06326nas a2201873 4500008004100000022001400041245007300055210006900128260001300197300001100210490000700221520118400228653001901412653001501431653001501446653000901461653001101470653002001481653003401501653003101535653001101566653001101577653002801588653002001616653001701636100001901653700002201672700002301694700002701717700002001744700002201764700001801786700001601804700001601820700002101836700002601857700001201883700002001895700002001915700001801935700002001953700002001973700002301993700001902016700002202035700002102057700002702078700001802105700001702123700002502140700002902165700002402194700001802218700002202236700001902258700002402277700002202301700002202323700002402345700002502369700001902394700002102413700002302434700002602457700002202483700002602505700002002531700002002551700002302571700001902594700002102613700002002634700002502654700001902679700001802698700002202716700002302738700002302761700002002784700002102804700002102825700002402846700001802870700002202888700002202910700001802932700001802950700002302968700002202991700002103013700001603034700002203050700001803072700002103090700001703111700001903128700001603147700001903163700001903182700002003201700002003221700002203241700002203263700002403285700002103309700002603330700002803356700001903384700001903403700002103422700002503443700002303468700002203491700001803513700002203531700001803553700001803571700002003589700002203609700001903631700002103650700002003671700001703691700001903708700002203727700001903749700002503768700002003793700002403813700002403837700001703861700002003878700001803898700002003916700002403936700002103960700001403981700002403995700002304019700001804042700002204060700002004082700002404102700002304126700002004149700002504169700001604194700002004210700002104230700002804251700002604279700001904305700001704324700002304341700001304364700001804377700002104395856003604416 2010 eng d a1546-171800aNew loci associated with kidney function and chronic kidney disease.0 aNew loci associated with kidney function and chronic kidney dise c2010 May a376-840 v423 a
Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
10aCohort Studies10aCreatinine10aCystatin C10aDiet10aEurope10aGenetic Markers10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aModels, Genetic10aRisk Factors1 aKöttgen, Anna1 aPattaro, Cristian1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aGlazer, Nicole, L1 aParsa, Afshin1 aGao, Xiaoyi1 aYang, Qiong1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aLi, Man1 aSchmidt, Helena1 aTanaka, Toshiko1 aIsaacs, Aaron1 aKetkar, Shamika1 aHwang, Shih-Jen1 aJohnson, Andrew, D1 aDehghan, Abbas1 aTeumer, Alexander1 aParé, Guillaume1 aAtkinson, Elizabeth, J1 aZeller, Tanja1 aLohman, Kurt1 aCornelis, Marilyn, C1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aTönjes, Anke1 aHayward, Caroline1 aAspelund, Thor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aRampersaud, Evadnie1 aMitchell, Braxton, D1 aArking, Dan, E1 aBoerwinkle, Eric1 aStruchalin, Maksim1 aCavalieri, Margherita1 aSingleton, Andrew1 aGiallauria, Francesco1 aMetter, Jeffrey1 ade Boer, Ian, H1 aHaritunians, Talin1 aLumley, Thomas1 aSiscovick, David1 aPsaty, Bruce, M1 aZillikens, Carola, M1 aOostra, Ben, A1 aFeitosa, Mary1 aProvince, Michael1 ade Andrade, Mariza1 aTurner, Stephen, T1 aSchillert, Arne1 aZiegler, Andreas1 aWild, Philipp, S1 aSchnabel, Renate, B1 aWilde, Sandra1 aMunzel, Thomas, F1 aLeak, Tennille, S1 