04323nas a2201033 4500008004100000022001400041245011200055210006900167260001300236300001300249490000600262520134000268653000901608653002001617653001901637653004001656653001101696653003801707653003401745653001101779653000901790653001601799653002601815653001201841653003601853653002401889100002601913700002501939700001901964700001901983700002202002700001202024700002302036700002102059700001902080700002402099700002002123700002202143700002102165700002502186700002402211700002302235700002602258700002102284700001902305700002302324700002102347700002102368700002202389700002202411700002202433700002002455700002202475700001602497700002002513700002002533700002202553700002602575700001602601700002302617700002202640700001602662700001602678700002502694700001902719700002102738700001902759700002402778700002402802700003002826700002702856700002202883700002402905700001902929700001902948700002602967700002802993700003003021700001903051700002203070700002403092700002603116700002303142700002303165700002503188700002103213700001903234856003603253 2009 eng d a1553-740400aNRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.0 aNRXN3 is a novel locus for waist circumference a genomewide asso c2009 Jun ae10005390 v53 a
Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
10aAged10aBody Mass Index10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aObesity10aPolymorphism, Single Nucleotide10aWaist Circumference1 aHeard-Costa, Nancy, L1 aZillikens, Carola, M1 aMonda, Keri, L1 aJohansson, Asa1 aHarris, Tamara, B1 aFu, Mao1 aHaritunians, Talin1 aFeitosa, Mary, F1 aAspelund, Thor1 aEiriksdottir, Gudny1 aGarcia, Melissa1 aLauner, Lenore, J1 aSmith, Albert, V1 aMitchell, Braxton, D1 aMcArdle, Patrick, F1 aShuldiner, Alan, R1 aBielinski, Suzette, J1 aBoerwinkle, Eric1 aBrancati, Fred1 aDemerath, Ellen, W1 aPankow, James, S1 aArnold, Alice, M1 aChen, Yii-Der Ida1 aGlazer, Nicole, L1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aAmin, Najaf1 aCampbell, Harry1 aGyllensten, Ulf1 aPattaro, Cristian1 aPramstaller, Peter, P1 aRudan, Igor1 aStruchalin, Maksim1 aVitart, Veronique1 aGao, Xiaoyi1 aKraja, Aldi1 aProvince, Michael, A1 aZhang, Qunyuan1 aAtwood, Larry, D1 aDupuis, Josée1 aHirschhorn, Joel, N1 aJaquish, Cashell, E1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWhite, Charles, C1 aAulchenko, Yurii, S1 aEstrada, Karol1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aOostra, Ben, A1 aKaplan, Robert, C1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aCupples, Adrienne, L1 aFox, Caroline, S1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/110714196nas a2204789 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2010 eng d a1546-171800aAssociation analyses of 249,796 individuals reveal 18 new loci associated with body mass index.0 aAssociation analyses of 249796 individuals reveal 18 new loci as c2010 Nov a937-480 v423 aObesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
10aBody Height10aBody Mass Index10aBody Size10aBody Weight10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aObesity10aPolymorphism, Single Nucleotide1 aSpeliotes, Elizabeth, K1 aWiller, Cristen, J1 aBerndt, Sonja, I1 aMonda, Keri, L1 aThorleifsson, Gudmar1 aJackson, Anne, U1 aAllen, Hana, Lango1 aLindgren, Cecilia, M1 aLuan, Jian'an1 aMägi, Reedik1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWinkler, Thomas, W1 aQi, Lu1 aWorkalemahu, Tsegaselassie1 aHeid, Iris, M1 aSteinthorsdottir, Valgerdur1 aStringham, Heather, M1 aWeedon, Michael, N1 aWheeler, Eleanor1 aWood, Andrew, R1 aFerreira, Teresa1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aEstrada, Karol1 aLiang, Liming1 aNemesh, James1 aPark, Ju-Hyun1 aGustafsson, Stefan1 aKilpeläinen, Tuomas, O1 aYang, Jian1 aBouatia-Naji, Nabila1 aEsko, Tõnu1 aFeitosa, Mary, F1 aKutalik, Zoltán1 aMangino, Massimo1 aRaychaudhuri, Soumya1 aScherag, Andre1 aSmith, Albert, Vernon1 aWelch, Ryan1 aZhao, Jing Hua1 aAben, Katja, K1 aAbsher, Devin, M1 aAmin, Najaf1 aDixon, Anna, L1 aFisher, Eva1 aGlazer, Nicole, L1 aGoddard, Michael, E1 aHeard-Costa, Nancy, L1 aHoesel, Volker1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJohnson, Toby1 aKetkar, Shamika1 aLamina, Claudia1 aLi, Shengxu1 aMoffatt, Miriam, F1 aMyers, Richard, H1 aNarisu, Narisu1 aPerry, John, R B1 aPeters, Marjolein, J1 aPreuss, Michael1 aRipatti, Samuli1 aRivadeneira, Fernando1 aSandholt, Camilla1 aScott, Laura, J1 aTimpson, Nicholas, J1 aTyrer, Jonathan, P1 avan Wingerden, Sophie1 aWatanabe, Richard, M1 aWhite, Charles, C1 aWiklund, Fredrik1 aBarlassina, Christina1 