutalik, Zoltán1 aLa Bianca, Martina1 aLachance, Genevieve1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLaven, Joop, S E1 aLawlor, Deborah, A1 aLe Marchand, Loïc1 aLi, Jingmei1 aLindblom, Annika1 aLindström, Sara1 aLindstrom, Tricia1 aLinet, Martha1 aLiu, Yongmei1 aLiu, Simin1 aLuan, Jian'an1 aMägi, Reedik1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMannermaa, Arto1 aMarco, Brumat1 aMarten, Jonathan1 aMartin, Nicholas, G1 aMbarek, Hamdi1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMeisinger, Christa1 aMeitinger, Thomas1 aMenni, Cristina1 aMetspalu, Andres1 aMilani, Lili1 aMilne, Roger, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMulas, Antonella1 aMulligan, Anna, M1 aMurray, Alison1 aNalls, Mike, A1 aNewman, Anne1 aNoordam, Raymond1 aNutile, Teresa1 aNyholt, Dale, R1 aOlshan, Andrew, F1 aOlsson, Håkan1 aPainter, Jodie, N1 aPatel, Alpa, V1 aPedersen, Nancy, L1 aPerjakova, Natalia1 aPeters, Annette1 aPeters, Ulrike1 aPharoah, Paul, D P1 aPolasek, Ozren1 aPorcu, Eleonora1 aPsaty, Bruce, M1 aRahman, Iffat1 aRennert, Gad1 aRennert, Hedy, S1 aRidker, Paul, M1 aRing, Susan, M1 aRobino, Antonietta1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRossouw, Jacques1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aSala, Cinzia, F1 aSaloustros, Emmanouil1 aSandler, Dale, P1 aSanna, Serena1 aSawyer, Elinor, J1 aSarnowski, Chloe1 aSchlessinger, David1 aSchmidt, Marjanka, K1 aSchoemaker, Minouk, J1 aSchraut, Katharina, E1 aScott, Christopher1 aShekari, Saleh1 aShrikhande, Amruta1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSorice, Rossella1 aSouthey, Melissa, C1 aSpector, Tim, D1 aSpinelli, John, J1 aStampfer, Meir1 aStöckl, Doris1 avan Meurs, Joyce, B J1 aStrauch, Konstantin1 aStyrkarsdottir, Unnur1 aSwerdlow, Anthony, J1 aTanaka, Toshiko1 aTeras, Lauren, R1 aTeumer, Alexander1 aÞorsteinsdottir, Unnur1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTraglia, Michela1 aTroester, Melissa, A1 aTruong, Thérèse1 aTyrrell, Jessica1 aUitterlinden, André, G1 aUlivi, Sheila1 aVachon, Celine, M1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVölzke, Henry1 aWang, Qin1 aWareham, Nicholas, J1 aWeinberg, Clarice, R1 aWeir, David, R1 aWilcox, Amber, N1 aDijk, Ko Willems1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWolk, Alicja1 aWood, Andrew, R1 aZhao, Wei1 aZygmunt, Marek1 aChen, Zhengming1 aLi, Liming1 aFranke, Lude1 aBurgess, Stephen1 aDeelen, Patrick1 aPers, Tune, H1 aGrøndahl, Marie, Louise1 aAndersen, Claus, Yding1 aPujol, Anna1 aLopez-Contreras, Andres, J1 aDaniel, Jeremy, A1 aStefansson, Kari1 aChang-Claude, Jenny1 aSchouw, Yvonne, T1 aLunetta, Kathryn, L1 aChasman, Daniel, I1 aEaston, Douglas, F1 aVisser, Jenny, A1 aOzanne, Susan, E1 aNamekawa, Satoshi, H1 aSolc, Petr1 aMurabito, Joanne, M1 aOng, Ken, K1 aHoffmann, Eva, R1 aMurray, Anna1 aRoig, Ignasi1 aPerry, John, R B1 aBiobank-based Integrative Omics Study (BIOS) Consortium1 aeQTLGen Consortium1 aBioBank Japan Project1 aChina Kadoorie Biobank Collaborative Group1 akConFab Investigators1 aLifeLines Cohort Study1 aInterAct Consortium1 a23andMe Research Team uhttps://chs-nhlbi.org/node/883503140nas a2200649 4500008004100000022001400041245009100055210006900146260001600215520129400231100003201525700002001557700001701577700001801594700001601612700002201628700002501650700002301675700001901698700002001717700002101737700002001758700002101778700002101799700001701820700002001837700001901857700001801876700001801894700001901912700002201931700002001953700002001973700002001993700002202013700001902035700002002054700002102074700001602095700002102111700002502132700002302157700001902180700002102199700001902220700002302239700002002262700002002282700002302302700001902325700001802344700001702362700002602379700003002405700001902435856003602454 2021 eng d a1573-728400aMeta-analysis of epigenome-wide association studies of carotid intima-media thickness.0 aMetaanalysis of epigenomewide association studies of carotid int c2021 Jun 063 aCommon carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
1 aPortilla-Fernández, Eliana1 aHwang, Shih-Jen1 aWilson, Rory1 aMaddock, Jane1 aHill, David1 aTeumer, Alexander1 aMishra, Pashupati, P1 aBrody, Jennifer, A1 aJoehanes, Roby1 aLigthart, Symen1 aGhanbari, Mohsen1 aKavousi, Maryam1 aRoks, Anton, J M1 aDanser, A, H Jan1 aLevy, Daniel1 aPeters, Annette1 aGhasemi, Sahar1 aSchminke, Ulf1 aDörr, Marcus1 aGrabe, Hans, J1 aLehtimäki, Terho1 aKähönen, Mika1 aHurme, Mikko, A1 aBartz, Traci, M1 aSotoodehnia, Nona1 aBis, Joshua, C1 aThiery, Joachim1 aKoenig, Wolfgang1 aOng, Ken, K1 aBell, Jordana, T1 aMeisinger, Christine1 aWardlaw, Joanna, M1 aStarr, John, M1 aSeissler, Jochen1 aThen, Cornelia1 aRathmann, Wolfgang1 aIkram, Arfan, M1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aVölzke, Henry1 