aIllig, Thomas1 aKlopp, Norman1 aMeisinger, Christa1 aWichmann, H-Erich1 aKoenig, Wolfgang1 aZgaga, Lina1 aZemunik, Tatijana1 aKolcic, Ivana1 aMinelli, Cosetta1 aHu, Frank, B1 aJohansson, Asa1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aSchreiber, Stefan1 aAulchenko, Yurii, S1 aFelix, Janine, F1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aImboden, Medea1 aNitsch, Dorothea1 aBrandstätter, Anita1 aKollerits, Barbara1 aKedenko, Lyudmyla1 aMägi, Reedik1 aStumvoll, Michael1 aKovacs, Peter1 aBoban, Mladen1 aCampbell, Susan1 aEndlich, Karlhans1 aVölzke, Henry1 aKroemer, Heyo, K1 aNauck, Matthias1 aVölker, Uwe1 aPolasek, Ozren1 aVitart, Veronique1 aBadola, Sunita1 aParker, Alexander, N1 aRidker, Paul, M1 aKardia, Sharon, L R1 aBlankenberg, Stefan1 aLiu, Yongmei1 aCurhan, Gary, C1 aFranke, Andre1 aRochat, Thierry1 aPaulweber, Bernhard1 aProkopenko, Inga1 aWang, Wei1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aShlipak, Michael, G1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKrämer, Bernhard, K1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aWitteman, Jacqueline, C1 aPramstaller, Peter, P1 aRettig, Rainer1 aHastie, Nick1 aChasman, Daniel, I1 aKao, W H1 aHeid, Iris, M1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/118305938nas a2201621 4500008004100000022001400041245004200055210004100097260001300138300001100151490000700162520145500169653003901624653001601663653004001679653001701719653003801736653001101774653002301785653002801808100002301836700002001859700001801879700002001897700001901917700002001936700002701956700002601983700002202009700002202031700001802053700002202071700001202093700002602105700002002131700002302151700002102174700001802195700001902213700002002232700002202252700001802274700001502292700002102307700001702328700002302345700002202368700002302390700001802413700001902431700002002450700002402470700002202494700002202516700002302538700002502561700001902586700002302605700002102628700002002649700002002669700002102689700002502710700001902735700002402754700002002778700002202798700002302820700001902843700002402862700002002886700002002906700002102926700002302947700002002970700002002990700001703010700002303027700002703050700002203077700001903099700001903118700002803137700001803165700001803183700002103201700002503222700002103247700002603268700002103294700002503315700002203340700002403362700002003386700002203406700002103428700001903449700002003468700001903488700002203507700001803529700002003547700002203567700002403589700002403613700002403637700001703661700001903678700001703697700002403714700002103738700001603759700001903775700001803794700001803812700001803830700002003848700001803868700002403886700002103910700002603931700002203957700002503979700002004004700002204024700002604046700002504072700002504097700001604122700001804138700001904156700002504175700002104200700002104221700001604242710002204258856003604280 2011 eng d a1533-345000aCUBN is a gene locus for albuminuria.0 aCUBN is a gene locus for albuminuria c2011 Mar a555-700 v223 aIdentification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