aChasman, Daniel, I1 aCooper, Matthew, N1 aJansson, John-Olov1 aLawrence, Robert, W1 aPellikka, Niina1 aProkopenko, Inga1 aShi, Jianxin1 aThiering, Elisabeth1 aAlavere, Helene1 aAlibrandi, Maria, T S1 aAlmgren, Peter1 aArnold, Alice, M1 aAspelund, Thor1 aAtwood, Larry, D1 aBalkau, Beverley1 aBalmforth, Anthony, J1 aBennett, Amanda, J1 aBen-Shlomo, Yoav1 aBergman, Richard, N1 aBergmann, Sven1 aBiebermann, Heike1 aBlakemore, Alexandra, I F1 aBoes, Tanja1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBrown, Morris, J1 aBuchanan, Thomas, A1 aBusonero, Fabio1 aCampbell, Harry1 aCappuccio, Francesco, P1 aCavalcanti-Proença, Christine1 aChen, Yii-Der Ida1 aChen, Chih-Mei1 aChines, Peter, S1 aClarke, Robert1 aCoin, Lachlan1 aConnell, John1 aDay, Ian, N M1 aHeijer, Martin, den1 aDuan, Jubao1 aEbrahim, Shah1 aElliott, Paul1 aElosua, Roberto1 aEiriksdottir, Gudny1 aErdos, Michael, R1 aEriksson, Johan, G1 aFacheris, Maurizio, F1 aFelix, Stephan, B1 aFischer-Posovszky, Pamela1 aFolsom, Aaron, R1 aFriedrich, Nele1 aFreimer, Nelson, B1 aFu, Mao1 aGaget, Stefan1 aGejman, Pablo, V1 aGeus, Eco, J C1 aGieger, Christian1 aGjesing, Anette, P1 aGoel, Anuj1 aGoyette, Philippe1 aGrallert, Harald1 aGrässler, Jürgen1 aGreenawalt, Danielle, M1 aGroves, Christopher, J1 aGudnason, Vilmundur1 aGuiducci, Candace1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHall, Alistair, S1 aHavulinna, Aki, S1 aHayward, Caroline1 aHeath, Andrew, C1 aHengstenberg, Christian1 aHicks, Andrew, A1 aHinney, Anke1 aHofman, Albert1 aHomuth, Georg1 aHui, Jennie1 aIgl, Wilmar1 aIribarren, Carlos1 aIsomaa, Bo1 aJacobs, Kevin, B1 aJarick, Ivonne1 aJewell, Elizabeth1 aJohn, Ulrich1 aJørgensen, Torben1 aJousilahti, Pekka1 aJula, Antti1 aKaakinen, Marika1 aKajantie, Eero1 aKaplan, Lee, M1 aKathiresan, Sekar1 aKettunen, Johannes1 aKinnunen, Leena1 aKnowles, Joshua, W1 aKolcic, Ivana1 aKönig, Inke, R1 aKoskinen, Seppo1 aKovacs, Peter1 aKuusisto, Johanna1 aKraft, Peter1 aKvaløy, Kirsti1 aLaitinen, Jaana1 aLantieri, Olivier1 aLanzani, Chiara1 aLauner, Lenore, J1 aLecoeur, Cécile1 aLehtimäki, Terho1 aLettre, Guillaume1 aLiu, Jianjun1 aLokki, Marja-Liisa1 aLorentzon, Mattias1 aLuben, Robert, N1 aLudwig, Barbara1 aManunta, Paolo1 aMarek, Diana1 aMarre, Michel1 aMartin, Nicholas, G1 aMcArdle, Wendy, L1 aMcCarthy, Anne1 aMcKnight, Barbara1 aMeitinger, 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aTeslovich, Tanya, M1 aThompson, John, R1 aThomson, Brian1 aTönjes, Anke1 aTuomi, Tiinamaija1 avan Meurs, Joyce, B J1 avan Ommen, Gert-Jan1 aVatin, Vincent1 aViikari, Jorma1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogel, Carla, I G1 aVoight, Benjamin, F1 aWaite, Lindsay, L1 aWallaschofski, Henri1 aWalters, Bragi, G1 aWiden, Elisabeth1 aWiegand, Susanna1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitte, Daniel, R1 aWitteman, Jacqueline, C1 aXu, Jianfeng1 aZhang, Qunyuan1 aZgaga, Lina1 aZiegler, Andreas1 aZitting, Paavo1 aBeilby, John, P1 aFarooqi, Sadaf1 aHebebrand, Johannes1 aHuikuri, Heikki, V1 aJames, Alan, L1 aKähönen, Mika1 aLevinson, Douglas, F1 aMacciardi, Fabio1 aNieminen, Markku, S1 aOhlsson, Claes1 aPalmer, Lyle, J1 aRidker, Paul, M1 aStumvoll, Michael1 aBeckmann, Jacques, S1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCollins, Francis, S1 aCupples, Adrienne, L1 aSmith, George Davey1 aErdmann, Jeanette1 aFroguel, Philippe1 aGrönberg, Henrik1 aGyllensten, Ulf1 aHall, Per1 aHansen, Torben1 aHarris, Tamara, B1 aHattersley, Andrew, T1 aHayes, Richard, B1 aHeinrich, Joachim1 aHu, Frank, B1 aHveem, Kristian1 aIllig, Thomas1 aJarvelin, Marjo-Riitta1 aKaprio, Jaakko1 aKarpe, Fredrik1 aKhaw, Kay-Tee1 aKiemeney, Lambertus, A1 aKrude, Heiko1 aLaakso, Markku1 aLawlor, Debbie, A1 aMetspalu, Andres1 aMunroe, Patricia, B1 aOuwehand, Willem, H1 aPedersen, Oluf1 aPenninx, Brenda, W1 aPeters, Annette1 aPramstaller, Peter, P1 aQuertermous, Thomas1 aReinehr, Thomas1 aRissanen, Aila1 aRudan, Igor1 aSamani, Nilesh, J1 aSchwarz, Peter, E H1 aShuldiner, Alan, R1 aSpector, Timothy, D1 aTuomilehto, Jaakko1 aUda, Manuela1 aUitterlinden, Andre1 aValle, Timo, T1 aWabitsch, Martin1 aWaeber, Gérard1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWilson, James, F1 aWright, Alan, F1 aZillikens, Carola, M1 aChatterjee, Nilanjan1 aMcCarroll, Steven, A1 aPurcell, Shaun1 aSchadt, Eric, E1 aVisscher, Peter, M1 aAssimes, Themistocles, L1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David, J1 aKaplan, Robert, C1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPeltonen, Leena1 