aDeary, Ian, J1 aWong, Andrew1 aWaldenberger, Melanie1 aO'Donnell, Christopher, J1 aDehghan, Abbas uhttps://chs-nhlbi.org/node/878903642nas a2200589 4500008004100000022001400041245009900055210006900154260001600223520192000239100002002159700001702179700002602196700002402222700002202246700001702268700002002285700002402305700001802329700002402347700001602371700002002387700002202407700002402429700002602453700002002479700002202499700002202521700002502543700002002568700002002588700002702608700002102635700002602656700002202682700002502704700001802729700002002747700002702767700002302794700001902817700002202836700001302858700002102871700002402892700001902916700002002935700002202955700001902977700002002996856003603016 2022 eng d a1875-890800aAssociations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis.0 aAssociations of Pulmonary Function with MRI Brain Volumes A Coor c2022 Oct 033 aBACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.
OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.
METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.
RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.
CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.
1 aFrenzel, Stefan1 aBis, Josh, C1 aGudmundsson, Elias, F1 aO'Donnell, Adrienne1 aSimino, Jeannette1 aYaqub, Amber1 aBartz, Traci, M1 aBrusselle, Guy, G O1 aBülow, Robin1 aDeCarli, Charles, S1 aEwert, Ralf1 aGharib, Sina, A1 aGhosh, Saptaparni1 aGireud-Goss, Monica1 aGottesman, Rebecca, F1 aIkram, Arfan, M1 aKnopman, David, S1 aLauner, Lenore, J1 aLondon, Stephanie, J1 aLongstreth, W T1 aLopez, Oscar, L1 avan Lent, Debora, Melo1 aO'Connor, George1 aSatizabal, Claudia, L1 aShrestha, Srishti1 aSigurdsson, Sigurdur1 aStubbe, Beate1 aTalluri, Rajesh1 aVasan, Ramachandran, S1 aVernooij, Meike, W1 aVölzke, Henry1 aWiggins, Kerri, L1 aYu, Bing1 aBeiser, Alexa, S1 aGudnason, Vilmundur1 aMosley, Thomas1 aPsaty, Bruce, M1 aWolters, Frank, J1 aGrabe, Hans, J1 aSeshadri, Sudha uhttps://chs-nhlbi.org/node/916308759nas a2202509 4500008004100000022001400041245012000055210006900175260000900244300001200253490000700265520183300272100002602105700002402131700002202155700002002177700002302197700001802220700002402238700002102262700001802283700002302301700002002324700002402344700002002368700002002388700002202408700002102430700001702451700002502468700002102493700001802514700001502532700001702547700002202564700002102586700002302607700002102630700002502651700002002676700002402696700002002720700002102740700002002761700002302781700001702804700002202821700002302843700002302866700001502889700002302904700002102927700001402948700001802962700002102980700002203001700001603023700002803039700001903067700001903086700002103105700001903126700002303145700001703168700002303185700002203208700002703230700001803257700001803275700001803293700001703311700001903328700001803347700001603365700001903381700002503400700002103425700002303446700002103469700002103490700002203511700001803533700002203551700001303573700003303586700002403619700001803643700002303661700002103684700002203705700001203727700002103739700002103760700002003781700002403801700002503825700002103850700001603871700002103887700002003908700002003928700001803948700001703966700002003983700002104003700002004024700002304044700002804067700001904095700002204114700002304136700002004159700001504179700001704194700001704211700001804228700002404246700002304270700002204293700002104315700002004336700002704356700002604383700002604409700002604435700001804461700002004479700001904499700002304518700001804541700001904559700002104578700002804599700002504627700001704652700002004669700001604689700002304705700001904728700002404747700001904771700002004790700002104810700002804831700002204859700002604881700001804907700001804925700002004943700001504963700001304978700001704991700001905008700001405027700002105041700002305062700002205085700002305107700001805130700001905148700001605167700002005183700002205203700002205225700001905247700001905266700001905285700001905304700002205323700002705345700001905372700001905391700002005410700002205430700002005452700002405472700001505496700001905511700002605530700001905556700002405575700001705599700001505616700001805631700002105649700002305670700002205693700001805715700002405733700002205757700002305779700002405802700002705826700002905853700002405882700002505906700002005931700001605951700001705967700002005984700002006004700002306024700002006047700002106067700002006088700002106108700001806129700002406147700002206171700002006193856003606213 2023 eng d a1664-802100aGene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.0 aGeneeducational attainment interactions in a multipopulation gen c2023 a12353370 v143 aEducational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.