10aAfrican Continental Ancestry Group10aAlbuminuria10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aHumans10aMutation, Missense10aReceptors, Cell Surface1 aBöger, Carsten, A1 aChen, Ming-Huei1 aTin, Adrienne1 aOlden, Matthias1 aKöttgen, Anna1 ade Boer, Ian, H1 aFuchsberger, Christian1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 aTeumer, Alexander1 aLiu, Ching-Ti1 aGlazer, Nicole, L1 aLi, Man1 aO'Connell, Jeffrey, R1 aTanaka, Toshiko1 aPeralta, Carmen, A1 aKutalik, Zoltán1 aLuan, Jian'an1 aZhao, Jing Hua1 aHwang, Shih-Jen1 aAkylbekova, Ermeg1 aKramer, Holly1 aHarst, Pim1 aSmith, Albert, V1 aLohman, Kurt1 ade Andrade, Mariza1 aHayward, Caroline1 aKollerits, Barbara1 aTönjes, Anke1 aAspelund, Thor1 aIngelsson, Erik1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aShuldiner, Alan, R1 aMitchell, Braxton, D1 aArking, Dan, E1 aFranceschini, Nora1 aBoerwinkle, Eric1 aEgan, Josephine1 aHernandez, Dena1 aReilly, Muredach1 aTownsend, Raymond, R1 aLumley, Thomas1 aSiscovick, David, S1 aPsaty, Bruce, M1 aKestenbaum, Bryan1 aHaritunians, Talin1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aMooser, Vincent1 aWaterworth, Dawn1 aJohnson, Andrew, D1 aFlorez, Jose, C1 aMeigs, James, B1 aLu, Xiaoning1 aTurner, Stephen, T1 aAtkinson, Elizabeth, J1 aLeak, Tennille, S1 aAasarød, Knut1 aSkorpen, Frank1 aSyvänen, Ann-Christine1 aIllig, Thomas1 aBaumert, Jens1 aKoenig, Wolfgang1 aKrämer, Bernhard, K1 aDevuyst, Olivier1 aMychaleckyj, Josyf, C1 aMinelli, Cosetta1 aBakker, Stephan, J L1 aKedenko, Lyudmyla1 aPaulweber, Bernhard1 aCoassin, Stefan1 aEndlich, Karlhans1 aKroemer, Heyo, K1 aBiffar, Reiner1 aStracke, Sylvia1 aVölzke, Henry1 aStumvoll, Michael1 aMägi, Reedik1 aCampbell, Harry1 aVitart, Veronique1 aHastie, Nicholas, D1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPolasek, Ozren1 aCurhan, Gary1 aKronenberg, Florian1 aProkopenko, Inga1 aRudan, Igor1 aArnlöv, Johan1 aHallan, Stein1 aNavis, Gerjan1 aParsa, Afshin1 aFerrucci, Luigi1 aCoresh, Josef1 aShlipak, Michael, G1 aBull, Shelley, B1 aPaterson, Nicholas, J1 aWichmann, H-Erich1 aWareham, Nicholas, J1 aLoos, Ruth, J F1 aRotter, Jerome, I1 aPramstaller, Peter, P1 aCupples, Adrienne, L1 aBeckmann, Jacques, S1 aYang, Qiong1 aHeid, Iris, M1 aRettig, Rainer1 aDreisbach, Albert, W1 aBochud, Murielle1 aFox, Caroline, S1 aKao, W, H L1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/127113785nas a2204513 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2011 eng d a1476-468700aGenetic variants in novel pathways influence blood pressure and cardiovascular disease risk.0 aGenetic variants in novel pathways influence blood pressure and c2011 Sep 11 a103-90 v4783 aBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
10aAfrica10aAsia10aBlood Pressure10aCardiovascular Diseases10aCoronary Artery Disease10aEurope10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aKidney Diseases10aPolymorphism, Single Nucleotide10aStroke1 aInternational Consortium for Blood Pressure Genome-Wide Association Studies1 aEhret, Georg, B1 aMunroe, Patricia, B1 aRice, Kenneth, M1 aBochud, Murielle1 aJohnson, Andrew, D1 aChasman, Daniel, I1 aSmith, Albert, V1 aTobin, Martin, D1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aPihur, Vasyl1 aVollenweider, Peter1 aO'Reilly, Paul, F1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aTeumer, Alexander1 aGlazer, Nicole, L1 aLauner, Lenore1 aZhao, Jing Hua1 aAulchenko, Yurii1 aHeath, Simon1 aSõber, Siim1 aParsa, Afshin1 aLuan, Jian'an1 aArora, Pankaj1 aDehghan, Abbas1 aZhang, Feng1 aLucas, Gavin1 aHicks, Andrew, A1 aJackson, Anne, U1 aPeden, John, F1 aTanaka, Toshiko1 aWild, Sarah, H1 aRudan, Igor1 aIgl, Wilmar1 aMilaneschi, Yuri1 aParker, Alex, N1 aFava, Cristiano1 aChambers, John, C1 