aSchlessinger, David1 aStrachan, David, P1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aFrayling, Timothy, M1 aThorsteinsdottir, Unnur1 aAbecasis, Goncalo, R1 aBarroso, Inês1 aBoehnke, Michael1 aStefansson, Kari1 aNorth, Kari, E1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aIngelsson, Erik1 aLoos, Ruth, J F1 aMAGIC1 aProcardis Consortium uhttps://chs-nhlbi.org/node/123712698nas a2203781 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2010 eng d a1476-468700aHundreds of variants clustered in genomic loci and biological pathways affect human height.0 aHundreds of variants clustered in genomic loci and biological pa c2010 Oct 14 a832-80 v4673 aMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
10aBody Height10aChromosomes, Human, Pair 310aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMetabolic Networks and Pathways10aMultifactorial Inheritance10aPhenotype10aPolymorphism, Single Nucleotide1 aAllen, Hana, Lango1 aEstrada, Karol1 aLettre, Guillaume1 aBerndt, Sonja, I1 aWeedon, Michael, N1 aRivadeneira, Fernando1 aWiller, Cristen, J1 aJackson, Anne, U1 aVedantam, Sailaja1 aRaychaudhuri, Soumya1 aFerreira, Teresa1 aWood, Andrew, R1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aSpeliotes, Elizabeth, K1 aWheeler, Eleanor1 aSoranzo, Nicole1 aPark, Ju-Hyun1 aYang, Jian1 aGudbjartsson, Daniel1 aHeard-Costa, Nancy, L1 aRandall, Joshua, C1 aQi, Lu1 aSmith, Albert, Vernon1 aMägi, Reedik1 aPastinen, Tomi1 aLiang, Liming1 aHeid, Iris, M1 aLuan, Jian'an1 aThorleifsson, Gudmar1 aWinkler, Thomas, W1 aGoddard, Michael, E1 aLo, Ken, Sin1 aPalmer, Cameron1 aWorkalemahu, Tsegaselassie1 aAulchenko, Yurii, S1 aJohansson, Asa1 aZillikens, Carola, M1 aFeitosa, Mary, F1 aEsko, Tõnu1 aJohnson, Toby1 aKetkar, Shamika1 aKraft, Peter1 aMangino, Massimo1 aProkopenko, Inga1 aAbsher, Devin1 aAlbrecht, Eva1 aErnst, Florian1 aGlazer, Nicole, L1 aHayward, Caroline1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aKnowles, Joshua, W1 aKutalik, Zoltán1 aMonda, Keri, L1 aPolasek, Ozren1 aPreuss, Michael1 aRayner, Nigel, W1 aRobertson, Neil, R1 aSteinthorsdottir, Valgerdur1 aTyrer, Jonathan, P1 aVoight, Benjamin, F1 aWiklund, Fredrik1 aXu, Jianfeng1 aZhao, Jing Hua1 aNyholt, Dale, R1 aPellikka, Niina1 aPerola, Markus1 aPerry, John, R B1 aSurakka, Ida1 aTammesoo, Mari-Liis1 aAltmaier, Elizabeth, L1 aAmin, Najaf1 aAspelund, Thor1 aBhangale, Tushar1 aBoucher, Gabrielle1 aChasman, Daniel, I1 aChen, Constance1 aCoin, Lachlan1 aCooper, Matthew, N1 aDixon, Anna, L1 aGibson, Quince1 aGrundberg, Elin1 aHao, Ke1 aJunttila, Juhani1 aKaplan, Lee, M1 aKettunen, Johannes1 aKönig, Inke, R1 aKwan, Tony1 aLawrence, Robert, W1 aLevinson, Douglas, F1 aLorentzon, Mattias1 aMcKnight, Barbara1 aMorris, Andrew, P1 aMüller, Martina1 aNgwa, Julius, Suh1 aPurcell, Shaun1 aRafelt, Suzanne1 aSalem, Rany, M1 aSalvi, Erika1 aSanna, Serena1 aShi, Jianxin1 aSovio, Ulla1 aThompson, John, R1 aTurchin, Michael, C1 aVandenput, Liesbeth1 aVerlaan, Dominique, J1 aVitart, Veronique1 aWhite, Charles, C1 aZiegler, Andreas1 aAlmgren, Peter1 aBalmforth, Anthony, J1 aCampbell, Harry1 aCitterio, Lorena1 aDe Grandi, Alessandro1 aDominiczak, Anna1 aDuan, Jubao1 aElliott, Paul1 aElosua, Roberto1 aEriksson, Johan, G1 aFreimer, Nelson, B1 aGeus, Eco, J C1 aGlorioso, Nicola1 aHaiqing, Shen1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHui, Jennie1 aIgl, Wilmar1 aIllig, Thomas1 aJula, Antti1 aKajantie, Eero1 aKilpeläinen, Tuomas, O1 aKoiranen, Markku1 aKolcic, Ivana1 aKoskinen, Seppo1 aKovacs, Peter1 aLaitinen, Jaana1 aLiu, Jianjun1 aLokki, Marja-Liisa1 aMarusic, Ana1 aMaschio, Andrea1 aMeitinger, Thomas1 aMulas, Antonella1 aParé, Guillaume1 aParker, Alex, N1 aPeden, John, F1 aPetersmann, Astrid1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPouta, Anneli1 aRidderstråle, Martin1 aRotter, Jerome, I1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSchmidt, Carsten, Oliver1 aSinisalo, Juha1 aSmit, Jan, H1 aStringham, Heather, M1 aWalters, Bragi1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aZagato, Laura1 aZgaga, Lina1 aZitting, Paavo1 aAlavere, Helene1 aFarrall, Martin1 aMcArdle, Wendy, L1 aNelis, Mari1 aPeters, Marjolein, J1 aRipatti, Samuli1 avan Meurs, Joyce, B J1 aAben, Katja, K1 aArdlie, Kristin, G1 aBeckmann, Jacques, S1 aBeilby, John, P1 aBergman, Richard, N1 aBergmann, Sven1 aCollins, Francis, S1 aCusi, Daniele1 aHeijer, Martin, den1 aEiriksdottir, Gudny1 aGejman, Pablo, V1 aHall, Alistair, S1 aHamsten, Anders1 aHuikuri, Heikki, V1 aIribarren, Carlos1 