1 aFuentes, Lisa, de Las1 aSchwander, Karen, L1 aBrown, Michael, R1 aBentley, Amy, R1 aWinkler, Thomas, W1 aSung, Yun, Ju1 aMunroe, Patricia, B1 aMiller, Clint, L1 aAschard, Hugo1 aAslibekyan, Stella1 aBartz, Traci, M1 aBielak, Lawrence, F1 aChai, Jin, Fang1 aCheng, Ching-Yu1 aDorajoo, Rajkumar1 aFeitosa, Mary, F1 aGuo, Xiuqing1 aHartwig, Fernando, P1 aHorimoto, Andrea1 aKolcic, Ivana1 aLim, Elise1 aLiu, Yongmei1 aManning, Alisa, K1 aMarten, Jonathan1 aMusani, Solomon, K1 aNoordam, Raymond1 aPadmanabhan, Sandosh1 aRankinen, Tuomo1 aRichard, Melissa, A1 aRidker, Paul, M1 aSmith, Albert, V1 aVojinovic, Dina1 aZonderman, Alan, B1 aAlver, Maris1 aBoissel, Mathilde1 aChristensen, Kaare1 aFreedman, Barry, I1 aGao, Chuan1 aGiulianini, Franco1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLi, Xiaoyin1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aPoveda, Alaitz1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRobino, Antonietta1 aSofer, Tamar1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVerweij, Niek1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhan, Yiqiang1 aAmin, Najaf1 aArking, Dan, E1 aBallantyne, Christie1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCampbell, Archie1 aCanouil, Mickaël1 aChai, Xiaoran1 aChen, Yii-Der Ida1 aChen, Xu1 aChitrala, Kumaraswamy, Naidu1 aConcas, Maria, Pina1 ade Faire, Ulf1 ade Mutsert, Renée1 ade Silva, Janaka1 ade Vries, Paul, S1 aDo, Ahn1 aFaul, Jessica, D1 aFisher, Virginia1 aFloyd, James, S1 aForrester, Terrence1 aFriedlander, Yechiel1 aGirotto, Giorgia1 aGu, Charles1 aHallmans, Göran1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHomuth, Georg1 aHunt, Steven1 aIkram, Arfan, M1 aJacobs, David, R1 aKavousi, Maryam1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aLangefeld, Carl, D1 aLiang, Jingjing1 aLiu, Kiang1 aLiu, Jianjun1 aLohman, Kurt1 aMägi, Reedik1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMilaneschi, Yuri1 aNauck, Matthias1 aNelson, Christopher, P1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPereira, Alexandre, C1 aPerls, Thomas1 aPeters, Annette1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRice, Kenneth1 aRice, Treva, K1 aRich, Stephen, S1 aSabanayagam, Charumathi1 aSchreiner, Pamela, J1 aShu, Xiao-Ou1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aStarr, John, M1 aStrauch, Konstantin1 aTai, Shyong, E1 aTaylor, Kent, D1 aTsai, Michael, Y1 aUitterlinden, André, G1 avan Heemst, Diana1 aWaldenberger, Melanie1 aWang, Ya-Xing1 aBin Wei, Wen-1 aWilson, Gregory1 aXuan, Deng1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aBecker, Diane, M1 aBonnefond, Amélie1 aBowden, Donald, W1 aCooper, Richard, S1 aDeary, Ian, J1 aDivers, Jasmin1 aEsko, Tõnu1 aFranks, Paul, W1 aFroguel, Philippe1 aGieger, Christian1 aJonas, Jost, B1 aKato, Norihiro1 aLakka, Timo, A1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aNorth, Kari, E1 aNtalla, Ioanna1 aPenninx, Brenda1 aSamani, Nilesh, J1 aSnieder, Harold1 aSpedicati, Beatrice1 aHarst, Pim1 aVölzke, Henry1 aWagenknecht, Lynne, E1 aWeir, David, R1 aWojczynski, Mary, K1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aBouchard, Claude1 aChasman, Daniel, I1 aEvans, Michele, K1 aFox, Ervin, R1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKardia, Sharon, L R1 aKrieger, Jose, Eduardo1 aMook-Kanamori, Dennis, O1 aPeyser, Patricia, A1 aProvince, Michael, M1 aPsaty, Bruce, M1 aRudan, Igor1 aSim, Xueling1 aSmith, Blair, H1 avan Dam, Rob, M1 aDuijn, Cornelia, M1 aWong, Tien, Yin1 aArnett, Donna, K1 aRao, Dabeeru, C1 aGauderman, James1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aRotter, Jerome, I1 aFornage, Myriam uhttps://chs-nhlbi.org/node/9535