aFox, Ervin, R1 aKumari, Meena1 aGo, Min Jin1 aHarst, Pim1 aKao, Wen Hong Linda1 aSjögren, Marketa1 aVinay, D G1 aAlexander, Myriam1 aTabara, Yasuharu1 aShaw-Hawkins, Sue1 aWhincup, Peter, H1 aLiu, Yongmei1 aShi, Gang1 aKuusisto, Johanna1 aTayo, Bamidele1 aSeielstad, Mark1 aSim, Xueling1 aNguyen, Khanh-Dung Hoang1 aLehtimäki, Terho1 aMatullo, Giuseppe1 aWu, Ying1 aGaunt, Tom, R1 aOnland-Moret, Charlotte, N1 aCooper, Matthew, N1 aPlatou, Carl, G P1 aOrg, Elin1 aHardy, Rebecca1 aDahgam, Santosh1 aPalmen, Jutta1 aVitart, Veronique1 aBraund, Peter, S1 aKuznetsova, Tatiana1 aUiterwaal, Cuno, S P M1 aAdeyemo, Adebowale1 aPalmas, Walter1 aCampbell, Harry1 aLudwig, Barbara1 aTomaszewski, Maciej1 aTzoulaki, Ioanna1 aPalmer, Nicholette, D1 aAspelund, Thor1 aGarcia, Melissa1 aChang, Yen-Pei, C1 aO'Connell, Jeffrey, R1 aSteinle, Nanette, I1 aGrobbee, Diederick, E1 aArking, Dan, E1 aKardia, Sharon, L1 aMorrison, Alanna, C1 aHernandez, Dena1 aNajjar, Samer1 aMcArdle, Wendy, L1 aHadley, David1 aBrown, Morris, J1 aConnell, John, M1 aHingorani, Aroon, D1 aDay, Ian, N M1 aLawlor, Debbie, A1 aBeilby, John, P1 aLawrence, Robert, W1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aDreisbach, Albert, W1 aLi, Yali1 aYoung, Hunter, J1 aBis, Joshua, C1 aKähönen, Mika1 aViikari, Jorma1 aAdair, Linda, S1 aLee, Nanette, R1 aChen, Ming-Huei1 aOlden, Matthias1 aPattaro, Cristian1 aBolton, Judith Hoffman, A1 aKöttgen, Anna1 aBergmann, Sven1 aMooser, Vincent1 aChaturvedi, Nish1 aFrayling, Timothy, M1 aIslam, Muhammad1 aJafar, Tazeen, H1 aErdmann, Jeanette1 aKulkarni, Smita, R1 aBornstein, Stefan, R1 aGrässler, Jürgen1 aGroop, Leif1 aVoight, Benjamin, F1 aKettunen, Johannes1 aHoward, Philip1 aTaylor, Andrew1 aGuarrera, Simonetta1 aRicceri, Fulvio1 aEmilsson, Valur1 aPlump, Andrew1 aBarroso, Inês1 aKhaw, Kay-Tee1 aWeder, Alan, B1 aHunt, Steven, C1 aSun, Yan, V1 aBergman, Richard, N1 aCollins, Francis, S1 aBonnycastle, Lori, L1 aScott, Laura, J1 aStringham, Heather, M1 aPeltonen, Leena1 aPerola, Markus1 aVartiainen, Erkki1 aBrand, Stefan-Martin1 aStaessen, Jan, A1 aWang, Thomas, J1 aBurton, Paul, R1 aArtigas, Maria, Soler1 aDong, Yanbin1 aSnieder, Harold1 aWang, Xiaoling1 aZhu, Haidong1 aLohman, Kurt, K1 aRudock, Megan, E1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aDoumatey, Ayo1 aShriner, Daniel1 aVeldre, Gudrun1 aViigimaa, Margus1 aKinra, Sanjay1 aPrabhakaran, Dorairaj1 aTripathy, Vikal1 aLangefeld, Carl, D1 aRosengren, Annika1 aThelle, Dag, S1 aCorsi, Anna Maria1 aSingleton, Andrew1 aForrester, Terrence1 aHilton, Gina1 aMcKenzie, Colin, A1 aSalako, Tunde1 aIwai, Naoharu1 aKita, Yoshikuni1 aOgihara, Toshio1 aOhkubo, Takayoshi1 aOkamura, Tomonori1 aUeshima, Hirotsugu1 aUmemura, Satoshi1 aEyheramendy, Susana1 aMeitinger, Thomas1 aWichmann, H-Erich1 aCho, Yoon Shin1 aKim, Hyung-Lae1 aLee, Jong-Young1 aScott, James1 aSehmi, Joban, S1 aZhang, Weihua1 aHedblad, Bo1 aNilsson, Peter1 aSmith, George Davey1 aWong, Andrew1 aNarisu, Narisu1 aStančáková, Alena1 aRaffel, Leslie, J1 aYao, Jie1 aKathiresan, Sekar1 aO'Donnell, Christopher, J1 aSchwartz, Stephen, M1 aIkram, Arfan, M1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aShrine, Nick, R G1 aWain, Louise, V1 aMorken, Mario, A1 aSwift, Amy, J1 aLaitinen, Jaana1 aProkopenko, Inga1 aZitting, Paavo1 aCooper, Jackie, A1 aHumphries, Steve, E1 aDanesh, John1 aRasheed, Asif1 aGoel, Anuj1 aHamsten, Anders1 aWatkins, Hugh1 aBakker, Stephan, J