aKähönen, Mika1 aKaprio, Jaakko1 aKathiresan, Sekar1 aKiemeney, Lambertus1 aKocher, Thomas1 aLauner, Lenore, J1 aLehtimäki, Terho1 aMelander, Olle1 aMosley, Tom, H1 aMusk, Arthur, W1 aNieminen, Markku, S1 aO'Donnell, Christopher, J1 aOhlsson, Claes1 aOostra, Ben1 aPalmer, Lyle, J1 aRaitakari, Olli1 aRidker, Paul, M1 aRioux, John, D1 aRissanen, Aila1 aRivolta, Carlo1 aSchunkert, Heribert1 aShuldiner, Alan, R1 aSiscovick, David, S1 aStumvoll, Michael1 aTönjes, Anke1 aTuomilehto, Jaakko1 avan Ommen, Gert-Jan1 aViikari, Jorma1 aHeath, Andrew, C1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aProvince, Michael, A1 aKayser, Manfred1 aArnold, Alice, M1 aAtwood, Larry, D1 aBoerwinkle, Eric1 aChanock, Stephen, J1 aDeloukas, Panos1 aGieger, Christian1 aGrönberg, Henrik1 aHall, Per1 aHattersley, Andrew, T1 aHengstenberg, Christian1 aHoffman, Wolfgang1 aLathrop, Mark, G1 aSalomaa, Veikko1 aSchreiber, Stefan1 aUda, Manuela1 aWaterworth, Dawn1 aWright, Alan, F1 aAssimes, Themistocles, L1 aBarroso, Inês1 aHofman, Albert1 aMohlke, Karen, L1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aCupples, Adrienne, L1 aErdmann, Jeanette1 aFox, Caroline, S1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHarris, Tamara, B1 aHayes, Richard, B1 aJarvelin, Marjo-Riitta1 aMooser, Vincent1 aMunroe, Patricia, B1 aOuwehand, Willem, H1 aPenninx, Brenda, W1 aPramstaller, Peter, P1 aQuertermous, Thomas1 aRudan, Igor1 aSamani, Nilesh, J1 aSpector, Timothy, D1 aVölzke, Henry1 aWatkins, Hugh1 aWilson, James, F1 aGroop, Leif, C1 aHaritunians, Talin1 aHu, Frank, B1 aKaplan, Robert, C1 aMetspalu, Andres1 aNorth, Kari, E1 aSchlessinger, David1 aWareham, Nicholas, J1 aHunter, David, J1 aO'Connell, Jeffrey, R1 aStrachan, David, P1 aWichmann, H-Erich1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aSchadt, Eric, E1 aThorsteinsdottir, Unnur1 aPeltonen, Leena1 aUitterlinden, André, G1 aVisscher, Peter, M1 aChatterjee, Nilanjan1 aLoos, Ruth, J F1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aIngelsson, Erik1 aLindgren, Cecilia, M1 aAbecasis, Goncalo, R1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N uhttps://chs-nhlbi.org/node/123411930nas a2203889 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2010 eng d a1546-171800aMeta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.0 aMetaanalysis identifies 13 new loci associated with waisthip rat c2010 Nov a949-600 v423 aWaist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
10aAdipose Tissue10aAge Factors10aChromosome Mapping10aFemale10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist-Hip Ratio1 aHeid, Iris, M1 aJackson, Anne, U1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aQi, Lu1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aZillikens, Carola, M1 aSpeliotes, Elizabeth, K1 aMägi, Reedik1 aWorkalemahu, Tsegaselassie1 aWhite, Charles, C1 aBouatia-Naji, Nabila1 aHarris, Tamara, B1 aBerndt, Sonja, I1 aIngelsson, Erik1 aWiller, Cristen, J1 aWeedon, Michael, N1 aLuan, Jian'an1 aVedantam, Sailaja1 aEsko, Tõnu1 aKilpeläinen, Tuomas, O1 aKutalik, Zoltán1 aLi, Shengxu1 aMonda, Keri, L1 aDixon, Anna, L1 aHolmes, Christopher, C1 aKaplan, Lee, M1 aLiang, Liming1 aMin, Josine, L1 aMoffatt, Miriam, F1 aMolony, Cliona1 aNicholson, George1 aSchadt, Eric, E1 aZondervan, Krina, T1 aFeitosa, Mary, F1 aFerreira, Teresa1 aAllen, Hana, Lango1 aWeyant, Robert, J1 aWheeler, Eleanor1 aWood, Andrew, R1 aEstrada, Karol1 aGoddard, Michael, E1 aLettre, Guillaume1 aMangino, Massimo1 aNyholt, Dale, R1 aPurcell, Shaun1 aSmith, Albert, Vernon1 aVisscher, Peter, M1 aYang, Jian1 aMcCarroll, Steven, A1 aNemesh, James1 aVoight, Benjamin, F1 aAbsher, Devin1 aAmin, Najaf1 aAspelund, Thor1 aCoin, Lachlan1 aGlazer, Nicole, L1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKapur, Karen1 aKetkar, Shamika1 aKnowles, Joshua, W1 aKraft, Peter1 aKraja, Aldi, T1 aLamina, Claudia1 aLeitzmann, Michael, F1 aMcKnight, Barbara1 aMorris, Andrew, P1 aOng, Ken, K1 aPerry, John, R B1 aPeters, Marjolein, J1 aPolasek, Ozren1 aProkopenko, Inga1 aRayner, Nigel, W1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRobertson, Neil, R1 aSanna, Serena1 aSovio, Ulla1 aSurakka, Ida1 aTeumer, Alexander1 avan Wingerden, Sophie1 aVitart, Veronique1 aZhao, Jing Hua1 aCavalcanti-Proença, Christine1 aChines, Peter, S1 aFisher, Eva1 aKulzer, Jennifer, R1 aLecoeur, Cécile1 aNarisu, Narisu1 aSandholt, Camilla1 aScott, Laura, J1 aSilander, Kaisa1 aStark, Klaus1 aTammesoo, Mari-Liis1 aTeslovich, Tanya, M1 aTimpson, Nicholas, John1 aWatanabe, Richard, M1 