07147nas 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 a
Forced 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/658204013nas a2201093 4500008004100000022001400041245012400055210006900179260000900248300000900257490000600266520085300272653003801125653001601163653001901179653003201198653001101230653002301241653001601264100003001280700002401310700001801334700001801352700002801370700001801398700002701416700002001443700001801463700001801481700002801499700002501527700002201552700002101574700002001595700002101615700002001636700002001656700002001676700002101696700002301717700002001740700002101760700002701781700002601808700002401834700001901858700002601877700001901903700001901922700002101941700002401962700002001986700002502006700001602031700001902047700002202066700002302088700001902111700002202130700002402152700002302176700001902199700002202218700002602240700002002266700001502286700002102301700002102322700002202343700001902365700002202384700001602406700002002422700002102442700002002463700002302483700002502506700002002531700002202551700001902573700001502592700002302607700002402630700002802654700002202682700002702704700002502731700002002756700002302776700002002799700002302819710004102842856003602883 2015 eng d a2041-172300aGenome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.0 aGenome of The Netherlands populationspecific imputations identif c2015 a60650 v63 aVariants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
10aATP-Binding Cassette Transporters10aCholesterol10aGene Frequency10aGenetic Association Studies10aHumans10aMutation, Missense10aNetherlands1 avan Leeuwen, Elisabeth, M1 aKarssen, Lennart, C1 aDeelen, Joris1 aIsaacs, Aaron1 aMedina-Gómez, Carolina1 aMbarek, Hamdi1 aKanterakis, Alexandros1 aTrompet, Stella1 aPostmus, Iris1 aVerweij, Niek1 avan Enckevort, David, J1 aHuffman, Jennifer, E1 aWhite, Charles, C1 aFeitosa, Mary, F1 aBartz, Traci, M1 aManichaikul, Ani1 aJoshi, Peter, K1 aPeloso, Gina, M1 aDeelen, Patrick1 avan Dijk, Freerk1 aWillemsen, Gonneke1 ade Geus, Eco, J1 aMilaneschi, Yuri1 aPenninx, Brenda, W J H1 aFrancioli, Laurent, C1 aMenelaou, Androniki1 aPulit, Sara, L1 aRivadeneira, Fernando1 aHofman, Albert1 aOostra, Ben, A1 aFranco, Oscar, H1 aLeach, Irene, Mateo1 aBeekman, Marian1 ade Craen, Anton, J M1 aUh, Hae-Won1 aTrochet, Holly1 aHocking, Lynne, J1 aPorteous, David, J1 aSattar, Naveed1 aPackard, Chris, J1 aBuckley, Brendan, M1 aBrody, Jennifer, A1 aBis, Joshua, C1 aRotter, Jerome, I1 aMychaleckyj, Josyf, C1 aCampbell, Harry1 aDuan, Qing1 aLange, Leslie, A1 aWilson, James, F1 aHayward, Caroline1 aPolasek, Ozren1 aVitart, Veronique1 aRudan, Igor1 aWright, Alan, F1 aRich, Stephen, S1 aPsaty, Bruce, M1 aBorecki, Ingrid, B1 aKearney, Patricia, M1 aStott, David, J1 aCupples, Adrienne1 aJukema, Wouter1 aHarst, Pim1 aSijbrands, Eric, J1 aHottenga, Jouke-Jan1 aUitterlinden, André, G1 aSwertz, Morris, A1 avan Ommen, Gert-Jan, B1 ade Bakker, Paul, I W1 aSlagboom, Eline1 aBoomsma, Dorret, I1 aWijmenga, Cisca1 aDuijn, Cornelia, M1 aGenome of the Netherlands Consortium uhttps://chs-nhlbi.org/node/668205543nas a2201657 4500008004100000022001400041245013300055210007000188260001600258300001600274490000800290520094500298100002101243700001601264700001901280700001201299700001901311700001301330700002101343700001601364700001601380700001701396700002601413700001801439700002301457700002601480700002101506700002101527700001901548700002001567700002101587700002101608700001901629700001701648700002401665700001901689700002001708700002101728700002001749700002101769700001701790700001801807700002801825700002101853700002101874700001801895700002101913700002201934700002101956700002401977700002402001700002002025700001802045700002302063700001602086700001702102700001902119700002202138700002302160700001802183700002602201700001902227700002202246700002002268700002802288700002402316700002602340700001802366700002202384700002202406700001902428700001602447700001302463700001802476700001902494700002302513700001902536700002302555700002102578700001702599700001502616700002302631700001602654700002202670700002102692700002202713700002202735700001902757700002402776700002002800700002202820700002802842700002102870700001902891700001902910700001902929700002702948700001902975700001902994700002203013700002103035700001603056700002403072700002203096700001703118700002403135700002103159700002103180700002003201700002003221700001703241700002003258700001703278700001803295700002203313700002203335700002003357700002003377700001703397700002003414700002103434700001503455700002303470700002503493700002403518700002503542700002303567700001803590700002503608700002103633700002503654700001303679700002103692700002603713700002303739700002603762700002603788700001703814700001803831856003603849 2016 eng d a1091-649000aKLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.0 aKLB is associated with alcohol drinking and its gene product βKl c2016 Dec 13 a14372-143770 v1133 aExcessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.
1 aSchumann, Gunter1 aLiu, Chunyu1 aO'Reilly, Paul1 aGao, He1 aSong, Parkyong1 aXu, Bing1 aRuggeri, Barbara1 aAmin, Najaf1 aJia, Tianye1 aPreis, Sarah1 aLepe, Marcelo, Segura1 aAkira, Shizuo1 aBarbieri, Caterina1 aBaumeister, Sebastian1 aCauchi, Stephane1 aClarke, Toni-Kim1 aEnroth, Stefan1 aFischer, Krista1 aHällfors, Jenni1 aHarris, Sarah, E1 aHieber, Saskia1 aHofer, Edith1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJoshi, Peter, K1 aKaartinen, Niina1 aLaitinen, Jaana1 aLemaitre, Rozenn1 aLoukola, Anu1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMangino, Massimo1 aManichaikul, Ani1 aMbarek, Hamdi1 aMilaneschi, Yuri1 aMoayyeri, Alireza1 aMukamal, Kenneth1 aNelson, Christopher1 aNettleton, Jennifer1 aPartinen, Eemil1 aRawal, Rajesh1 aRobino, Antonietta1 aRose, Lynda1 aSala, Cinzia1 aSatoh, Takashi1 aSchmidt, Reinhold1 aSchraut, Katharina1 aScott, Robert1 aSmith, Albert, Vernon1 aStarr, John, M1 aTeumer, Alexander1 aTrompet, Stella1 aUitterlinden, André, G1 aVenturini, Cristina1 aVergnaud, Anne-Claire1 aVerweij, Niek1 aVitart, Veronique1 aVuckovic, Dragana1 aWedenoja, Juho1 aYengo, Loic1 aYu, Bing1 aZhang, Weihua1 aZhao, Jing Hua1 aBoomsma, Dorret, I1 aChambers, John1 aChasman, Daniel, I1 aDaniela, Toniolo1 ade Geus, Eco1 aDeary, Ian1 aEriksson, Johan, G1 aEsko, Tõnu1 aEulenburg, Volker1 aFranco, Oscar, H1 aFroguel, Philippe1 aGieger, Christian1 aGrabe, Hans, J1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHarris, Tamara, B1 aHartikainen, Anna-Liisa1 aHeath, Andrew, C1 aHocking, Lynne1 aHofman, Albert1 aHuth, Cornelia1 aJarvelin, Marjo-Riitta1 aJukema, Wouter1 aKaprio, Jaakko1 aKooner, Jaspal, S1 aKutalik, Zoltán1 aLahti, Jari1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLiu, Yongmei1 aMadden, Pamela, A F1 aMartin, Nicholas1 aMorrison, Alanna1 aPenninx, Brenda1 aPirastu, Nicola1 aPsaty, Bruce1 aRaitakari, Olli1 aRidker, Paul1 aRose, Richard1 aRotter, Jerome, I1 aSamani, Nilesh, J1 aSchmidt, Helena1 aSpector, Tim, D1 aStott, David1 aStrachan, David1 aTzoulaki, Ioanna1 aHarst, Pim1 aDuijn, Cornelia, M1 aMarques-Vidal, Pedro1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWilson, James1 aWolffenbuttel, Bruce1 aBakalkin, Georgy1 aEvangelou, Evangelos1 aLiu, Yun1 aRice, Kenneth, M1 aDesrivières, Sylvane1 aKliewer, Steven, A1 aMangelsdorf, David, J1 aMüller, Christian, P1 aLevy, Daniel1 aElliott, Paul uhttps://chs-nhlbi.org/node/725605818nas a2201705 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520107200254100002201326700002301348700002501371700002001396700002501416700002201441700001801463700002201481700002501503700002001528700002301548700002001571700003001591700001901621700002301640700002201663700001701685700001901702700001801721700001901739700001901758700002801777700001601805700002401821700002001845700002401865700002001889700002301909700001801932700001701950700001901967700002701986700001802013700001902031700001702050700001502067700001602082700002102098700002302119700001602142700002202158700002502180700002102205700001802226700002002244700002502264700001302289700002002302700002402322700001802346700002002364700002302384700002302407700002102430700002502451700002402476700001602500700003202516700002002548700002102568700002202589700002402611700002002635700002102655700002502676700001902701700002002720700002802740700001902768700001902787700001702806700002602823700001802849700002202867700001502889700002002904700002702924700001502951700002002966700002102986700001903007700002303026700001903049700002303068700001703091700002003108700002003128700002603148700002203174700002003196700001803216700002103234700002003255700002303275700001703298700001903315700002803334700002003362700001903382700002103401700001903422700001603441700002903457700002103486700002403507700002003531700002003551700002303571700001903594700001803613700002103631700002103652700001903673700002003692700002103712700002003733700002403753700002103777700001903798700002303817700002203840700002103862700001903883700001803902700002003920700002103940700002003961700003003981700002304011700002304034700001904057856003604076 2016 eng d a1460-208300aA meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.0 ametaanalysis of 120 246 individuals identifies 18 new loci for f c2016 Jan 15 a358-700 v253 aGenome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
1 ade Vries, Paul, S1 aChasman, Daniel, I1 aSabater-Lleal, Maria1 aChen, Ming-Huei1 aHuffman, Jennifer, E1 aSteri, Maristella1 aTang, Weihong1 aTeumer, Alexander1 aMarioni, Riccardo, E1 aGrossmann, Vera1 aHottenga, Jouke, J1 aTrompet, Stella1 aMüller-Nurasyid, Martina1 aZhao, Jing Hua1 aBrody, Jennifer, A1 aKleber, Marcus, E1 aGuo, Xiuqing1 aWang, Jie, Jin1 aAuer, Paul, L1 aAttia, John, R1 aYanek, Lisa, R1 aAhluwalia, Tarunveer, S1 aLahti, Jari1 aVenturini, Cristina1 aTanaka, Toshiko1 aBielak, Lawrence, F1 aJoshi, Peter, K1 aRocanin-Arjo, Ares1 aKolcic, Ivana1 aNavarro, Pau1 aRose, Lynda, M1 aOldmeadow, Christopher1 aRiess, Helene1 aMazur, Johanna1 aBasu, Saonli1 aGoel, Anuj1 aYang, Qiong1 aGhanbari, Mohsen1 aWillemsen, Gonneke1 aRumley, Ann1 aFiorillo, Edoardo1 ade Craen, Anton, J M1 aGrotevendt, Anne1 aScott, Robert1 aTaylor, Kent, D1 aDelgado, Graciela, E1 aYao, Jie1 aKifley, Annette1 aKooperberg, Charles1 aQayyum, Rehan1 aLopez, Lorna, M1 aBerentzen, Tina, L1 aRäikkönen, Katri1 aMangino, Massimo1 aBandinelli, Stefania1 aPeyser, Patricia, A1 aWild, Sarah1 aTrégouët, David-Alexandre1 aWright, Alan, F1 aMarten, Jonathan1 aZemunik, Tatijana1 aMorrison, Alanna, C1 aSennblad, Bengt1 aTofler, Geoffrey1 ade Maat, Moniek, P M1 aGeus, Eco, J C1 aLowe, Gordon, D1 aZoledziewska, Magdalena1 aSattar, Naveed1 aBinder, Harald1 aVölker, Uwe1 aWaldenberger, Melanie1 aKhaw, Kay-Tee1 aMcKnight, Barbara1 aHuang, Jie1 aJenny, Nancy, S1 aHolliday, Elizabeth, G1 aQi, Lihong1 aMcevoy, Mark, G1 aBecker, Diane, M1 aStarr, John, M1 aSarin, Antti-Pekka1 aHysi, Pirro, G1 aHernandez, Dena, G1 aJhun, Min, A1 aCampbell, Harry1 aHamsten, Anders1 aRivadeneira, Fernando1 aMcArdle, Wendy, L1 aSlagboom, Eline1 aZeller, Tanja1 aKoenig, Wolfgang1 aPsaty, Bruce, M1 aHaritunians, Talin1 aLiu, Jingmin1 aPalotie, Aarno1 aUitterlinden, André, G1 aStott, David, J1 aHofman, Albert1 aFranco, Oscar, H1 aPolasek, Ozren1 aRudan, Igor1 aMorange, Pierre-Emmanuel1 aWilson, James, F1 aKardia, Sharon, L R1 aFerrucci, Luigi1 aSpector, Tim, D1 aEriksson, Johan, G1 aHansen, Torben1 aDeary, Ian, J1 aBecker, Lewis, C1 aScott, Rodney, J1 aMitchell, Paul1 aMärz, Winfried1 aWareham, Nick, J1 aPeters, Annette1 aGreinacher, Andreas1 aWild, Philipp, S1 aJukema, Wouter1 aBoomsma, Dorret, I1 aHayward, Caroline1 aCucca, Francesco1 aTracy, Russell1 aWatkins, Hugh1 aReiner, Alex, P1 aFolsom, Aaron, R1 aRidker, Paul, M1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aStrachan, David, P1 aDehghan, Abbas uhttps://chs-nhlbi.org/node/693604981nas a2201333 4500008004100000022001400041245015700055210006900212260001300281300001000294490000700304520112400311100003001435700001601465700001901481700002501500700002101525700002101546700002101567700002301588700002001611700001501631700002101646700002401667700001701691700001901708700001801727700001801745700002001763700002001783700001801803700002501821700002801846700002201874700001801896700002701914700002801941700001901969700002101988700001902009700002102028700001902049700002602068700002302094700002802117700002602145700002102171700002202192700002502214700002302239700002102262700002202283700001902305700001802324700002002342700002102362700001602383700001802399700001702417700002202434700002002456700002102476700002202497700002002519700002202539700002002561700002002581700002102601700002702622700002302649700002302672700001402695700002302709700002802732700002302760700002202783700001702805700002402822700002302846700002502869700002602894700002302920700002002943700002902963700002002992700002303012700002003035700002203055700001803077700001503095700001903110700002903129700002303158700002203181700001903203700002003222700002603242700002203268700001903290700002203309700002103331700002103352700002403373700002103397700002003418700002303438700002103461700002203482700002503504700002303529710002703552710003203579856003603611 2016 eng d a1468-624400aMeta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.0 aMetaanalysis of 49 549 individuals imputed with the 1000 Genomes c2016 Jul a441-90 v533 aBACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.
METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.
RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.
CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
1 avan Leeuwen, Elisabeth, M1 aSabo, Aniko1 aBis, Joshua, C1 aHuffman, Jennifer, E1 aManichaikul, Ani1 aSmith, Albert, V1 aFeitosa, Mary, F1 aDemissie, Serkalem1 aJoshi, Peter, K1 aDuan, Qing1 aMarten, Jonathan1 avan Klinken, Jan, B1 aSurakka, Ida1 aNolte, Ilja, M1 aZhang, Weihua1 aMbarek, Hamdi1 aLi-Gao, Ruifang1 aTrompet, Stella1 aVerweij, Niek1 aEvangelou, Evangelos1 aLyytikäinen, Leo-Pekka1 aTayo, Bamidele, O1 aDeelen, Joris1 avan der Most, Peter, J1 avan der Laan, Sander, W1 aArking, Dan, E1 aMorrison, Alanna1 aDehghan, Abbas1 aFranco, Oscar, H1 aHofman, Albert1 aRivadeneira, Fernando1 aSijbrands, Eric, J1 aUitterlinden, André, G1 aMychaleckyj, Josyf, C1 aCampbell, Archie1 aHocking, Lynne, J1 aPadmanabhan, Sandosh1 aBrody, Jennifer, A1 aRice, Kenneth, M1 aWhite, Charles, C1 aHarris, Tamara1 aIsaacs, Aaron1 aCampbell, Harry1 aLange, Leslie, A1 aRudan, Igor1 aKolcic, Ivana1 aNavarro, Pau1 aZemunik, Tatijana1 aSalomaa, Veikko1 aKooner, Angad, S1 aKooner, Jaspal, S1 aLehne, Benjamin1 aScott, William, R1 aTan, Sian-Tsung1 ade Geus, Eco, J1 aMilaneschi, Yuri1 aPenninx, Brenda, W J H1 aWillemsen, Gonneke1 ade Mutsert, Renée1 aFord, Ian1 aGansevoort, Ron, T1 aSegura-Lepe, Marcelo, P1 aRaitakari, Olli, T1 aViikari, Jorma, S1 aNikus, Kjell1 aForrester, Terrence1 aMcKenzie, Colin, A1 ade Craen, Anton, J M1 ade Ruijter, Hester, M1 aPasterkamp, Gerard1 aSnieder, Harold1 aOldehinkel, Albertine, J1 aSlagboom, Eline1 aCooper, Richard, S1 aKähönen, Mika1 aLehtimäki, Terho1 aElliott, Paul1 aHarst, Pim1 aJukema, Wouter1 aMook-Kanamori, Dennis, O1 aBoomsma, Dorret, I1 aChambers, John, C1 aSwertz, Morris1 aRipatti, Samuli1 avan Dijk, Ko, Willems1 aVitart, Veronique1 aPolasek, Ozren1 aHayward, Caroline1 aWilson, James, G1 aWilson, James, F1 aGudnason, Vilmundur1 aRich, Stephen, S1 aPsaty, Bruce, M1 aBorecki, Ingrid, B1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aCupples, Adrienne, L1 aDuijn, Cornelia, M1 aLifeLines Cohort Study1 aCHARGE Lipids Working Group uhttps://chs-nhlbi.org/node/701105566nas a2201489 4500008004100000022001400041245010700055210006900162260001600231300000800247490000600255520135700261100002001618700002001638700002801658700002001686700001701706700002601723700002001749700001901769700002601788700002501814700001401839700001901853700002101872700002901893700002101922700002301943700002301966700002201989700001402011700002802025700002002053700002002073700002102093700002002114700002502134700002502159700002202184700001902206700002402225700001902249700002102268700002402289700001902313700002402332700002102356700001602377700002102393700002402414700002102438700002302459700001702482700002102499700001402520700002602534700002002560700002202580700002102602700002402623700002302647700002002670700002002690700001802710700001502728700002102743700002302764700002402787700001902811700001802830700002502848700002202873700001702895700001502912700002502927700002402952700002602976700002003002700002603022700002203048700001803070700002203088700002003110700002003130700002003150700002303170700002203193700003503215700002603250700002303276700002303299700002403322700001803346700001803364700002303382700002303405700002203428700002203450700001903472700002703491700001803518700002003536700002403556700001903580700002103599700001703620700002003637700002303657700002103680700001903701700002403720700002803744700002303772700001903795700001903814700002103833700002303854700002203877700002003899700002403919700001903943700002003962700001603982700002103998700002104019856003604040 2017 eng d a2041-172300aGenome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.0 aGenomewide metaanalysis associates HLADQA1DRB1 and LPA and lifes c2017 Oct 13 a9100 v83 aGenomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
1 aJoshi, Peter, K1 aPirastu, Nicola1 aKentistou, Katherine, A1 aFischer, Krista1 aHofer, Edith1 aSchraut, Katharina, E1 aClark, David, W1 aNutile, Teresa1 aBarnes, Catriona, L K1 aTimmers, Paul, R H J1 aShen, Xia1 aGandin, Ilaria1 aMcDaid, Aaron, F1 aHansen, Thomas, Folkmann1 aGordon, Scott, D1 aGiulianini, Franco1 aBoutin, Thibaud, S1 aAbdellaoui, Abdel1 aZhao, Wei1 aMedina-Gómez, Carolina1 aBartz, Traci, M1 aTrompet, Stella1 aLange, Leslie, A1 aRaffield, Laura1 avan der Spek, Ashley1 aGalesloot, Tessel, E1 aProitsi, Petroula1 aYanek, Lisa, R1 aBielak, Lawrence, F1 aPayton, Antony1 aMurgia, Federico1 aConcas, Maria, Pina1 aBiino, Ginevra1 aTajuddin, Salman, M1 aSeppälä, Ilkka1 aAmin, Najaf1 aBoerwinkle, Eric1 aBørglum, Anders, D1 aCampbell, Archie1 aDemerath, Ellen, W1 aDemuth, Ilja1 aFaul, Jessica, D1 aFord, Ian1 aGialluisi, Alessandro1 aGögele, Martin1 aGraff, Mariaelisa1 aHingorani, Aroon1 aHottenga, Jouke-Jan1 aHougaard, David, M1 aHurme, Mikko, A1 aIkram, Arfan, M1 aJylhä, Marja1 aKuh, Diana1 aLigthart, Lannie1 aLill, Christina, M1 aLindenberger, Ulman1 aLumley, Thomas1 aMägi, Reedik1 aMarques-Vidal, Pedro1 aMedland, Sarah, E1 aMilani, Lili1 aNagy, Reka1 aOllier, William, E R1 aPeyser, Patricia, A1 aPramstaller, Peter, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRuggiero, Daniela1 aSaba, Yasaman1 aSchmidt, Reinhold1 aSchmidt, Helena1 aSlagboom, Eline1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aSteinhagen-Thiessen, Elisabeth1 avan Rooij, Frank, J A1 aVerbeek, André, L1 aVermeulen, Sita, H1 aVollenweider, Peter1 aWang, Yunpeng1 aWerge, Thomas1 aWhitfield, John, B1 aZonderman, Alan, B1 aLehtimäki, Terho1 aEvans, Michele, K1 aPirastu, Mario1 aFuchsberger, Christian1 aBertram, Lars1 aPendleton, Neil1 aKardia, Sharon, L R1 aCiullo, Marina1 aBecker, Diane, M1 aWong, Andrew1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWilson, James, G1 aJukema, Wouter1 aKiemeney, Lambertus1 aUitterlinden, André, G1 aFranceschini, Nora1 aNorth, Kari, E1 aWeir, David, R1 aMetspalu, Andres1 aBoomsma, Dorret, I1 aHayward, Caroline1 aChasman, Daniel1 aMartin, Nicholas, G1 aSattar, Naveed1 aCampbell, Harry1 aEsko, Tõnu1 aKutalik, Zoltán1 aWilson, James, F uhttps://chs-nhlbi.org/node/756803989nas a2201057 4500008004100000022001400041245012200055210006900177260001600246300001000262490000600272520101400278100002101292700002201313700001801335700002501353700002001378700002001398700002101418700002101439700001801460700002201478700002601500700002101526700001301547700001901560700001601579700001401595700001501609700002701624700002101651700001901672700002501691700002101716700001501737700001501752700001801767700001601785700001901801700001901820700002001839700001801859700002001877700002301897700001601920700002701936700001501963700002101978700002101999700002302020700002502043700002202068700002102090700002502111700002102136700002702157700002202184700001602206700002502222700002102247700001702268700002102285700001602306700002002322700001902342700002502361700002502386700002402411700002202435700001902457700001802476700002102494700002302515700001902538700002002557700002202577700002302599700002102622700001902643700001702662700001702679700002402696700002002720700002602740700002402766700002102790700002102811700002102832710004202853856003602895 2017 eng d a2041-172300aLarge-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.0 aLargescale GWAS identifies multiple loci for hand grip strength c2017 Jul 12 a160150 v83 aHand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.