L1 aGilst, Wiek, H1 aJanipalli, Charles, S1 aMani, Radha, K1 aYajnik, Chittaranjan, S1 aHofman, Albert1 aMattace-Raso, Francesco, U S1 aOostra, Ben, A1 aDemirkan, Ayse1 aIsaacs, Aaron1 aRivadeneira, Fernando1 aLakatta, Edward, G1 aOrrù, Marco1 aScuteri, Angelo1 aAla-Korpela, Mika1 aKangas, Antti, J1 aLyytikäinen, Leo-Pekka1 aSoininen, Pasi1 aTukiainen, Taru1 aWürtz, Peter1 aOng, Rick Twee-Hee1 aDörr, Marcus1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aZelenika, Diana1 aDeloukas, Panos1 aMangino, Massimo1 aSpector, Tim, D1 aZhai, Guangju1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aTerzic, Janos1 aKumar, Kranthi, M V1 aDenniff, Matthew1 aZukowska-Szczechowska, Ewa1 aWagenknecht, Lynne, E1 aFowkes, Gerald, F R1 aCharchar, Fadi, J1 aSchwarz, Peter, E H1 aHayward, Caroline1 aGuo, Xiuqing1 aRotimi, Charles1 aBots, Michiel, L1 aBrand, Eva1 aSamani, Nilesh, J1 aPolasek, Ozren1 aTalmud, Philippa, J1 aNyberg, Fredrik1 aKuh, Diana1 aLaan, Maris1 aHveem, Kristian1 aPalmer, Lyle, J1 aSchouw, Yvonne, T1 aCasas, Juan, P1 aMohlke, Karen, L1 aVineis, Paolo1 aRaitakari, Olli1 aGanesh, Santhi, K1 aWong, Tien, Y1 aTai, Shyong, E1 aCooper, Richard, S1 aLaakso, Markku1 aRao, Dabeeru, C1 aHarris, Tamara, B1 aMorris, Richard, W1 aDominiczak, Anna, F1 aKivimaki, Mika1 aMarmot, Michael, G1 aMiki, Tetsuro1 aSaleheen, Danish1 aChandak, Giriraj, R1 aCoresh, Josef1 aNavis, Gerjan1 aSalomaa, Veikko1 aHan, Bok-Ghee1 aZhu, Xiaofeng1 aKooner, Jaspal, S1 aMelander, Olle1 aRidker, Paul, M1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWright, Alan, F1 aWilson, James, F1 aFerrucci, Luigi1 aFarrall, Martin1 aTuomilehto, Jaakko1 aPramstaller, Peter, P1 aElosua, Roberto1 aSoranzo, Nicole1 aSijbrands, Eric, J G1 aAltshuler, David1 aLoos, Ruth, J F1 aShuldiner, Alan, R1 aGieger, Christian1 aMeneton, Pierre1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aRettig, Rainer1 aUda, Manuela1 aStrachan, David, P1 aWitteman, Jacqueline, C M1 aHartikainen, Anna-Liisa1 aBeckmann, Jacques, S1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aBoehnke, Michael1 aLarson, Martin, G1 aJarvelin, Marjo-Riitta1 aPsaty, Bruce, M1 aAbecasis, Goncalo, R1 aChakravarti, Aravinda1 aElliott, Paul1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aCaulfield, Mark, J1 aJohnson, Toby1 aCARDIoGRAM consortium1 aCKDGen Consortium1 aKidneyGen Consortium1 aEchoGen consortium1 aCHARGE-HF consortium 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2012 eng d a1553-740400aGenome-wide association and functional follow-up reveals new loci for kidney function.0 aGenomewide association and functional followup reveals new loci c2012 ae10025840 v83 aChronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
10aAfrican Americans10aAged10aAnimals10aCaspase 910aCyclin-Dependent Kinases10aDEAD-box RNA Helicases10aDNA Helicases10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aGene Knockdown Techniques10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aMale10aMiddle Aged10aPhosphoric Diester Hydrolases10aZebrafish1 aPattaro, Cristian1 aKöttgen, Anna1 aTeumer, Alexander1 aGarnaas, Maija1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aTaliun, Daniel1 aLi, Man1 aGao, Xiaoyi1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aO'Seaghdha, Conall, M1 aGlazer, Nicole1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aJohnson, Andrew, D1 aGierman, Hinco, J1 