aWelch, Ryan1 aChasman, Daniel, I1 aCooper, Matthew, N1 aJansson, John-Olov1 aKettunen, Johannes1 aLawrence, Robert, W1 aPellikka, Niina1 aPerola, Markus1 aVandenput, Liesbeth1 aAlavere, Helene1 aAlmgren, Peter1 aAtwood, Larry, D1 aBennett, Amanda, J1 aBiffar, Reiner1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBuchanan, Thomas, A1 aCampbell, Harry1 aDay, Ian, N M1 aDei, Mariano1 aDörr, Marcus1 aElliott, Paul1 aErdos, Michael, R1 aEriksson, Johan, G1 aFreimer, Nelson, B1 aFu, Mao1 aGaget, Stefan1 aGeus, Eco, J C1 aGjesing, Anette, P1 aGrallert, Harald1 aGrässler, Jürgen1 aGroves, Christopher, J1 aGuiducci, Candace1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHavulinna, Aki, S1 aHerzig, Karl-Heinz1 aHicks, Andrew, A1 aHui, Jennie1 aIgl, Wilmar1 aJousilahti, Pekka1 aJula, Antti1 aKajantie, Eero1 aKinnunen, Leena1 aKolcic, Ivana1 aKoskinen, Seppo1 aKovacs, Peter1 aKroemer, Heyo, K1 aKrzelj, Vjekoslav1 aKuusisto, Johanna1 aKvaloy, Kirsti1 aLaitinen, Jaana1 aLantieri, Olivier1 aLathrop, Mark, G1 aLokki, Marja-Liisa1 aLuben, Robert, N1 aLudwig, Barbara1 aMcArdle, Wendy, L1 aMcCarthy, Anne1 aMorken, Mario, A1 aNelis, Mari1 aNeville, Matt, J1 aParé, Guillaume1 aParker, Alex, N1 aPeden, John, F1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPlatou, Carl, G P1 aPouta, Anneli1 aRidderstråle, Martin1 aSamani, Nilesh, J1 aSaramies, Jouko1 aSinisalo, Juha1 aSmit, Jan, H1 aStrawbridge, Rona, J1 aStringham, Heather, M1 aSwift, Amy, J1 aTeder-Laving, Maris1 aThomson, Brian1 aUsala, Gianluca1 avan Meurs, Joyce, B J1 avan Ommen, Gert-Jan1 aVatin, Vincent1 aVolpato, Claudia, B1 aWallaschofski, Henri1 aWalters, Bragi, G1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitte, Daniel, R1 aZgaga, Lina1 aZitting, Paavo1 aBeilby, John, P1 aJames, Alan, L1 aKähönen, Mika1 aLehtimäki, Terho1 aNieminen, Markku, S1 aOhlsson, Claes1 aPalmer, Lyle, J1 aRaitakari, Olli1 aRidker, Paul, M1 aStumvoll, Michael1 aTönjes, Anke1 aViikari, Jorma1 aBalkau, Beverley1 aBen-Shlomo, Yoav1 aBergman, Richard, N1 aBoeing, Heiner1 aSmith, George Davey1 aEbrahim, Shah1 aFroguel, Philippe1 aHansen, Torben1 aHengstenberg, Christian1 aHveem, Kristian1 aIsomaa, Bo1 aJørgensen, Torben1 aKarpe, Fredrik1 aKhaw, Kay-Tee1 aLaakso, Markku1 aLawlor, Debbie, A1 aMarre, Michel1 aMeitinger, Thomas1 aMetspalu, Andres1 aMidthjell, Kristian1 aPedersen, Oluf1 aSalomaa, Veikko1 aSchwarz, Peter, E H1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aValle, Timo, T1 aWareham, Nicholas, J1 aArnold, Alice, M1 aBeckmann, Jacques, S1 aBergmann, Sven1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aCollins, Francis, S1 aEiriksdottir, Gudny1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHattersley, Andrew, T1 aHofman, Albert1 aHu, Frank, B1 aIllig, Thomas1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aKao, Linda, W H1 aKaprio, Jaakko1 aLauner, Lenore, J1 aMunroe, Patricia, B1 aOostra, Ben1 aPenninx, Brenda, W1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRissanen, Aila1 aRudan, Igor1 aShuldiner, Alan, R1 aSoranzo, Nicole1 aSpector, Timothy, D1 aSyvänen, Ann-Christine1 aUda, Manuela1 aUitterlinden, Andre1 aVölzke, Henry1 aVollenweider, Peter1 aWilson, James, F1 aWitteman, Jacqueline, C1 aWright, Alan, F1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFrayling, Timothy, M1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David, J1 aKaplan, Robert, C1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPeltonen, Leena1 aSchlessinger, David1 aStrachan, David, P1 aHirschhorn, Joel, N1 aAssimes, Themistocles, L1 aWichmann, H-Erich1 aThorsteinsdottir, Unnur1 aDuijn, Cornelia, M1 aStefansson, Kari1 aCupples, Adrienne, L1 aLoos, Ruth, J F1 aBarroso, Inês1 aMcCarthy, Mark, I1 aFox, Caroline, S1 aMohlke, Karen, L1 aLindgren, Cecilia, M1 aMAGIC uhttps://chs-nhlbi.org/node/123608598nas a2202365 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2012 eng d a1476-468700aFTO genotype is associated with phenotypic variability of body mass index.0 aFTO genotype is associated with phenotypic variability of body m c2012 Oct 11 a267-720 v4903 aThere is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aBody Height10aBody Mass Index10aCo-Repressor Proteins10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteins10aRepressor Proteins1 aYang, Jian1 aLoos, Ruth, J F1 aPowell, Joseph, E1 aMedland, Sarah, E1 aSpeliotes, Elizabeth, K1 aChasman, Daniel, I1 aRose, Lynda, M1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aMägi, Reedik1 aWaite, Lindsay1 