1 aWillems, Sara, M1 aWright, Daniel, J1 aDay, Felix, R1 aTrajanoska, Katerina1 aJoshi, Peter, K1 aMorris, John, A1 aMatteini, Amy, M1 aGarton, Fleur, C1 aGrarup, Niels1 aOskolkov, Nikolay1 aThalamuthu, Anbupalam1 aMangino, Massimo1 aLiu, Jun1 aDemirkan, Ayse1 aLek, Monkol1 aXu, Liwen1 aWang, Guan1 aOldmeadow, Christopher1 aGaulton, Kyle, J1 aLotta, Luca, A1 aMiyamoto-Mikami, Eri1 aRivas, Manuel, A1 aWhite, Tom1 aLoh, Po-Ru1 aAadahl, Mette1 aAmin, Najaf1 aAttia, John, R1 aAustin, Krista1 aBenyamin, Beben1 aBrage, Søren1 aCheng, Yu-Ching1 aCięszczyk, Paweł1 aDerave, Wim1 aEriksson, Karl-Fredrik1 aEynon, Nir1 aLinneberg, Allan1 aLucia, Alejandro1 aMassidda, Myosotis1 aMitchell, Braxton, D1 aMiyachi, Motohiko1 aMurakami, Haruka1 aPadmanabhan, Sandosh1 aPandey, Ashutosh1 aPapadimitriou, Ioannis1 aRajpal, Deepak, K1 aSale, Craig1 aSchnurr, Theresia, M1 aSessa, Francesco1 aShrine, Nick1 aTobin, Martin, D1 aVarley, Ian1 aWain, Louise, V1 aWray, Naomi, R1 aLindgren, Cecilia, M1 aMacArthur, Daniel, G1 aWaterworth, Dawn, M1 aMcCarthy, Mark, I1 aPedersen, Oluf1 aKhaw, Kay-Tee1 aKiel, Douglas, P1 aPitsiladis, Yannis1 aFuku, Noriyuki1 aFranks, Paul, W1 aNorth, Kathryn, N1 aDuijn, Cornelia, M1 aMather, Karen, A1 aHansen, Torben1 aHansson, Ola1 aSpector, Tim1 aMurabito, Joanne, M1 aRichards, Brent1 aRivadeneira, Fernando1 aLangenberg, Claudia1 aPerry, John, R B1 aWareham, Nick, J1 aScott, Robert, A1 aGEFOS Any-Type of Fracture Consortium uhttps://chs-nhlbi.org/node/768809467nas a2203025 4500008004100000022001400041245013800055210006900193260001600262520108200278100002001360700001601380700001701396700001901413700002701432700002501459700002201484700002401506700002101530700001901551700002601570700002401596700002501620700001601645700001901661700002001680700001701700700002101717700002001738700001701758700002201775700002001797700001901817700002101836700001601857700001901873700002801892700002001920700002501940700001701965700002001982700002302002700002102025700002202046700001502068700001902083700001702102700002202119700001802141700002602159700002202185700002002207700002202227700002002249700002002269700001902289700002102308700002702329700002502356700001802381700002102399700001902420700002102439700002202460700001802482700002502500700001502525700002402540700002102564700001902585700002102604700002002625700002002645700002702665700002202692700001802714700002602732700002302758700001902781700001702800700001802817700002102835700002402856700002102880700001802901700001802919700002002937700002202957700002402979700002103003700001803024700002403042700002303066700001703089700002003106700002303126700001803149700002103167700002103188700001803209700002003227700002103247700002303268700001203291700002603303700002203329700002303351700001703374700002003391700002203411700001903433700002703452700001603479700002703495700001903522700002303541700002203564700001603586700002003602700002203622700001803644700001803662700002003680700002403700700001803724700002203742700002003764700002403784700001203808700001503820700002003835700002903855700002003884700002003904700002103924700001703945700002203962700002403984700002104008700002504029700002304054700001904077700002904096700001904125700001404144700002504158700001904183700002104202700001904223700002704242700001804269700002604287700002304313700001604336700001804352700002004370700002204390700002004412700002304432700002204455700001604477700001804493700002404511700002004535700002304555700002204578700001804600700002004618700002204638700002104660700002104681700001904702700002004721700002204741700001904763700002004782700001604802700002104818700002404839700002804863700001704891700002404908700001604932700002304948700002004971700001304991700002705004700001705031700001605048700001705064700002305081700002905104700002405133700002005157700001505177700002305192700002605215700002005241700001905261700001905280700002105299700002205320700002205342700002405364700002205388700002205410700002305432700002005455700001605475700001805491700001905509700002005528700002405548700002105572700002105593700002105614700001605635700001705651700001805668700002605686700002005712700002105732700001905753700002105772700002005793700001905813700002205832700002305854700002405877700002005901700002005921700001905941700001605960700001905976700002305995700001906018700002106037700002006058700002306078700002106101700002106122700002906143700002406172700001806196700002306214700002606237700001906263700002206282700001706304700002106321700002006342700002306362700002006385856003606405 2017 eng d a1524-456300aNovel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.0 aNovel Blood Pressure Locus and Gene Discovery Using GenomeWide A c2017 Jul 243 aElevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
1 aWain, Louise, V1 aVaez, Ahmad1 aJansen, Rick1 aJoehanes, Roby1 avan der Most, Peter, J1 aErzurumluoglu, Mesut1 aO'Reilly, Paul, F1 aCabrera, Claudia, P1 aWarren, Helen, R1 aRose, Lynda, M1 aVerwoert, Germaine, C1 aHottenga, Jouke-Jan1 aStrawbridge, Rona, J1 aEsko, Tõnu1 aArking, Dan, E1 aHwang, Shih-Jen1 aGuo, Xiuqing1 aKutalik, Zoltán1 aTrompet, Stella1 aShrine, Nick1 aTeumer, Alexander1 aRied, Janina, S1 aBis, Joshua, C1 aSmith, Albert, V1 aAmin, Najaf1 aNolte, Ilja, M1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aWareham, Nicholas, J1 aHofer, Edith1 aJoshi, Peter, K1 aKristiansson, Kati1 aTraglia, Michela1 aHavulinna, Aki, S1 aGoel, Anuj1 aNalls, Mike, A1 aSõber, Siim1 aVuckovic, Dragana1 aLuan, Jian'an1 aM, Fabiola, del Greco1 aAyers, Kristin, L1 aMarrugat, Jaume1 aRuggiero, Daniela1 aLopez, Lorna, M1 aNiiranen, Teemu1 aEnroth, Stefan1 aJackson, Anne, U1 aNelson, Christopher, P1 aHuffman, Jennifer, E1 aZhang, Weihua1 aMarten, Jonathan1 aGandin, Ilaria1 aHarris, Sarah, E1 aZemunik, Tatijana1 aLu, Yingchang1 aEvangelou, Evangelos1 aShah, Nabi1 ade Borst, Martin, H1 aMangino, Massimo1 aPrins, Bram, P1 aCampbell, Archie1 aLi-Gao, Ruifang1 aChauhan, Ganesh1 aOldmeadow, Christopher1 aAbecasis, Goncalo1 aAbedi, Maryam1 aBarbieri, Caterina, M1 aBarnes, Michael, R1 aBatini, Chiara1 aBeilby, John1 aBlake, Tineka1 aBoehnke, Michael1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrown, Morris1 aBrumat, Marco1 aCampbell, Harry1 aChambers, John, C1 aCocca, Massimiliano1 aCollins, Francis1 aConnell, John1 aCordell, Heather, J1 aDamman, Jeffrey, J1 aDavies, Gail1 ade Geus, Eco, J1 ade Mutsert, Renée1 aDeelen, Joris1 aDemirkale, Yusuf1 aDoney, Alex, S F1 aDörr, Marcus1 aFarrall, Martin1 aFerreira, Teresa1 aFrånberg, Mattias1 aGao, He1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGiulianini, Franco1 aGow, Alan, J1 aHamsten, Anders1 aHarris, Tamara, B1 aHofman, Albert1 aHolliday, Elizabeth, G1 aHui, Jennie1 aJarvelin, Marjo-Riitta1 aJohansson, Asa1 aJohnson, Andrew, D1 aJousilahti, Pekka1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKhaw, Kay-Tee1 aKolcic, Ivana1 aKoskinen, Seppo1 aLangenberg, Claudia1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aMach, François1 aMamasoula, Chrysovalanto1 aMenni, Cristina1 aMifsud, Borbala1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, D1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNandakumar, Priyanka1 aNguyen, Quang, Tri1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalotie, Aarno1 aParé, Guillaume1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPoulter, Neil1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRen, Meixia1 aRice, Kenneth1 aRidker, Paul, M1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRotter, Jerome, I1 aRudan, Igor1 aSaba, Yasaman1 aPierre, Aude, Saint1 aSala, Cinzia, F1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aScott, Rodney1 aSeelen, Marc, A1 aShields, Denis, C1 aSiscovick, David1 aSorice, Rossella1 aStanton, Alice1 aStott, David, J1 aSundström, Johan1 aSwertz, Morris1 aTaylor, Kent, D1 aThom, Simon1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, André, G1 aVölker, Uwe1 aVollenweider, Peter1 aWild, Sarah1 aWillemsen, Gonneke1 aWright, Alan, F1 aYao, Jie1 aThériault, Sébastien1 aConen, David1 aAttia, John1 aSever, Peter1 aDebette, Stephanie1 aMook-Kanamori, Dennis, O1 aZeggini, Eleftheria1 aSpector, Tim, D1 aHarst, Pim1 aPalmer, Colin, N A1 aVergnaud, Anne-Claire1 aLoos, Ruth, J F1 aPolasek, Ozren1 aStarr, John, M1 aGirotto, Giorgia1 aHayward, Caroline1 aKooner, Jaspal, S1 aLindgren, Cecila, M1 aVitart, Veronique1 aSamani, Nilesh, J1 aTuomilehto, Jaakko1 aGyllensten, Ulf1 aKnekt, Paul1 aDeary, Ian, J1 aCiullo, Marina1 aElosua, Roberto1 aKeavney, Bernard, D1 aHicks, Andrew, A1 aScott, Robert, A1 aGasparini, Paolo1 aLaan, Maris1 aLiu, Yongmei1 aWatkins, Hugh1 aHartman, Catharina, A1 aSalomaa, Veikko1 aToniolo, Daniela1 aPerola, Markus1 aWilson, James, F1 aSchmidt, Helena1 aZhao, Jing Hua1 aLehtimäki, Terho1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aPeters, Annette1 aRettig, Rainer1 aJames, Alan1 aJukema, Wouter1 aStrachan, David, P1 aPalmas, Walter1 aMetspalu, Andres1 aIngelsson, Erik1 aBoomsma, Dorret, I1 aFranco, Oscar, H1 aBochud, Murielle1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aElliott, Paul1 aChasman, Daniel, I1 aChakravarti, Aravinda1 aKnight, Joanne1 aMorris, Andrew, P1 aLevy, Daniel1 aTobin, Martin, D1 aSnieder, Harold1 aCaulfield, Mark, J1 aEhret, Georg, B uhttps://chs-nhlbi.org/node/749210328nas a2203505 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2018 eng d a1546-171800aGenetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.0 aGenetic analysis of over 1 million people identifies 535 new loc c2018 Oct a1412-14250 v503 aHigh blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