aFeitosa, Mary1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aChouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aCavalieri, Margherita1 aRao, Madhumathi1 aHu, Frank, B1 aDemirkan, Ayse1 aOostra, Ben, A1 ade Andrade, Mariza1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aKolcic, Ivana1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aEndlich, Karlhans1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aKetkar, Shamika1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aGiulianini, Franco1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMetzger, Marie1 aMitchell, Paul1 aCiullo, Marina1 aKim, Stuart, K1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aSiscovick, David, S1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline, C M1 aHayward, Caroline1 aRidker, Paul1 aParsa, Afshin1 aBochud, Murielle1 aHeid, Iris, M1 aGoessling, Wolfram1 aChasman, Daniel, I1 aKao, Linda, W H1 aFox, Caroline, S1 aCARDIoGRAM consortium1 aICBP Consortium1 aCARe Consortium1 aWellcome Trust Case Control Consortium 2 (WTCCC2) uhttps://chs-nhlbi.org/node/137707440nas a2202173 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520143200253653002301685653004001708653001901748653002201767653003401789653001101823653001101834653003701845653001401882653003601896653003301932100001801965700002701983700001902010700002602029700002202055700002302077700002302100700002202123700002202145700002002167700002002187700001802207700001802225700001902243700001202262700001802274700002002292700001602312700002502328700002402353700001902377700001802396700002002414700002102434700002602455700002302481700002002504700001202524700002002536700002702556700001702583700002502600700001902625700001802644700001902662700002102681700002702702700002102729700002102750700002202771700001602793700002202809700001802831700001902849700002102868700002002889700001902909700002302928700002002951700002202971700002202993700001903015700002403034700002503058700002103083700002003104700001703124700001403141700001903155700001903174700002303193700002003216700002503236700002303261700002303284700002103307700001803328700002003346700002203366700001603388700002203404700001803426700002103444700002403465700001603489700001903505700001903524700002003543700002003563700002203583700002003605700001903625700001903644700001903663700001803682700002103700700002003721700002003741700001703761700001903778700001803797700002203815700001803837700001903855700002803874700002603902700002403928700001903952700001703971700002203988700002204010700001904032700002504051700002204076700001904098700002004117700001904137700002204156700002204178700001904200700001604219700002304235700002504258700001804283700001404301700002404315700001704339700002104356700002404377700001704401700001704418700001904435700001904454700002404473700002004497700002104517700001804538700002104556700001904577700001904596700002904615700002404644700002104668700002404689700002304713700001804736700002204754700002004776700002304796700002004819700002404839700001704863700002004880700001604900700002004916700002104936700001804957700002604975700001905001700002105020700002505041700002205066700002005088700002105108700001805129700002405147700002105171700001505192700002305207856003605230 2013 eng d a1533-345000aCommon variants in Mendelian kidney disease genes and their association with renal function.0 aCommon variants in Mendelian kidney disease genes and their asso c2013 Dec a2105-170 v243 aMany common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