aSmith, Albert, Vernon1 aYerges-Armstrong, Laura, M1 aMonda, Keri, L1 aHadley, David1 aMahajan, Anubha1 aLi, Guo1 aKapur, Karen1 aVitart, Veronique1 aHuffman, Jennifer, E1 aWang, Sophie, R1 aPalmer, Cameron1 aEsko, Tõnu1 aFischer, Krista1 aZhao, Jing Hua1 aDemirkan, Ayse1 aIsaacs, Aaron1 aFeitosa, Mary, F1 aLuan, Jian'an1 aHeard-Costa, Nancy, L1 aWhite, Charles1 aJackson, Anne, U1 aPreuss, Michael1 aZiegler, Andreas1 aEriksson, Joel1 aKutalik, Zoltán1 aFrau, Francesca1 aNolte, Ilja, M1 avan Vliet-Ostaptchouk, Jana, V1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aVerweij, Niek1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aEstrada, Karol1 aBragg-Gresham, Jennifer, Lynn1 aSanna, Serena1 aSidore, Carlo1 aTyrer, Jonathan1 aTeumer, Alexander1 aProkopenko, Inga1 aMangino, Massimo1 aLindgren, Cecilia, M1 aAssimes, Themistocles, L1 aShuldiner, Alan, R1 aHui, Jennie1 aBeilby, John, P1 aMcArdle, Wendy, L1 aHall, Per1 aHaritunians, Talin1 aZgaga, Lina1 aKolcic, Ivana1 aPolasek, Ozren1 aZemunik, Tatijana1 aOostra, Ben, A1 aJunttila, Juhani1 aGrönberg, Henrik1 aSchreiber, Stefan1 aPeters, Annette1 aHicks, Andrew, A1 aStephens, Jonathan1 aFoad, Nicola, S1 aLaitinen, Jaana1 aPouta, Anneli1 aKaakinen, Marika1 aWillemsen, Gonneke1 aVink, Jacqueline, M1 aWild, Sarah, H1 aNavis, Gerjan1 aAsselbergs, Folkert, W1 aHomuth, Georg1 aJohn, Ulrich1 aIribarren, Carlos1 aHarris, Tamara1 aLauner, Lenore1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBoerwinkle, Eric1 aCadby, Gemma1 aPalmer, Lyle, J1 aJames, Alan, L1 aMusk, Arthur, W1 aIngelsson, Erik1 aPsaty, Bruce, M1 aBeckmann, Jacques, S1 aWaeber, Gérard1 aVollenweider, Peter1 aHayward, Caroline1 aWright, Alan, F1 aRudan, Igor1 aGroop, Leif, C1 aMetspalu, Andres1 aKhaw, Kay, Tee1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aProvince, Michael, A1 aWareham, Nicholas, J1 aTardif, Jean-Claude1 aHuikuri, Heikki, V1 aCupples, Adrienne, L1 aAtwood, Larry, D1 aFox, Caroline, S1 aBoehnke, Michael1 aCollins, Francis, S1 aMohlke, Karen, L1 aErdmann, Jeanette1 aSchunkert, Heribert1 aHengstenberg, Christian1 aStark, Klaus1 aLorentzon, Mattias1 aOhlsson, Claes1 aCusi, Daniele1 aStaessen, Jan, A1 avan der Klauw, Melanie, M1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aJolley, Jennifer, D1 aRipatti, Samuli1 aJarvelin, Marjo-Riitta1 aGeus, Eco, J C1 aBoomsma, Dorret, I1 aPenninx, Brenda1 aWilson, James, F1 aCampbell, Harry1 aChanock, Stephen, J1 aHarst, Pim1 aHamsten, Anders1 aWatkins, Hugh1 aHofman, Albert1 aWitteman, Jacqueline, C1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aZillikens, Carola, M1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aAbecasis, Goncalo, R1 aSchlessinger, David1 aSchipf, Sabine1 aStumvoll, Michael1 aTönjes, Anke1 aSpector, Tim, D1 aNorth, Kari, E1 aLettre, Guillaume1 aMcCarthy, Mark, I1 aBerndt, Sonja, I1 aHeath, Andrew, C1 aMadden, Pamela, A F1 aNyholt, Dale, R1 aMontgomery, Grant, W1 aMartin, Nicholas, G1 aMcKnight, Barbara1 aStrachan, David, P1 aHill, William, G1 aSnieder, Harold1 aRidker, Paul, M1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N1 aGoddard, Michael, E1 aVisscher, Peter, M uhttps://chs-nhlbi.org/node/617506047nas a2201393 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2013 eng d a1553-740400aGenome-wide association of body fat distribution in African ancestry populations suggests new loci.0 aGenomewide association of body fat distribution in African ances c2013 ae10036810 v93 aCentral obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
10aAdiposity10aAfrican Continental Ancestry Group10aBody Fat Distribution10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aObesity10aPolymorphism, Single Nucleotide10aWaist-Hip Ratio1 aLiu, Ching-Ti1 aMonda, Keri, L1 aTaylor, Kira, C1 aLange, Leslie1 aDemerath, Ellen, W1 aPalmas, Walter1 aWojczynski, Mary, K1 aEllis, Jaclyn, C1 aVitolins, Mara, Z1 aLiu, Simin1 aPapanicolaou, George, J1 aIrvin, Marguerite, R1 aXue, Luting1 aGriffin, Paula, J1 aNalls, Michael, A1 aAdeyemo, Adebowale1 aLiu, Jiankang1 aLi, Guo1 aRuiz-Narvaez, Edward, A1 aChen, Wei-Min1 aChen, Fang1 aHenderson, Brian, E1 aMillikan, Robert, C1 aAmbrosone, Christine, B1 aStrom, Sara, S1 aGuo, Xiuqing1 aAndrews, Jeanette, S1 aSun, Yan, V1 aMosley, Thomas, H1 aYanek, Lisa, R1 aShriner, Daniel1 aHaritunians, Talin1 aRotter, Jerome, I1 aSpeliotes, Elizabeth, K1 aSmith, Megan1 aRosenberg, Lynn1 aMychaleckyj, Josyf1 aNayak, Uma1 aSpruill, Ida1 aGarvey, Timothy1 aPettaway, Curtis1 aNyante, Sarah1 aBandera, Elisa, V1 aBritton, Angela, F1 