1 aEvangelou, Evangelos1 aWarren, Helen, R1 aMosen-Ansorena, David1 aMifsud, Borbala1 aPazoki, Raha1 aGao, He1 aNtritsos, Georgios1 aDimou, Niki1 aCabrera, Claudia, P1 aKaraman, Ibrahim1 aNg, Fu, Liang1 aEvangelou, Marina1 aWitkowska, Katarzyna1 aTzanis, Evan1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aEdwards, Digna, R Velez1 aSun, Yan, V1 aCho, Kelly1 aGaziano, Michael1 aWilson, Peter, W F1 aTsao, Philip, S1 aKovesdy, Csaba, P1 aEsko, Tõnu1 aMägi, Reedik1 aMilani, Lili1 aAlmgren, Peter1 aBoutin, Thibaud1 aDebette, Stephanie1 aDing, Jun1 aGiulianini, Franco1 aHolliday, Elizabeth, G1 aJackson, Anne, U1 aLi-Gao, Ruifang1 aLin, Wei-Yu1 aLuan, Jian'an1 aMangino, Massimo1 aOldmeadow, Christopher1 aPrins, Bram, Peter1 aQian, Yong1 aSargurupremraj, Muralidharan1 aShah, Nabi1 aSurendran, Praveen1 aThériault, Sébastien1 aVerweij, Niek1 aWillems, Sara, M1 aZhao, Jing-Hua1 aAmouyel, Philippe1 aConnell, John1 ade Mutsert, Renée1 aDoney, Alex, S F1 aFarrall, Martin1 aMenni, Cristina1 aMorris, Andrew, D1 aNoordam, Raymond1 aParé, Guillaume1 aPoulter, Neil, R1 aShields, Denis, C1 aStanton, Alice1 aThom, Simon1 aAbecasis, Goncalo1 aAmin, Najaf1 aArking, Dan, E1 aAyers, Kristin, L1 aBarbieri, Caterina, M1 aBatini, Chiara1 aBis, Joshua, C1 aBlake, Tineka1 aBochud, Murielle1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrumat, Marco1 aCampbell, Archie1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChauhan, Ganesh1 aCiullo, Marina1 aCocca, Massimiliano1 aCollins, Francis1 aCordell, Heather, J1 aDavies, Gail1 ade Borst, Martin, H1 ade Geus, Eco, J1 aDeary, Ian, J1 aDeelen, Joris1 aM, Fabiola, del Greco1 aDemirkale, Cumhur, Yusuf1 aDörr, Marcus1 aEhret, Georg, B1 aElosua, Roberto1 aEnroth, Stefan1 aErzurumluoglu, Mesut1 aFerreira, Teresa1 aFrånberg, Mattias1 aFranco, Oscar, H1 aGandin, Ilaria1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGoel, Anuj1 aGow, Alan, J1 aGudnason, 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2018 eng d a1537-660500aGenome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.0 aGenome Analyses of 200000 Individuals Identify 58 Loci for Chron c2018 Nov 01 a691-7060 v1033 aC-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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aFelix, Stephan, B1 aPers, Tune, H1 aBakker, Stephan, J L1 aKraft, Peter1 aPeters, Annette1 aVaidya, Dhananjay1 aDelgado, Graciela1 aSmit, Johannes, H1 aGroßmann, Vera1 aSinisalo, Juha1 aSeppälä, Ilkka1 aWilliams, Stephen, R1 aHolliday, Elizabeth, G1 aMoed, Matthijs1 aLangenberg, Claudia1 aRäikkönen, Katri1 aDing, Jingzhong1 aCampbell, Harry1 aSale, Michèle, M1 aChen, Yii-der, I1 aJames, Alan, L1 aRuggiero, Daniela1 aSoranzo, Nicole1 aHartman, Catharina, A1 aSmith, Erin, N1 aBerenson, Gerald, S1 aFuchsberger, Christian1 aHernandez, Dena1 aTiesler, Carla, M T1 aGiedraitis, Vilmantas1 aLiewald, David1 aFischer, Krista1 aMellström, Dan1 aLarsson, Anders1 aWang, Yunmei1 aScott, William, R1 aLorentzon, Matthias1 aBeilby, John1 aRyan, Kathleen, A1 aPennell, Craig, E1 aVuckovic, Dragana1 aBalkau, Beverly1 aConcas, Maria, Pina1 aSchmidt, Reinhold1 ade Leon, Carlos, F Mendes1 aBottinger, Erwin, P1 aKloppenburg, Margreet1 aPaternoster, Lavinia1 aBoehnke, Michael1 aMusk, A, W1 aWillemsen, Gonneke1 aEvans, David, M1 aMadden, Pamela, A F1 aKähönen, Mika1 aKutalik, Zoltán1 aZoledziewska, Magdalena1 aKarhunen, Ville1 aKritchevsky, Stephen, B1 aSattar, Naveed1 aLachance, Genevieve1 aClarke, Robert1 aHarris, Tamara, B1 aRaitakari, Olli, T1 aAttia, John, R1 avan Heemst, Diana1 aKajantie, Eero1 aSorice, Rossella1 aGambaro, Giovanni1 aScott, Robert, A1 aHicks, Andrew, A1 aFerrucci, Luigi1 aStandl, Marie1 aLindgren, Cecilia, M1 aStarr, John, M1 aKarlsson, Magnus1 aLind, Lars1 aLi, Jun, Z1 aChambers, John, C1 aMori, Trevor, A1 ade Geus, Eco, J C N1 aHeath, Andrew, C1 aMartin, Nicholas, G1 aAuvinen, Juha1 aBuckley, Brendan, M1 ade Craen, Anton, J M1 aWaldenberger, Melanie1 aStrauch, Konstantin1 aMeitinger, Thomas1 aScott, Rodney, J1 aMcEvoy, Mark1 aBeekman, Marian1 aBombieri, Cristina1 aRidker, Paul, M1 aMohlke, Karen, L1 aPedersen, Nancy, L1 aMorrison, Alanna, C1 aBoomsma, Dorret, I1 aWhitfield, John, B1 aStrachan, David, P1 aHofman, Albert1 aVollenweider, Peter1 aCucca, Francesco1 aJarvelin, Marjo-Riitta1 aJukema, Wouter1 aSpector, Tim, D1 aHamsten, Anders1 aZeller, Tanja1 aUitterlinden, André, G1 aNauck, Matthias1 aGudnason, Vilmundur1 aQi, Lu1 aGrallert, Harald1 aBorecki, Ingrid, B1 aRotter, Jerome, I1 aMärz, Winfried1 aWild, Philipp, S1 aLokki, Marja-Liisa1 aBoyle, Michael1 aSalomaa, Veikko1 aMelbye, Mads1 aEriksson, Johan, G1 aWilson, James, F1 aPenninx, Brenda, W J H1 aBecker, Diane, M1 aWorrall, Bradford, B1 aGibson, Greg1 aKrauss, Ronald, M1 aCiullo, Marina1 aZaza, Gianluigi1 aWareham, Nicholas, J1 aOldehinkel, Albertine, J1 aPalmer, Lyle, J1 aMurray, Sarah, S1 aPramstaller, Peter, P1 aBandinelli, Stefania1 aHeinrich, Joachim1 aIngelsson, Erik1 aDeary, Ian, J1 aMägi, Reedik1 aVandenput, Liesbeth1 aHarst, Pim1 aDesch, Karl, C1 aKooner, Jaspal, S1 aOhlsson, Claes1 aHayward, Caroline1 aLehtimäki, Terho1 aShuldiner, Alan, R1 aArnett, Donna, K1 aBeilin, Lawrence, J1 aRobino, Antonietta1 aFroguel, Philippe1 aPirastu, Mario1 aJess, Tine1 aKoenig, Wolfgang1 aLoos, Ruth, J F1 aEvans, Denis, A1 aSchmidt, Helena1 aSmith, George Davey1 aSlagboom, Eline1 aEiriksdottir, Gudny1 aMorris, Andrew, P1 aPsaty, Bruce, M1 aTracy, Russell, P1 aNolte, Ilja, M1 aBoerwinkle, Eric1 aVisvikis-Siest, Sophie1 aReiner, Alex, P1 aGross, Myron1 aBis, Joshua, C1 aFranke, Lude1 aFranco, Oscar, H1 aBenjamin, Emelia, J1 aChasman, Daniel, I1 aDupuis, Josée1 aSnieder, Harold1 aDehghan, Abbas1 aAlizadeh, Behrooz, Z1 aLifeLines Cohort Study1 aCHARGE Inflammation Working Group uhttps://chs-nhlbi.org/node/792005033nas a2201381 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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/766705032nas a2201033 4500008004100000022001400041245016100055210006900216260001600285520189700301100002502198700002502223700002202248700002102270700002802291700001302319700002102332700002802353700001902381700002002400700002502420700001702445700002002462700002602482700002002508700002502528700001802553700001902571700002102590700002002611700002002631700001802651700002002669700002002689700002202709700002402731700002102755700002502776700002202801700001602823700002302839700002002862700002202882700002502904700001902929700003002948700001902978700001802997700002003015700002203035700002203057700002003079700001603099700002103115700001503136700002603151700002803177700001903205700002103224700001803245700002003263700002903283700002203312700002203334700003003356700002103386700001903407700002403426700002103450700002203471700002003493700002003513700002403533700002403557700002103581700002003602700002003622700001903642700001903661700003203680700002403712700002303736700003003759700002303789700002703812700002303839710010003862856003603962 2018 eng d a1524-453900aGenome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.0 aGenomeWide Association TransEthnic MetaAnalyses Identifies Novel c2018 Nov 203 aBACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.
METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.
RESULTS: We identified 13 novel genome-wide significant (p≤2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.
CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
1 aSabater-Lleal, Maria1 aHuffman, Jennifer, E1 ade Vries, Paul, S1 aMarten, Jonathan1 aMastrangelo, Michael, A1 aSong, Ci1 aPankratz, Nathan1 aWard-Caviness, Cavin, K1 aYanek, Lisa, R1 aTrompet, Stella1 aDelgado, Graciela, E1 aGuo, Xiuqing1 aBartz, Traci, M1 aMartinez-Perez, Angel1 aGermain, Marine1 ade Haan, Hugoline, G1 aOzel, Ayse, B1 aPolasek, Ozren1 aSmith, Albert, V1 aEicher, John, D1 aReiner, Alex, P1 aTang, Weihong1 aDavies, Neil, M1 aStott, David, J1 aRotter, Jerome, I1 aTofler, Geoffrey, H1 aBoerwinkle, Eric1 ade Maat, Moniek, P M1 aKleber, Marcus, E1 aWelsh, Paul1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aVaidya, Dhananjay1 aSoria, José, Manuel1 aSuchon, Pierre1 aVlieg, Astrid, van Hylcka1 aDesch, Karl, C1 aKolcic, Ivana1 aJoshi, Peter, K1 aLauner, Lenore, J1 aHarris, Tamara, B1 aCampbell, Harry1 aRudan, Igor1 aBecker, Diane, M1 aLi, Jun, Z1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aCushman, Mary1 aPsaty, Bruce, M1 aMorange, Pierre-Emmanuel1 aMcKnight, Barbara1 aChong, Michael, R1 aFernandez-Cadenas, Israel1 aRosand, Jonathan1 aLindgren, Arne1 aGudnason, Vilmundur1 aWilson, James, F1 aHayward, Caroline1 aGinsburg, David1 aFornage, Myriam1 aRosendaal, Frits, R1 aSouto, Juan, Carlos1 aBecker, Lewis, C1 aJenny, Nancy, S1 aMärz, Winfried1 aJukema, Wouter1 aDehghan, Abbas1 aTrégouët, David-Alexandre1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aStrachan, David, P1 aLowenstein, Charles, J1 aSmith, Nicholas, L1 aINVENT Consortium; MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC) uhttps://chs-nhlbi.org/node/792407247nas 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/791308823nas a2202773 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2018 eng d a2041-172300aStudy of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.0 aStudy of 300486 individuals identifies 148 independent genetic l c2018 May 29 a20980 v93 aGeneral cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