10aDatabases, Genetic10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aHumans10aKidney10aMendelian Randomization Analysis10aPhenotype10aPolymorphism, Single Nucleotide10aRenal Insufficiency, Chronic1 aParsa, Afshin1 aFuchsberger, Christian1 aKöttgen, Anna1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 ade Andrade, Mariza1 aChasman, Daniel, I1 aTeumer, Alexander1 aEndlich, Karlhans1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aKim, Young, J1 aTaliun, Daniel1 aLi, Man1 aFeitosa, Mary1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aGlazer, Nicole1 aIsaacs, Aaron1 aRao, Madhumathi1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aCouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aHofer, Edith1 aHu, Frank1 aDemirkan, Ayse1 aOostra, Ben, A1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aGiulianini, Franco1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aZgaga, Lina1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aStengel, Bénédicte1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMitchell, Paul1 aCiullo, Marina1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline1 aHayward, Caroline1 aRidker, Paul, M1 aBochud, Murielle1 aHeid, Iris, M1 aSiscovick, David, S1 aFox, Caroline, S1 aKao, Linda1 aBöger, Carsten, A uhttps://chs-nhlbi.org/node/628803475nas a2200601 4500008004100000022001400041245017800055210006900233260001300302300001000315490000600325520173700331653001002068653000902078653001002087653002002097653001902117653001102136653003202147653002202179653003402201653001302235653001902248653001102267653000902278653002202287653001602309653003602325653002702361653001602388100001802404700002202422700002302444700002002467700002402487700002302511700001202534700002402546700001702570700002202587700002102609700001702630700001702647700002102664700001902685700002302704700002202727700002302749700002102772700001902793700002502812856003602837 2014 eng d a1942-326800aSequence variation in TMEM18 in association with body mass index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aSequence variation in TMEM18 in association with body mass index c2014 Jun a344-90 v73 aBACKGROUND: Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI.
METHODS AND RESULTS: We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m(2) higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P=3.46×10(-4)) using a Bonferroni threshold of P<4.6×10(-4). Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r(2)<0.2), statistically significant association, rs186019316 (P=2.11×10(-4)). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3' genome-wide association study region.
CONCLUSIONS: Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.
10aAdult10aAged10aAging10aBody Mass Index10aCohort Studies10aFemale10aGenetic Association Studies10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aMale10aMembrane Proteins10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA10aYoung Adult1 aLiu, Ching-Ti1 aYoung, Kristin, L1 aBrody, Jennifer, A1 aOlden, Matthias1 aWojczynski, Mary, K1 aHeard-Costa, Nancy1 aLi, Guo1 aMorrison, Alanna, C1 aMuzny, Donna1 aGibbs, Richard, A1 aReid, Jeffrey, G1 aShao, Yaming1 aZhou, Yanhua1 aBoerwinkle, Eric1 aHeiss, Gerardo1 aWagenknecht, Lynne1 aMcKnight, Barbara1 aBorecki, Ingrid, B1 aFox, Caroline, S1 aNorth, Kari, E1 aCupples, Adrienne, L uhttps://chs-nhlbi.org/node/6579