aZonderman, Alan, B1 aRasmussen-Torvik, Laura, J1 aChen, Yii-Der Ida1 aDing, Jingzhong1 aLohman, Kurt1 aKritchevsky, Stephen, B1 aZhao, Wei1 aPeyser, Patricia, A1 aKardia, Sharon, L R1 aKabagambe, Edmond1 aBroeckel, Ulrich1 aChen, Guanjie1 aZhou, Jie1 aWassertheil-Smoller, Sylvia1 aNeuhouser, Marian, L1 aRampersaud, Evadnie1 aPsaty, Bruce1 aKooperberg, Charles1 aManson, JoAnn, E1 aKuller, Lewis, H1 aOchs-Balcom, Heather, M1 aJohnson, Karen, C1 aSucheston, Lara1 aOrdovas, Jose, M1 aPalmer, Julie, R1 aHaiman, Christopher, A1 aMcKnight, Barbara1 aHoward, Barbara, V1 aBecker, Diane, M1 aBielak, Lawrence, F1 aLiu, Yongmei1 aAllison, Matthew, A1 aGrant, Struan, F A1 aBurke, Gregory, L1 aPatel, Sanjay, R1 aSchreiner, Pamela, J1 aBorecki, Ingrid, B1 aEvans, Michele, K1 aTaylor, Herman1 aSale, Michèle, M1 aHoward, Virginia1 aCarlson, Christopher, S1 aRotimi, Charles, N1 aCushman, Mary1 aHarris, Tamara, B1 aReiner, Alexander, P1 aCupples, Adrienne, L1 aNorth, Kari, E1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/628712626nas a2204177 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2013 eng d a1546-171800aGenome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.0 aGenomewide metaanalysis identifies 11 new loci for anthropometri c2013 May a501-120 v453 aApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
10aAnthropometry10aBody Height10aBody Mass Index10aCase-Control Studies10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMeta-Analysis as Topic10aObesity10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aWaist-Hip Ratio1 aBerndt, Sonja, I1 aGustafsson, Stefan1 aMägi, Reedik1 aGanna, Andrea1 aWheeler, Eleanor1 aFeitosa, Mary, F1 aJustice, Anne, E1 aMonda, Keri, L1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aEsko, Tõnu1 aFall, Tove1 aFerreira, Teresa1 aGentilini, Davide1 aJackson, Anne, U1 aLuan, Jian'an1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWiller, Cristen, J1 aWinkler, Thomas, W1 aWood, Andrew, R1 aWorkalemahu, Tsegaselassie1 aHu, Yi-Juan1 aLee, Sang, Hong1 aLiang, Liming1 aLin, Dan-Yu1 aMin, Josine, L1 aNeale, Benjamin, M1 aThorleifsson, Gudmar1 aYang, Jian1 aAlbrecht, Eva1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aCadby, Gemma1 aHeijer, Martin, den1 aEklund, Niina1 aFischer, Krista1 aGoel, Anuj1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aJarick, Ivonne1 aJohansson, Asa1 aJohnson, Toby1 aKanoni, Stavroula1 aKleber, Marcus, E1 aKönig, Inke, R1 aKristiansson, Kati1 aKutalik, Zoltán1 aLamina, Claudia1 aLecoeur, Cécile1 aLi, Guo1 aMangino, Massimo1 aMcArdle, Wendy, L1 aMedina-Gómez, Carolina1 aMüller-Nurasyid, Martina1 aNgwa, Julius, S1 aNolte, Ilja, M1 aPaternoster, Lavinia1 aPechlivanis, Sonali1 aPerola, Markus1 aPeters, Marjolein, J1 aPreuss, Michael1 aRose, Lynda, M1 aShi, Jianxin1 aShungin, Dmitry1 aSmith, Albert, Vernon1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTeumer, Alexander1 aTrip, Mieke, D1 aTyrer, Jonathan1 avan Vliet-Ostaptchouk, Jana, V1 aVandenput, Liesbeth1 aWaite, Lindsay, L1 aZhao, Jing Hua1 aAbsher, Devin1 aAsselbergs, Folkert, W1 aAtalay, Mustafa1 aAttwood, Antony, P1 aBalmforth, Anthony, J1 aBasart, Hanneke1 aBeilby, John1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBruinenberg, Marcel1 aCampbell, Harry1 aChasman, Daniel, I1 aChines, Peter, S1 aCollins, Francis, S1 aConnell, John, M1 aCookson, William, O1 ade Faire, Ulf1 ade Vegt, Femmie1 aDei, Mariano1 aDimitriou, Maria1 aEdkins, Sarah1 aEstrada, Karol1 aEvans, David, M1 aFarrall, Martin1 aFerrario, Marco, M1 aFerrieres, Jean1 aFranke, Lude1 aFrau, Francesca1 aGejman, Pablo, V1 aGrallert, Harald1 aGrönberg, Henrik1 aGudnason, Vilmundur1 aHall, Alistair, S1 aHall, Per1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aHeath, Andrew, C1 aHebebrand, Johannes1 aHomuth, Georg1 aHu, Frank, B1 aHunt, Sarah, E1 aHyppönen, Elina1 aIribarren, Carlos1 aJacobs, Kevin, B1 aJansson, John-Olov1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKee, Frank1 aKhaw, Kay-Tee1 aKivimaki, Mika1 aKoenig, Wolfgang1 aKraja, Aldi, T1 aKumari, Meena1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaitinen, Jaana, H1 aLakka, Timo, A1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLind, Lars1 aLindström, Jaana1 aLiu, Jianjun1 aLiuzzi, Antonio1 aLokki, Marja-Liisa1 aLorentzon, Mattias1 aMadden, Pamela, A1 aMagnusson, Patrik, K1 aManunta, Paolo1 aMarek, Diana1 aMärz, Winfried1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMihailov, Evelin1 aMilani, Lili1 aMontgomery, Grant, W1 aMooser, Vincent1 