1 aDavies, Gail1 aLam, Max1 aHarris, Sarah, E1 aTrampush, Joey, W1 aLuciano, Michelle1 aHill, David1 aHagenaars, Saskia, P1 aRitchie, Stuart, J1 aMarioni, Riccardo, E1 aFawns-Ritchie, Chloe1 aLiewald, David, C M1 aOkely, Judith, A1 aAhola-Olli, Ari, V1 aBarnes, Catriona, L K1 aBertram, Lars1 aBis, Joshua, C1 aBurdick, Katherine, E1 aChristoforou, Andrea1 aDeRosse, Pamela1 aDjurovic, Srdjan1 aEspeseth, Thomas1 aGiakoumaki, Stella1 aGiddaluru, Sudheer1 aGustavson, Daniel, E1 aHayward, Caroline1 aHofer, Edith1 aIkram, Arfan, M1 aKarlsson, Robert1 aKnowles, Emma1 aLahti, Jari1 aLeber, Markus1 aLi, Shuo1 aMather, Karen, A1 aMelle, Ingrid1 aMorris, Derek1 aOldmeadow, Christopher1 aPalviainen, Teemu1 aPayton, Antony1 aPazoki, Raha1 aPetrovic, Katja1 aReynolds, Chandra, A1 aSargurupremraj, Muralidharan1 aScholz, Markus1 aSmith, Jennifer, A1 aSmith, Albert, V1 aTerzikhan, Natalie1 aThalamuthu, Anbupalam1 aTrompet, Stella1 avan der Lee, Sven, J1 aWare, Erin, B1 aWindham, Gwen1 aWright, Margaret, J1 aYang, Jingyun1 aYu, Jin1 aAmes, David1 aAmin, Najaf1 aAmouyel, Philippe1 aAndreassen, Ole, A1 aArmstrong, Nicola, J1 aAssareh, Amelia, A1 aAttia, John, R1 aAttix, Deborah1 aAvramopoulos, Dimitrios1 aBennett, David, A1 aBöhmer, Anne, C1 aBoyle, Patricia, A1 aBrodaty, Henry1 aCampbell, Harry1 aCannon, Tyrone, D1 aCirulli, Elizabeth, T1 aCongdon, Eliza1 aConley, Emily, Drabant1 aCorley, Janie1 aCox, Simon, R1 aDale, Anders, M1 aDehghan, Abbas1 aDick, Danielle1 aDickinson, Dwight1 aEriksson, Johan, G1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFord, Ian1 aFreimer, Nelson, A1 aGao, He1 aGiegling, Ina1 aGillespie, Nathan, A1 aGordon, Scott, D1 aGottesman, Rebecca, F1 aGriswold, Michael, E1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHartmann, Annette, M1 aHatzimanolis, Alex1 aHeiss, Gerardo1 aHolliday, Elizabeth, G1 aJoshi, Peter, K1 aKähönen, Mika1 aKardia, Sharon, L R1 aKarlsson, Ida1 aKleineidam, Luca1 aKnopman, David, S1 aKochan, Nicole, A1 aKonte, Bettina1 aKwok, John, B1 aLe Hellard, Stephanie1 aLee, Teresa1 aLehtimäki, Terho1 aLi, Shu-Chen1 aLiu, Tian1 aKoini, Marisa1 aLondon, Edythe1 aLongstreth, Will, T1 aLopez, Oscar, L1 aLoukola, Anu1 aLuck, Tobias1 aLundervold, Astri, J1 aLundquist, Anders1 aLyytikäinen, Leo-Pekka1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aMurray, Alison, D1 aNeed, Anna, C1 aNoordam, Raymond1 aNyberg, Lars1 aOllier, William1 aPapenberg, Goran1 aPattie, Alison1 aPolasek, Ozren1 aPoldrack, Russell, A1 aPsaty, Bruce, M1 aReppermund, Simone1 aRiedel-Heller, Steffi, G1 aRose, Richard, J1 aRotter, Jerome, I1 aRoussos, Panos1 aRovio, Suvi, P1 aSaba, Yasaman1 aSabb, Fred, W1 aSachdev, Perminder, S1 aSatizabal, Claudia, L1 aSchmid, Matthias1 aScott, Rodney, J1 aScult, Matthew, A1 aSimino, Jeannette1 aSlagboom, Eline1 aSmyrnis, Nikolaos1 aSoumaré, Aïcha1 aStefanis, Nikos, C1 aStott, David, J1 aStraub, Richard, E1 aSundet, Kjetil1 aTaylor, Adele, M1 aTaylor, Kent, D1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, Andre1 aVitart, 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2019 eng d a2041-172300aAssociations of autozygosity with a broad range of human phenotypes.0 aAssociations of autozygosity with a broad range of human phenoty c2019 Oct 31 a49570 v103 aIn many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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2019 eng d a1546-171800aA catalog of genetic loci associated with kidney function from analyses of a million individuals.0 acatalog of genetic loci associated with kidney function from ana c2019 06 a957-9720 v513 aChronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aInheritance Patterns10aKidney Function Tests10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRenal Insufficiency, Chronic10aUromodulin1 aWuttke, Matthias1 aLi, Yong1 aLi, Man1 aSieber, Karsten, B1 aFeitosa, Mary, F1 aGorski, Mathias1 aTin, Adrienne1 aWang, Lihua1 aChu, Audrey, Y1 aHoppmann, Anselm1 aKirsten, Holger1 aGiri, Ayush1 aChai, Jin-Fang1 aSveinbjornsson, Gardar1 aTayo, Bamidele, O1 aNutile, Teresa1 aFuchsberger, Christian1 aMarten, Jonathan1 aCocca, Massimiliano1 aGhasemi, Sahar1 aXu, Yizhe1 aHorn, Katrin1 aNoce, Damia1 avan der Most, Peter, J1 aSedaghat, Sanaz1 aYu, Zhi1 aAkiyama, Masato1 aAfaq, Saima1 aAhluwalia, Tarunveer, S1 aAlmgren, Peter1 aAmin, Najaf1 aArnlöv, Johan1 aBakker, Stephan, J L1 aBansal, Nisha1 aBaptista, Daniela1 aBergmann, Sven1 aBiggs, Mary, L1 aBiino, Ginevra1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoissel, Mathilde1 aBottinger, Erwin, P1 aBoutin, Thibaud, S1 aBrenner, Hermann1 aBrumat, Marco1 aBurkhardt, Ralph1 aButterworth, Adam, S1 aCampana, Eric1 aCampbell, Archie1 aCampbell, Harry1 aCanouil, Mickaël1 aCarroll, Robert, J1 aCatamo, Eulalia1 aChambers, John, C1 aChee, Miao-Ling1 aChee, Miao-Li1 aChen, Xu1 aCheng, Ching-Yu1 aCheng, Yurong1 aChristensen, Kaare1 aCifkova, Renata1 aCiullo, Marina1 aConcas, Maria, Pina1 aCook, James, P1 aCoresh, Josef1 aCorre, Tanguy1 aSala, Cinzia, Felicita1 aCusi, Daniele1 aDanesh, John1 aDaw, Warwick1 ade Borst, Martin, H1 aDe Grandi, Alessandro1 ade Mutsert, Renée1 ade Vries, Aiko, P J1 aDegenhardt, Frauke1 aDelgado, Graciela1 aDemirkan, Ayse1 aDi Angelantonio, Emanuele1 aDittrich, Katalin1 aDivers, Jasmin1 aDorajoo, Rajkumar1 aEckardt, Kai-Uwe1 aEhret, Georg1 aElliott, Paul1 aEndlich, Karlhans1 aEvans, Michele, K1 aFelix, Janine, F1 aFoo, Valencia, Hui Xian1 aFranco, Oscar, H1 aFranke, Andre1 aFreedman, Barry, I1 aFreitag-Wolf, Sandra1 aFriedlander, Yechiel1 aFroguel, Philippe1 aGansevoort, Ron, T1 aGao, He1 aGasparini, Paolo1 aGaziano, Michael1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGiulianini, Franco1 aGögele, Martin1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHaller, Toomas1 aHamet, Pavel1 aHarris, Tamara, B1 aHartman, Catharina, A1 aHayward, Caroline1 aHellwege, Jacklyn, N1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHofer, Edith1 aHuang, Wei1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aIndridason, Olafur, S1 aIngelsson, Erik1 aIsing, Marcus1 aJaddoe, Vincent, W V1 aJakobsdottir, Johanna1 aJonas, Jost, B1 aJoshi, Peter, K1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKanai, Masahiro1 aKastarinen, Mika1 aKerr, Shona, M1 aKhor, Chiea-Chuen1 aKiess, Wieland1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, 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aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNoordam, Raymond1 aO'Connell, Jeffrey1 aO'Donoghue, Michelle, L1 aOlafsson, Isleifur1 aOldehinkel, Albertine, J1 aOrho-Melander, Marju1 aOuwehand, Willem, H1 aPadmanabhan, Sandosh1 aPalmer, Nicholette, D1 aPalsson, Runolfur1 aPenninx, Brenda, W J H1 aPerls, Thomas1 aPerola, Markus1 aPirastu, Mario1 aPirastu, Nicola1 aPistis, Giorgio1 aPodgornaia, Anna, I1 aPolasek, Ozren1 aPonte, Belen1 aPorteous, David, J1 aPoulain, Tanja1 aPramstaller, Peter, P1 aPreuss, Michael, H1 aPrins, Bram, P1 aProvince, Michael, A1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRizzi, Federica1 aRoberts, David, J1 aRobino, Antonietta1 aRossing, Peter1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSalomaa, Veikko1 aSalvi, Erika1 aSaum, Kai-Uwe1 aSchmidt, Helena1 aSchmidt, Reinhold1 aSchöttker, Ben1 aSchulz, Christina-Alexandra1 aSchupf, Nicole1 aShaffer, Christian, M1 aShi, Yuan1 aSmith, Albert, V1 aSmith, Blair, H1 aSoranzo, Nicole1 aSpracklen, Cassandra, N1 aStrauch, Konstantin1 aStringham, Heather, M1 aStumvoll, Michael1 aSvensson, Per, O1 aSzymczak, Silke1 aTai, E-Shyong1 aTajuddin, Salman, M1 aTan, Nicholas, Y Q1 aTaylor, Kent, D1 aTeren, Andrej1 aTham, Yih-Chung1 aThiery, Joachim1 aThio, Chris, H L1 aThomsen, Hauke1 aThorleifsson, Gudmar1 aToniolo, Daniela1 aTönjes, Anke1 aTremblay, Johanne1 aTzoulaki, Ioanna1 aUitterlinden, André, G1 aVaccargiu, Simona1 avan Dam, Rob, M1 aHarst, Pim1 aDuijn, Cornelia, M1 aEdward, Digna, R Velez1 aVerweij, Niek1 aVogelezang, Suzanne1 aVölker, Uwe1 aVollenweider, Peter1 aWaeber, Gérard1 aWaldenberger, Melanie1 aWallentin, Lars1 aWang, Ya, Xing1 aWang, Chaolong1 aWaterworth, Dawn, M1 aBin Wei, Wen1 aWhite, Harvey1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aWojczynski, Mary, K1 aWong, Charlene1 aWong, Tien-Yin1 aXu, Liang1 aYang, Qiong1 aYasuda, Masayuki1 aYerges-Armstrong, Laura, M1 aZhang, Weihua1 aZonderman, Alan, B1 aRotter, Jerome, I1 aBochud, Murielle1 aPsaty, Bruce, M1 aVitart, Veronique1 aWilson, James, G1 aDehghan, Abbas1 aParsa, Afshin1 aChasman, Daniel, I1 aHo, Kevin1 aMorris, Andrew, P1 aDevuyst, Olivier1 aAkilesh, Shreeram1 aPendergrass, Sarah, A1 aSim, Xueling1 aBöger, Carsten, A1 aOkada, Yukinori1 aEdwards, Todd, L1 aSnieder, Harold1 aStefansson, Kari1 aHung, Adriana, M1 aHeid, Iris, M1 aScholz, Markus1 aTeumer, Alexander1 aKöttgen, Anna1 aPattaro, Cristian1 aLifeLines Cohort Study1 aV. A. Million Veteran Program uhttps://chs-nhlbi.org/node/810905901nas a2201993 4500008004100000022001400041245012500055210006900180260001600249490000600265520115800271100002301429700001901452700001801471700002001489700001601509700001501525700002601540700002001566700001501586700001301601700001301614700001701627700001601644700001401660700001701674700001501691700002001706700002001726700001401746700001801760700001201778700001301790700001401803700001601817700001701833700001401850700001401864700001401878700001901892700001401911700001601925700001101941700001501952700001401967700001301981700002301994700001802017700001502035700001702050700001102067700001802078700001602096700001702112700001602129700001702145700001402162700002402176700001302200700001402213700001502227700001402242700001802256700001402274700001402288700001602302700001502318700001702333700001202350700001502362700001702377700001502394700001202409700001402421700001502435700001702450700001602467700001602483700001402499700001402513700001202527700001502539700001502554700001902569700001302588700001502601700001802616700001202634700001202646700001302658700001502671700001302686700001302699700001702712700001602729700001402745700001702759700001502776700002002791700002002811700001402831700001802845700001202863700001302875700001402888700001602902700001702918700001402935700001402949700001402963700001902977700001402996700001603010700001103026700001503037700001403052700001303066700002303079700001803102700001503120700001703135700001103152700001803163700001603181700001703197700001603214700001703230700001403247700002403261700001303285700001403298700001503312700001403327700001803341700001403359700001403373700001603387700001503403700001703418700001203435700001503447700001703462700001503479700001203494700001403506700001503520700001703535700001603552700001603568700001403584700001403598700001203612700001503624700001503639700001903654700001303673700001503686700001803701700001203719700001203731700001303743700001403756700001603770700002103786700002103807700002003828710002303848856003603871 2019 eng d a2050-084X00aGenomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances.0 aGenomics of 1 million parent lifespans implicates novel pathways c2019 Jan 150 v83 aWe use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near , , , , , and 13q21.31, and identify and replicate novel findings near , , and . We also validate previous findings near 5q33.3/ and , whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.
Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
1 aTimmers, Paul, Rhj1 aMounier, Ninon1 aLäll, Kristi1 aFischer, Krista1 aNing, Zheng1 aFeng, Xiao1 aBretherick, Andrew, D1 aClark, David, W1 aAgbessi, M1 aAhsan, H1 aAlves, I1 aAndiappan, A1 aAwadalla, P1 aBattle, A1 aBonder, M, J1 aBoomsma, D1 aChristiansen, M1 aClaringbould, A1 aDeelen, P1 avan Dongen, J1 aEsko, T1 aFavé, M1 aFranke, L1 aFrayling, T1 aGharib, S, A1 aGibson, G1 aHemani, G1 aJansen, R1 aKalnapenkis, A1 aKasela, S1 aKettunen, J1 aKim, Y1 aKirsten, H1 aKovacs, P1 aKrohn, K1 aKronberg-Guzman, J1 aKukushkina, V1 aKutalik, Z1 aKähönen, M1 aLee, B1 aLehtimäki, T1 aLoeffler, M1 aMarigorta, U1 aMetspalu, A1 avan Meurs, J1 aMilani, L1 aMüller-Nurasyid, M1 aNauck, M1 aNivard, M1 aPenninx, B1 aPerola, M1 aPervjakova, N1 aPierce, B1 aPowell, J1 aProkisch, H1 aPsaty, B M1 aRaitakari, O1 aRing, S1 aRipatti, S1 aRotzschke, O1 aRuëger, S1 aSaha, A1 aScholz, M1 aSchramm, K1 aSeppälä, I1 aStumvoll, M1 aSullivan, P1 aTeumer, A1 aThiery, J1 aTong, L1 aTönjes, A1 aVerlouw, J1 aVisscher, P, M1 aVõsa, U1 aVölker, U1 aYaghootkar, H1 aYang, J1 aZeng, B1 aZhang, F1 aAgbessi, M1 aAhsan, H1 aAlves, I1 aAndiappan, A1 aAwadalla, P1 aBattle, A1 aBonder, M, J1 aBoomsma, D1 aChristiansen, M1 aClaringbould, A1 aDeelen, P1 avan Dongen, J1 aEsko, T1 aFavé, M1 aFranke, L1 aFrayling, T1 aGharib, S, A1 aGibson, G1 aHemani, G1 aJansen, R1 aKalnapenkis, A1 aKasela, S1 aKettunen, J1 aKim, Y1 aKirsten, H1 aKovacs, P1 aKrohn, K1 aKronberg-Guzman, J1 aKukushkina, V1 aKutalik, Z1 aKähönen, M1 aLee, B1 aLehtimäki, T1 aLoeffler, M1 aMarigorta, U1 aMetspalu, A1 avan Meurs, J1 aMilani, L1 aMüller-Nurasyid, M1 aNauck, M1 aNivard, M1 aPenninx, B1 aPerola, M1 aPervjakova, N1 aPierce, B1 aPowell, J1 aProkisch, H1 aPsaty, B M1 aRaitakari, O1 aRing, S1 aRipatti, S1 aRotzschke, O1 aRuëger, S1 aSaha, A1 aScholz, M1 aSchramm, K1 aSeppälä, I1 aStumvoll, M1 aSullivan, P1 aTeumer, A1 aThiery, J1 aTong, L1 aTönjes, A1 aVerlouw, J1 aVisscher, P, M1 aVõsa, U1 aVölker, U1 aYaghootkar, H1 aYang, J1 aZeng, B1 aZhang, F1 aShen, Xia1 aEsko, Tõnu1 aKutalik, Zoltán1 aWilson, James, F1 aJoshi, Peter, K1 aeQTLGen Consortium uhttps://chs-nhlbi.org/node/798109183nas a2202869 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2019 eng d a1546-171800aTarget genes, variants, tissues and transcriptional pathways influencing human serum urate levels.0 aTarget genes variants tissues and transcriptional pathways influ c2019 Oct a1459-14740 v513 aElevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
1 aTin, Adrienne1 aMarten, Jonathan1 aKuhns, Victoria, L Halperin1 aLi, Yong1 aWuttke, Matthias1 aKirsten, Holger1 aSieber, Karsten, B1 aQiu, Chengxiang1 aGorski, Mathias1 aYu, Zhi1 aGiri, Ayush1 aSveinbjornsson, Gardar1 aLi, Man1 aChu, Audrey, Y1 aHoppmann, Anselm1 aO'Connor, Luke, J1 aPrins, Bram1 aNutile, Teresa1 aNoce, Damia1 aAkiyama, Masato1 aCocca, Massimiliano1 aGhasemi, Sahar1 avan der Most, Peter, J1 aHorn, Katrin1 aXu, Yizhe1 aFuchsberger, Christian1 aSedaghat, Sanaz1 aAfaq, Saima1 aAmin, Najaf1 aArnlöv, Johan1 aBakker, Stephan, J L1 aBansal, Nisha1 aBaptista, Daniela1 aBergmann, Sven1 aBiggs, Mary, L1 aBiino, Ginevra1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBoutin, Thibaud, S1 aBrumat, Marco1 aBurkhardt, Ralph1 aCampana, Eric1 aCampbell, Archie1 aCampbell, Harry1 aCarroll, Robert, J1 aCatamo, Eulalia1 aChambers, John, C1 aCiullo, Marina1 aConcas, Maria, Pina1 aCoresh, Josef1 aCorre, Tanguy1 aCusi, Daniele1 aFelicita, Sala, Cinzia1 ade Borst, Martin, H1 aDe Grandi, Alessandro1 ade Mutsert, Renée1 ade Vries, Aiko, P J1 aDelgado, Graciela1 aDemirkan, Ayse1 aDevuyst, Olivier1 aDittrich, Katalin1 aEckardt, Kai-Uwe1 aEhret, Georg1 aEndlich, Karlhans1 aEvans, Michele, K1 aGansevoort, Ron, T1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGögele, Martin1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHaller, Toomas1 aHamet, Pavel1 aHarris, Tamara, B1 aHayward, Caroline1 aHicks, Andrew, A1 aHofer, Edith1 aHolm, Hilma1 aHuang, Wei1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aLewis, Raychel, M1 aIngelsson, Erik1 aJakobsdottir, Johanna1 aJonsdottir, Ingileif1 aJonsson, Helgi1 aJoshi, Peter, K1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKerr, Shona, M1 aKiess, Wieland1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKörner, Antje1 aKovacs, Peter1 aKrämer, Bernhard, K1 aKronenberg, Florian1 aKubo, Michiaki1 aKuhnel, Brigitte1 aLa Bianca, Martina1 aLange, Leslie, A1 aLehne, Benjamin1 aLehtimäki, Terho1 aLiu, Jun1 aLoeffler, Markus1 aLoos, Ruth, J F1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMahajan, Anubha1 aMartin, Nicholas, G1 aMärz, Winfried1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMeisinger, Christa1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aO'Donnell, Christopher, J1 aWilson, Otis, D1 aGaziano, Michael1 aMishra, Pashupati, P1 aMohlke, Karen, L1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMüller-Nurasyid, Martina1 aNadkarni, Girish, N1 aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNoordam, Raymond1 aO'Connell, Jeffrey, R1 aOlafsson, Isleifur1 aPadmanabhan, Sandosh1 aPenninx, Brenda, W J H1 aPerls, Thomas1 aPeters, Annette1 aPirastu, Mario1 aPirastu, Nicola1 aPistis, Giorgio1 aPolasek, Ozren1 aPonte, Belen1 aPorteous, David, J1 aPoulain, Tanja1 aPreuss, Michael, H1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRizzi, Federica1 aRobino, Antonietta1 aRudan, Igor1 aKrajcoviechova, Alena1 aCifkova, Renata1 aRueedi, Rico1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSaba, Yasaman1 aSalvi, Erika1 aSchmidt, Helena1 aSchmidt, Reinhold1 aShaffer, Christian, M1 aSmith, Albert, V1 aSmith, Blair, H1 aSpracklen, Cassandra, N1 aStrauch, Konstantin1 aStumvoll, Michael1 aSulem, Patrick1 aTajuddin, Salman, M1 aTeren, Andrej1 aThiery, Joachim1 aThio, Chris, H L1 aThorsteinsdottir, Unnur1 aToniolo, Daniela1 aTönjes, Anke1 aTremblay, Johanne1 aUitterlinden, André, G1 aVaccargiu, Simona1 aHarst, Pim1 aDuijn, Cornelia, M1 aVerweij, Niek1 aVölker, Uwe1 aVollenweider, Peter1 aWaeber, Gérard1 aWaldenberger, Melanie1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aYang, Qiong1 aZhang, Weihua1 aZonderman, Alan, B1 aBochud, Murielle1 aWilson, James, G1 aPendergrass, Sarah, A1 aHo, Kevin1 aParsa, Afshin1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aBöger, Carsten, A1 aSnieder, Harold1 aButterworth, Adam, S1 aOkada, Yukinori1 aEdwards, Todd, L1 aStefansson, Kari1 aSusztak, Katalin1 aScholz, Markus1 aHeid, Iris, M1 aHung, Adriana, M1 aTeumer, Alexander1 aPattaro, Cristian1 aWoodward, Owen, M1 aVitart, Veronique1 aKöttgen, Anna1 aGerman Chronic Kidney Disease Study1 aLifeLines Cohort Study1 aV. A. Million Veteran Program uhttps://chs-nhlbi.org/node/820707958nas a2202377 4500008004100000022001400041245011500055210006900170260001600239300000900255490000700264520122900271100001901500700001801519700002501537700002401562700002701586700002201613700002201635700002101657700002201678700002301700700002001723700002101743700002201764700002101786700002201807700002401829700002101853700002001874700001801894700001901912700001601931700002401947700003201971700002902003700002002032700002902052700002602081700002002107700002002127700002202147700002602169700001602195700002002211700002102231700001902252700001502271700002502286700002202311700002702333700002202360700002202382700002402404700001802428700002002446700002502466700001802491700001702509700002302526700002102549700002502570700002202595700002302617700001902640700002302659700002602682700001702708700001802725700002702743700002602770700002202796700002802818700002302846700002602869700002002895700002002915700002102935700001802956700001702974700002302991700001903014700002403033700002203057700002203079700002103101700002403122700002003146700002403166700002303190700001903213700001303232700001803245700002203263700003003285700002003315700002603335700002103361700002403382700002203406700002703428700001503455700001803470700001903488700002303507700002203530700002403552700002303576700001803599700001803617700001903635700001803654700002403672700001803696700001903714700001903733700002303752700002003775700001803795700002203813700002603835700002703861700002203888700002603910700001403936700001903950700002503969700002003994700001804014700002204032700001704054700001804071700002204089700001604111700002504127700002004152700001704172700002304189700001804212700002204230700002004252700001304272700002304285700001804308700002904326700002104355700002104376700001404397700002304411700001504434700002304449700001704472700001904489700003204508700002404540700002204564700002304586700002004609700002304629700002404652700002804676700002204704700002404726700002404750700001904774700002504793700002104818700001904839700001904858700002104877700002004898700002404918700002204942700002704964700002204991700002105013700002305034700002005057700001705077700001905094700002405113700002205137700001905159700001905178700002905197700002005226700002805246700001605274700001905290700002505309700002805334700002805362700002405390700001905414700002105433700002405454700002005478700002205498700002405520856003605544 2020 eng d a2041-172300aMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.0 aMultiancestry GWAS of the electrocardiographic PR interval ident c2020 May 21 a25420 v113 aThe electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
1 aNtalla, Ioanna1 aWeng, Lu-Chen1 aCartwright, James, H1 aHall, Amelia, Weber1 aSveinbjornsson, Gardar1 aTucker, Nathan, R1 aChoi, Seung, Hoan1 aChaffin, Mark, D1 aRoselli, Carolina1 aBarnes, Michael, R1 aMifsud, Borbala1 aWarren, Helen, R1 aHayward, Caroline1 aMarten, Jonathan1 aCranley, James, J1 aConcas, Maria, Pina1 aGasparini, Paolo1 aBoutin, Thibaud1 aKolcic, Ivana1 aPolasek, Ozren1 aRudan, Igor1 aAraujo, Nathalia, M1 aLima-Costa, Maria, Fernanda1 aRibeiro, Antonio, Luiz P1 aSouza, Renan, P1 aTarazona-Santos, Eduardo1 aGiedraitis, Vilmantas1 aIngelsson, Erik1 aMahajan, Anubha1 aMorris, Andrew, P1 aM, Fabiola, del Greco1 aFoco, Luisa1 aGögele, Martin1 aHicks, Andrew, A1 aCook, James, P1 aLind, Lars1 aLindgren, Cecilia, M1 aSundström, Johan1 aNelson, Christopher, P1 aRiaz, Muhammad, B1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aUlivi, Sheila1 aKähönen, Mika1 aMishra, Pashupati, P1 aMononen, Nina1 aNikus, Kjell1 aCaulfield, Mark, J1 aDominiczak, Anna1 aPadmanabhan, Sandosh1 aMontasser, May, E1 aO'Connell, Jeff, R1 aRyan, Kathleen1 aShuldiner, Alan, R1 aAeschbacher, Stefanie1 aConen, David1 aRisch, Lorenz1 aThériault, Sébastien1 aHutri-Kähönen, Nina1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aRaitakari, Olli, T1 aBarnes, Catriona, L K1 aCampbell, Harry1 aJoshi, Peter, K1 aWilson, James, F1 aIsaacs, Aaron1 aKors, Jan, A1 aDuijn, Cornelia, M1 aHuang, Paul, L1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aLauner, Lenore, J1 aSmith, Albert, V1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aNadkarni, Girish, N1 aPreuss, Michael, H1 aCorrea, Adolfo1 aMei, Hao1 aWilson, James1 aMeitinger, Thomas1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aWaldenberger, Melanie1 aMangino, Massimo1 aSpector, Timothy, D1 aRienstra, Michiel1 avan de Vegte, Yordi, J1 aHarst, Pim1 aVerweij, Niek1 aKääb, Stefan1 aSchramm, Katharina1 aSinner, Moritz, F1 aStrauch, Konstantin1 aCutler, Michael, J1 aFatkin, Diane1 aLondon, Barry1 aOlesen, Morten1 aRoden, Dan, M1 aShoemaker, Benjamin1 aSmith, Gustav1 aBiggs, Mary, L1 aBis, Joshua, C1 aBrody, Jennifer, A1 aPsaty, Bruce, M1 aRice, Kenneth1 aSotoodehnia, Nona1 aDe Grandi, Alessandro1 aFuchsberger, Christian1 aPattaro, Cristian1 aPramstaller, Peter, P1 aFord, Ian1 aJukema, Wouter1 aMacfarlane, Peter, W1 aTrompet, Stella1 aDörr, Marcus1 aFelix, Stephan, B1 aVölker, Uwe1 aWeiss, Stefan1 aHavulinna, Aki, S1 aJula, Antti1 aSääksjärvi, Katri1 aSalomaa, Veikko1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aLin, Henry, J1 aRotter, Jerome, I1 aTaylor, Kent, D1 aYao, Jie1 ade Mutsert, Renée1 aMaan, Arie, C1 aMook-Kanamori, Dennis, O1 aNoordam, Raymond1 aCucca, Francesco1 aDing, Jun1 aLakatta, Edward, G1 aQian, Yong1 aTarasov, Kirill, V1 aLevy, Daniel1 aLin, Honghuang1 aNewton-Cheh, Christopher, H1 aLunetta, Kathryn, L1 aMurray, Alison, D1 aPorteous, David, J1 aSmith, Blair, H1 aStricker, Bruno, H1 aUitterlinden, Andre1 avan den Berg, Marten, E1 aHaessler, Jeffrey1 aJackson, Rebecca, D1 aKooperberg, Charles1 aPeters, Ulrike1 aReiner, Alexander, P1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBoerwinkle, Eric1 aEhret, Georg, B1 aSoliman, Elsayed, Z1 aAvery, Christy, L1 aGogarten, Stephanie, M1 aKerr, Kathleen, F1 aLaurie, Cathy, C1 aSeyerle, Amanda, A1 aStilp, Adrienne1 aAssa, Solmaz1 aSaid, Abdullah1 avan der Ende, Yldau1 aLambiase, Pier, D1 aOrini, Michele1 aRamirez, Julia1 aVan Duijvenboden, Stefan1 aArnar, David, O1 aGudbjartsson, Daniel, F1 aHolm, Hilma1 aSulem, Patrick1 aThorleifsson, Gudmar1 aThorolfsdottir, Rosa, B1 aThorsteinsdottir, Unnur1 aBenjamin, Emelia, J1 aTinker, Andrew1 aStefansson, Kari1 aEllinor, Patrick, T1 aJamshidi, Yalda1 aLubitz, Steven, A1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/836811212nas a2203445 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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/883512282nas a2204021 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2022 eng d a2399-364200aDifferential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.0 aDifferential and shared genetic effects on kidney function betwe c2022 Jun 13 a5800 v53 aReduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
10aCreatinine10aDiabetes Mellitus10aDiabetic Nephropathies10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney1 aWinkler, Thomas, W1 aRasheed, Humaira1 aTeumer, Alexander1 aGorski, Mathias1 aRowan, Bryce, X1 aStanzick, Kira, J1 aThomas, Laurent, F1 aTin, Adrienne1 aHoppmann, Anselm1 aChu, Audrey, Y1 aTayo, Bamidele1 aThio, Chris, H L1 aCusi, Daniele1 aChai, Jin-Fang1 aSieber, Karsten, B1 aHorn, Katrin1 aLi, Man1 aScholz, Markus1 aCocca, Massimiliano1 aWuttke, Matthias1 avan der Most, Peter, J1 aYang, Qiong1 aGhasemi, Sahar1 aNutile, Teresa1 aLi, Yong1 aPontali, Giulia1 aGünther, Felix1 aDehghan, Abbas1 aCorrea, Adolfo1 aParsa, Afshin1 aFeresin, Agnese1 ade Vries, Aiko, P J1 aZonderman, Alan, B1 aSmith, Albert, V1 aOldehinkel, Albertine, J1 aDe Grandi, Alessandro1 aRosenkranz, Alexander, R1 aFranke, Andre1 aTeren, Andrej1 aMetspalu, Andres1 aHicks, Andrew, A1 aMorris, Andrew, P1 aTönjes, Anke1 aMorgan, Anna1 aPodgornaia, Anna, I1 aPeters, Annette1 aKörner, Antje1 aMahajan, Anubha1 aCampbell, Archie1 aFreedman, Barry, I1 aSpedicati, Beatrice1 aPonte, Belen1 aSchöttker, Ben1 aBrumpton, Ben1 aBanas, Bernhard1 aKrämer, Bernhard, K1 aJung, Bettina1 aÅsvold, Bjørn, Olav1 aSmith, Blair, H1 aNing, Boting1 aPenninx, Brenda, W J H1 aVanderwerff, Brett, R1 aPsaty, Bruce, M1 aKammerer, Candace, M1 aLangefeld, Carl, D1 aHayward, Caroline1 aSpracklen, Cassandra, N1 aRobinson-Cohen, Cassianne1 aHartman, Catharina, A1 aLindgren, Cecilia, M1 aWang, Chaolong1 aSabanayagam, Charumathi1 aHeng, Chew-Kiat1 aLanzani, Chiara1 aKhor, Chiea-Chuen1 aCheng, Ching-Yu1 aFuchsberger, Christian1 aGieger, Christian1 aShaffer, Christian, M1 aSchulz, Christina-Alexandra1 aWiller, Cristen, J1 aChasman, Daniel, I1 aGudbjartsson, Daniel, F1 aRuggiero, Daniela1 aToniolo, Daniela1 aCzamara, Darina1 aPorteous, David, J1 aWaterworth, Dawn, M1 aMascalzoni, Deborah1 aMook-Kanamori, Dennis, O1 aReilly, Dermot, F1 aDaw, Warwick1 aHofer, Edith1 aBoerwinkle, Eric1 aSalvi, Erika1 aBottinger, Erwin, P1 aTai, E-Shyong1 aCatamo, Eulalia1 aRizzi, Federica1 aGuo, Feng1 aRivadeneira, Fernando1 aGuilianini, Franco1 aSveinbjornsson, Gardar1 aEhret, Georg1 aWaeber, Gérard1 aBiino, Ginevra1 aGirotto, Giorgia1 aPistis, Giorgio1 aNadkarni, Girish, N1 aDelgado, Graciela, E1 aMontgomery, Grant, W1 aSnieder, Harold1 aCampbell, Harry1 aWhite, Harvey, D1 aGao, He1 aStringham, Heather, M1 aSchmidt, Helena1 aLi, Hengtong1 aBrenner, Hermann1 aHolm, Hilma1 aKirsten, Holgen1 aKramer, Holly1 aRudan, Igor1 aNolte, Ilja, M1 aTzoulaki, Ioanna1 aOlafsson, Isleifur1 aMartins, Jade1 aCook, James, P1 aWilson, James, F1 aHalbritter, Jan1 aFelix, Janine, F1 aDivers, Jasmin1 aKooner, Jaspal, S1 aLee, Jeannette, Jen-Mai1 aO'Connell, Jeffrey1 aRotter, Jerome, I1 aLiu, Jianjun1 aXu, Jie1 aThiery, Joachim1 aArnlöv, Johan1 aKuusisto, Johanna1 aJakobsdottir, Johanna1 aTremblay, Johanne1 aChambers, John, C1 aWhitfield, John, B1 aGaziano, John, M1 aMarten, Jonathan1 aCoresh, Josef1 aJonas, Jost, B1 aMychaleckyj, Josyf, C1 aChristensen, Kaare1 aEckardt, Kai-Uwe1 aMohlke, Karen, L1 aEndlich, Karlhans1 aDittrich, Katalin1 aRyan, Kathleen, A1 aRice, Kenneth, M1 aTaylor, Kent, D1 aHo, Kevin1 aNikus, Kjell1 aMatsuda, Koichi1 aStrauch, Konstantin1 aMiliku, Kozeta1 aHveem, Kristian1 aLind, Lars1 aWallentin, Lars1 aYerges-Armstrong, Laura, M1 aRaffield, Laura, M1 aPhillips, Lawrence, S1 aLauner, Lenore, J1 aLyytikäinen, Leo-Pekka1 aLange, Leslie, A1 aCitterio, Lorena1 aKlaric, Lucija1 aIkram, Arfan, M1 aIsing, Marcus1 aKleber, Marcus, E1 aFrancescatto, Margherita1 aConcas, Maria, Pina1 aCiullo, Marina1 aPiratsu, Mario1 aOrho-Melander, Marju1 aLaakso, Markku1 aLoeffler, Markus1 aPerola, Markus1 ade Borst, Martin, H1 aGögele, Martin1 aLa Bianca, Martina1 aLukas, Mary, Ann1 aFeitosa, Mary, F1 aBiggs, Mary, L1 aWojczynski, Mary, K1 aKavousi, Maryam1 aKanai, Masahiro1 aAkiyama, Masato1 aYasuda, Masayuki1 aNauck, Matthias1 aWaldenberger, Melanie1 aChee, Miao-Li1 aChee, Miao-Ling1 aBoehnke, Michael1 aPreuss, Michael, H1 aStumvoll, Michael1 aProvince, Michael, A1 aEvans, Michele, K1 aO'Donoghue, Michelle, L1 aKubo, Michiaki1 aKähönen, Mika1 aKastarinen, Mika1 aNalls, Mike, A1 aKuokkanen, Mikko1 aGhanbari, Mohsen1 aBochud, Murielle1 aJosyula, Navya, Shilpa1 aMartin, Nicholas, G1 aTan, Nicholas, Y Q1 aPalmer, Nicholette, D1 aPirastu, Nicola1 aSchupf, Nicole1 aVerweij, Niek1 aHutri-Kähönen, Nina1 aMononen, Nina1 aBansal, Nisha1 aDevuyst, Olivier1 aMelander, Olle1 aRaitakari, Olli, T1 aPolasek, Ozren1 aManunta, Paolo1 aGasparini, Paolo1 aMishra, Pashupati, P1 aSulem, Patrick1 aMagnusson, Patrik, K E1 aElliott, Paul1 aRidker, Paul, M1 aHamet, Pavel1 aSvensson, Per, O1 aJoshi, Peter, K1 aKovacs, Peter1 aPramstaller, Peter, P1 aRossing, Peter1 aVollenweider, Peter1 aHarst, Pim1 aDorajoo, Rajkumar1 aSim, Ralene, Z H1 aBurkhardt, Ralph1 aTao, Ran1 aNoordam, Raymond1 aMägi, Reedik1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aRueedi, Rico1 avan Dam, Rob, M1 aCarroll, Robert, J1 aGansevoort, Ron, T1 aLoos, Ruth, J F1 aFelicita, Sala, Cinzia1 aSedaghat, Sanaz1 aPadmanabhan, Sandosh1 aFreitag-Wolf, Sandra1 aPendergrass, Sarah, A1 aGraham, Sarah, E1 aGordon, Scott, D1 aHwang, Shih-Jen1 aKerr, Shona, M1 aVaccargiu, Simona1 aPatil, Snehal, B1 aHallan, Stein1 aBakker, Stephan, J L1 aLim, Su-Chi1 aLucae, Susanne1 aVogelezang, Suzanne1 aBergmann, Sven1 aCorre, Tanguy1 aAhluwalia, Tarunveer, S1 aLehtimäki, Terho1 aBoutin, Thibaud, S1 aMeitinger, Thomas1 aWong, Tien-Yin1 aBergler, Tobias1 aRabelink, Ton, J1 aEsko, Tõnu1 aHaller, Toomas1 aThorsteinsdottir, Unnur1 aVölker, Uwe1 aFoo, Valencia, Hui Xian1 aSalomaa, Veikko1 aVitart, Veronique1 aGiedraitis, Vilmantas1 aGudnason, Vilmundur1 aJaddoe, Vincent, W V1 aHuang, Wei1 aZhang, Weihua1 aBin Wei, Wen1 aKiess, Wieland1 aMärz, Winfried1 aKoenig, Wolfgang1 aLieb, Wolfgang1 aGào, Xīn1 aSim, Xueling1 aWang, Ya, Xing1 aFriedlander, Yechiel1 aTham, Yih-Chung1 aKamatani, Yoichiro1 aOkada, Yukinori1 aMilaneschi, Yuri1 aYu, Zhi1 aStark, Klaus, J1 aStefansson, Kari1 aBöger, Carsten, A1 aHung, Adriana, M1 aKronenberg, Florian1 aKöttgen, Anna1 aPattaro, Cristian1 aHeid, Iris, M1 aLifeLines Cohort Study1 aDiscovEHR/MyCode study1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/911205288nas a2201585 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2022 eng d a1476-557800aGenome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.0 aGenomewide metaanalyses reveal novel loci for verbal shortterm m c2022 Aug 163 aUnderstanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
1 aLahti, Jari1 aTuominen, Samuli1 aYang, Qiong1 aPergola, Giulio1 aAhmad, Shahzad1 aAmin, Najaf1 aArmstrong, Nicola, J1 aBeiser, Alexa1 aBey, Katharina1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBressler, Jan1 aCampbell, Archie1 aCampbell, Harry1 aChen, Qiang1 aCorley, Janie1 aCox, Simon, R1 aDavies, Gail1 aDe Jager, Philip, L1 aDerks, Eske, M1 aFaul, Jessica, D1 aFitzpatrick, Annette, L1 aFohner, Alison, E1 aFord, Ian1 aFornage, Myriam1 aGerring, Zachary1 aGrabe, Hans, J1 aGrodstein, Francine1 aGudnason, Vilmundur1 aSimonsick, Eleanor1 aHolliday, Elizabeth, G1 aJoshi, Peter, K1 aKajantie, Eero1 aKaprio, Jaakko1 aKarell, Pauliina1 aKleineidam, Luca1 aKnol, Maria, J1 aKochan, Nicole, A1 aKwok, John, B1 aLeber, Markus1 aLam, Max1 aLee, Teresa1 aLi, Shuo1 aLoukola, Anu1 aLuck, Tobias1 aMarioni, Riccardo, E1 aMather, Karen, A1 aMedland, Sarah1 aMirza, Saira, S1 aNalls, Mike, A1 aNho, Kwangsik1 aO'Donnell, Adrienne1 aOldmeadow, Christopher1 aPainter, Jodie1 aPattie, Alison1 aReppermund, Simone1 aRisacher, Shannon, L1 aRose, Richard, J1 aSadashivaiah, Vijay1 aScholz, Markus1 aSatizabal, Claudia, L1 aSchofield, Peter, W1 aSchraut, Katharina, E1 aScott, Rodney, J1 aSimino, Jeannette1 aSmith, Albert, V1 aSmith, Jennifer, A1 aStott, David, J1 aSurakka, Ida1 aTeumer, Alexander1 aThalamuthu, Anbupalam1 aTrompet, Stella1 aTurner, Stephen, T1 avan der Lee, Sven, J1 aVillringer, Arno1 aVölker, Uwe1 aWilson, Robert, S1 aWittfeld, Katharina1 aVuoksimaa, Eero1 aXia, Rui1 aYaffe, Kristine1 aYu, Lei1 aZare, Habil1 aZhao, Wei1 aAmes, David1 aAttia, John1 aBennett, David, A1 aBrodaty, Henry1 aChasman, Daniel, I1 aGoldman, Aaron, L1 aHayward, Caroline1 aIkram, Arfan, M1 aJukema, Wouter1 aKardia, Sharon, L R1 aLencz, Todd1 aLoeffler, Markus1 aMattay, Venkata, S1 aPalotie, Aarno1 aPsaty, Bruce, M1 aRamirez, Alfredo1 aRidker, Paul, M1 aRiedel-Heller, Steffi, G1 aSachdev, Perminder, S1 aSaykin, Andrew, J1 aScherer, Martin1 aSchofield, Peter, R1 aSidney, Stephen1 aStarr, John, M1 aTrollor, Julian1 aUlrich, William1 aWagner, Michael1 aWeir, David, R1 aWilson, James, F1 aWright, Margaret, J1 aWeinberger, Daniel, R1 aDebette, Stephanie1 aEriksson, Johan, G1 aMosley, Thomas, H1 aLauner, Lenore, J1 aDuijn, Cornelia, M1 aDeary, Ian, J1 aSeshadri, Sudha1 aRäikkönen, Katri uhttps://chs-nhlbi.org/node/916907212nas a2201753 4500008004100000245012700041210006900168260001600237520220800253100002502461700001902486700001602505700001902521700002302540700001902563700002302582700002102605700001802626700002002644700002402664700002302688700002902711700002302740700002002763700002102783700002102804700002102825700002402846700002202870700001902892700001502911700002102926700002002947700001802967700001902985700002103004700002503025700002603050700002103076700001903097700001903116700002803135700002203163700002203185700001903207700002003226700001803246700001703264700001503281700002003296700002803316700001703344700001703361700002703378700002503405700002003430700002003450700002003470700002403490700001203514700001603526700002003542700002803562700001603590700002103606700001903627700002103646700002703667700002103694700002403715700001603739700002203755700002403777700002503801700001703826700001403843700002103857700002003878700002203898700001903920700002003939700001503959700002003974700002203994700002404016700002004040700001804060700002004078700002704098700001804125700001704143700002104160700001604181700001804197700002404215700002004239700002004259700002604279700001904305700002004324700002304344700002304367700002504390700002004415700003004435700001804465700002304483700001804506700002104524700001904545700002004564700001804584700001904602700002304621700002204644700002004666700001904686700002204705700002004727700001904747700002304766700002104789700002004810700002304830700002504853700002904878700002904907700001904936700002604955700001904981700002205000700002005022700002405042700002005066700001705086700001805103700002105121700001305142700003205155700002305187700002205210700002205232700002505254700002405279700002305303710003105326710006505357856003605422 2023 eng d00aWhole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.0 aWhole genome analysis of plasma fibrinogen reveals populationdif c2023 Jun 123 aUNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.
KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
1 aHuffman, Jennifer, E1 aNicolas, Jayna1 aHahn, Julie1 aHeath, Adam, S1 aRaffield, Laura, M1 aYanek, Lisa, R1 aBrody, Jennifer, A1 aThibord, Florian1 aAlmasy, Laura1 aBartz, Traci, M1 aBielak, Lawrence, F1 aBowler, Russell, P1 aCarrasquilla, Germán, D1 aChasman, Daniel, I1 aChen, Ming-Huei1 aEmmert, David, B1 aGhanbari, Mohsen1 aHaessle, Jeffery1 aHottenga, Jouke-Jan1 aKleber, Marcus, E1 aLe, Ngoc-Quynh1 aLee, Jiwon1 aLewis, Joshua, P1 aLi-Gao, Ruifang1 aLuan, Jian'an1 aMalmberg, Anni1 aMangino, Massimo1 aMarioni, Riccardo, E1 aMartinez-Perez, Angel1 aPankratz, Nathan1 aPolasek, Ozren1 aRichmond, Anne1 aRodriguez, Benjamin, At1 aRotter, Jerome, I1 aSteri, Maristella1 aSuchon, Pierre1 aTrompet, Stella1 aWeiss, Stefan1 aZare, Marjan1 aAuer, Paul1 aCho, Michael, H1 aChristofidou, Paraskevi1 aDavies, Gail1 ade Geus, Eco1 aDeleuze, Jean-Francois1 aDelgado, Graciela, E1 aEkunwe, Lynette1 aFaraday, Nauder1 aGögele, Martin1 aGreinacher, Andreas1 aHe, Gao1 aHoward, Tom1 aJoshi, Peter, K1 aKilpeläinen, Tuomas, O1 aLahti, Jari1 aLinneberg, Allan1 aNaitza, Silvia1 aNoordam, Raymond1 aPaüls-Vergés, Ferran1 aRich, Stephen, S1 aRosendaal, Frits, R1 aRudan, Igor1 aRyan, Kathleen, A1 aSouto, Juan, Carlos1 avan Rooij, Frank, Ja1 aWang, Heming1 aZhao, Wei1 aBecker, Lewis, C1 aBeswick, Andrew1 aBrown, Michael, R1 aCade, Brian, E1 aCampbell, Harry1 aCho, Kelly1 aCrapo, James, D1 aCurran, Joanne, E1 ade Maat, Moniek, Pm1 aDoyle, Margaret1 aElliott, Paul1 aFloyd, James, S1 aFuchsberger, Christian1 aGrarup, Niels1 aGuo, Xiuqing1 aHarris, Sarah, E1 aHou, Lifang1 aKolcic, Ivana1 aKooperberg, Charles1 aMenni, Cristina1 aNauck, Matthias1 aO'Connell, Jeffrey, R1 aOrrù, Valeria1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aSmith, Jennifer, A1 aSoria, José, Manuel1 aStott, David, J1 aVlieg, Astrid, van Hylcka1 aWatkins, Hugh1 aWillemsen, Gonneke1 aWilson, Peter1 aBen-Shlomo, Yoav1 aBlangero, John1 aBoomsma, Dorret1 aCox, Simon, R1 aDehghan, Abbas1 aEriksson, Johan, G1 aFiorillo, Edoardo1 aFornage, Myriam1 aHansen, Torben1 aHayward, Caroline1 aIkram, Arfan, M1 aJukema, Wouter1 aKardia, Sharon, Lr1 aLange, Leslie, A1 aMärz, Winfried1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aMook-Kanamori, Dennis, O1 aMorange, Pierre-Emmanuel1 aPedersen, Oluf1 aPramstaller, Peter, P1 aRedline, Susan1 aReiner, Alexander1 aRidker, Paul, M1 aSilverman, Edwin, K1 aSpector, Tim, D1 aVölker, Uwe1 aWareham, Nick1 aWilson, James, F1 aYao, Jie1 aTrégouët, David-Alexandre1 aJohnson, Andrew, D1 aWolberg, Alisa, S1 ade Vries, Paul, S1 aSabater-Lleal, Maria1 aMorrison, Alanna, C1 aSmith, Nicholas, L1 aVA Million Veteran Program1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/944907235nas a2202173 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2024 eng d a2041-172300aX-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.0 aXchromosome and kidney function evidence from a multitrait genet c2024 Jan 18 a5860 v153 aX-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
10aAndrogens10aChromosomes, Human, X10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aKidney10aMale10aPolymorphism, Single Nucleotide10aResponse Elements10aTetraspanins1 aScholz, Markus1 aHorn, Katrin1 aPott, Janne1 aWuttke, Matthias1 aKühnapfel, Andreas1 aNasr, Kamal1 aKirsten, Holger1 aLi, Yong1 aHoppmann, Anselm1 aGorski, Mathias1 aGhasemi, Sahar1 aLi, Man1 aTin, Adrienne1 aChai, Jin-Fang1 aCocca, Massimiliano1 aWang, Judy1 aNutile, Teresa1 aAkiyama, Masato1 aÅsvold, Bjørn, Olav1 aBansal, Nisha1 aBiggs, Mary, L1 aBoutin, Thibaud1 aBrenner, Hermann1 aBrumpton, Ben1 aBurkhardt, Ralph1 aCai, Jianwen1 aCampbell, Archie1 aCampbell, Harry1 aChalmers, John1 aChasman, Daniel, I1 aChee, Miao, Ling1 aChee, Miao, Li1 aChen, Xu1 aCheng, Ching-Yu1 aCifkova, Renata1 aDaviglus, Martha1 aDelgado, Graciela1 aDittrich, Katalin1 aEdwards, Todd, L1 aEndlich, Karlhans1 aGaziano, Michael1 aGiri, Ayush1 aGiulianini, Franco1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aHallan, Stein1 aHamet, Pavel1 aHartman, Catharina, A1 aHayward, Caroline1 aHeid, Iris, M1 aHellwege, Jacklyn, N1 aHolleczek, Bernd1 aHolm, Hilma1 aHutri-Kähönen, Nina1 aHveem, Kristian1 aIsermann, Berend1 aJonas, Jost, B1 aJoshi, Peter, K1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKastarinen, Mika1 aKhor, Chiea, Chuen1 aKiess, Wieland1 aKleber, Marcus, E1 aKörner, Antje1 aKovacs, Peter1 aKrajcoviechova, Alena1 aKramer, Holly1 aKrämer, Bernhard, K1 aKuokkanen, Mikko1 aKähönen, Mika1 aLange, Leslie, A1 aLash, James, P1 aLehtimäki, Terho1 aLi, Hengtong1 aLin, Bridget, M1 aLiu, Jianjun1 aLoeffler, Markus1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMartin, Nicholas, G1 aMatsuda, Koichi1 aMilaneschi, Yuri1 aMishra, Pashupati, P1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMychaleckyj, Josyf, C1 aMärz, Winfried1 aNauck, Matthias1 aNikus, Kjell1 aNolte, Ilja, M1 aNoordam, Raymond1 aOkada, Yukinori1 aOlafsson, Isleifur1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPirastu, Nicola1 aPolasek, Ozren1 aPorteous, David, J1 aPoulain, Tanja1 aPsaty, Bruce, M1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRasheed, Humaira1 aReilly, Dermot, F1 aRice, Kenneth, M1 aRichmond, Anne1 aRidker, Paul, M1 aRotter, Jerome, I1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalomaa, Veikko1 aSchneiderman, Neil1 aSchöttker, Ben1 aSims, Mario1 aSnieder, Harold1 aStark, Klaus, J1 aStefansson, Kari1 aStocker, Hannah1 aStumvoll, Michael1 aSulem, Patrick1 aSveinbjornsson, Gardar1 aSvensson, Per, O1 aTai, E-Shyong1 aTaylor, Kent, D1 aTayo, Bamidele, O1 aTeren, Andrej1 aTham, Yih-Chung1 aThiery, Joachim1 aThio, Chris, H L1 aThomas, Laurent, F1 aTremblay, Johanne1 aTönjes, Anke1 avan der Most, Peter, J1 aVitart, Veronique1 aVölker, Uwe1 aWang, Ya, Xing1 aWang, Chaolong1 aBin Wei, Wen1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aWinkler, Thomas, W1 aWong, Tien-Yin1 aWoodward, Mark1 aSim, Xueling1 aChu, Audrey, Y1 aFeitosa, Mary, F1 aThorsteinsdottir, Unnur1 aHung, Adriana, M1 aTeumer, Alexander1 aFranceschini, Nora1 aParsa, Afshin1 aKöttgen, Anna1 aSchlosser, Pascal1 aPattaro, Cristian uhttps://chs-nhlbi.org/node/9579