aMühleisen, Thomas, W1 aMunroe, Patricia, B1 aMusk, Arthur, W1 aNarisu, Narisu1 aNavis, Gerjan1 aNicholson, George1 aNohr, Ellen, A1 aOng, Ken, K1 aOostra, Ben, A1 aPalmer, Colin, N A1 aPalotie, Aarno1 aPeden, John, F1 aPedersen, Nancy1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aProkopenko, Inga1 aPütter, Carolin1 aRadhakrishnan, Aparna1 aRaitakari, Olli1 aRendon, Augusto1 aRivadeneira, Fernando1 aRudan, Igor1 aSaaristo, Timo, E1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSanna, Serena1 aSaramies, Jouko1 aSchipf, Sabine1 aSchreiber, Stefan1 aSchunkert, Heribert1 aShin, So-Youn1 aSignorini, Stefano1 aSinisalo, Juha1 aSkrobek, Boris1 aSoranzo, Nicole1 aStančáková, Alena1 aStark, Klaus1 aStephens, Jonathan, C1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStumvoll, Michael1 aSwift, Amy, J1 aTheodoraki, Eirini, V1 aThorand, Barbara1 aTrégouët, David-Alexandre1 aTremoli, Elena1 avan der Klauw, Melanie, M1 avan Meurs, Joyce, B J1 aVermeulen, Sita, H1 aViikari, Jorma1 aVirtamo, Jarmo1 aVitart, Veronique1 aWaeber, Gérard1 aWang, Zhaoming1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWinkelmann, Bernhard, R1 aWitteman, Jacqueline, C M1 aWolffenbuttel, Bruce, H R1 aWong, Andrew1 aWright, Alan, F1 aZillikens, Carola, M1 aAmouyel, Philippe1 aBoehm, Bernhard, O1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCupples, Adrienne, L1 aCusi, Daniele1 aDedoussis, George, V1 aErdmann, Jeanette1 aEriksson, Johan, G1 aFranks, Paul, W1 aFroguel, Philippe1 aGieger, Christian1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHengstenberg, Christian1 aHicks, Andrew, A1 aHingorani, Aroon1 aHinney, Anke1 aHofman, Albert1 aHovingh, Kees, G1 aHveem, Kristian1 aIllig, Thomas1 aJarvelin, Marjo-Riitta1 aJöckel, Karl-Heinz1 aKeinanen-Kiukaanniemi, Sirkka, M1 aKiemeney, Lambertus, A1 aKuh, Diana1 aLaakso, Markku1 aLehtimäki, Terho1 aLevinson, Douglas, F1 aMartin, Nicholas, G1 aMetspalu, Andres1 aMorris, Andrew, D1 aNieminen, Markku, S1 aNjølstad, Inger1 aOhlsson, Claes1 aOldehinkel, Albertine, J1 aOuwehand, Willem, H1 aPalmer, Lyle, J1 aPenninx, Brenda1 aPower, Chris1 aProvince, Michael, A1 aPsaty, Bruce, M1 aQi, Lu1 aRauramaa, Rainer1 aRidker, Paul, M1 aRipatti, Samuli1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSnieder, Harold1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStefansson, Kari1 aTönjes, Anke1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 aUusitupa, Matti1 aHarst, Pim1 aVollenweider, Peter1 aWallaschofski, Henri1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWichmann, H-Erich1 aWilson, James, F1 aAbecasis, Goncalo, R1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunian, Talin1 aHeid, Iris, M1 aHunter, David1 aKaplan, Robert, C1 aKarpe, Fredrik1 aMoffatt, Miriam, F1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPawitan, Yudi1 aSchadt, Eric, E1 aSchlessinger, David1 aSteinthorsdottir, Valgerdur1 aStrachan, David, P1 aThorsteinsdottir, Unnur1 aDuijn, Cornelia, M1 aVisscher, Peter, M1 aDi Blasio, Anna, Maria1 aHirschhorn, Joel, N1 aLindgren, Cecilia, M1 aMorris, Andrew, P1 aMeyre, David1 aScherag, Andre1 aMcCarthy, Mark, I1 aSpeliotes, Elizabeth, K1 aNorth, Kari, E1 aLoos, Ruth, J F1 aIngelsson, Erik uhttps://chs-nhlbi.org/node/615209008nas a2202809 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2013 eng d a1546-171800aA meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.0 ametaanalysis identifies new loci associated with body mass index c2013 Jun a690-60 v453 aGenome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
10aAfrican Americans10aBody Mass Index10aCase-Control Studies10aGene Frequency10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aObesity10aPolymorphism, Single Nucleotide1 aMonda, Keri, L1 aChen, Gary, K1 aTaylor, Kira, C1 aPalmer, Cameron1 aEdwards, Todd, L1 aLange, Leslie, A1 aC Y Ng, Maggie1 aAdeyemo, Adebowale, A1 aAllison, Matthew, A1 aBielak, Lawrence, F1 aChen, Guanjie1 aGraff, Mariaelisa1 aIrvin, Marguerite, R1 aRhie, Suhn, K1 aLi, Guo1 aLiu, Yongmei1 aLiu, Youfang1 aLu, Yingchang1 aNalls, Michael, A1 aSun, Yan, V1 aWojczynski, Mary, K1 aYanek, Lisa, R1 aAldrich, Melinda, C1 aAdemola, Adeyinka1 aAmos, Christopher, I1 aBandera, Elisa, V1 aBock, Cathryn, H1 aBritton, Angela1 aBroeckel, Ulrich1 aCai, Quiyin1 aCaporaso, Neil, E1 aCarlson, Chris, S1 aCarpten, John1 aCasey, Graham1 aChen, Wei-Min1 aChen, Fang1 aChen, Yii-der, I1 aChiang, Charleston, W K1 aCoetzee, Gerhard, A1 aDemerath, Ellen1 aDeming-Halverson, Sandra, L1 aDriver, Ryan, W1 aDubbert, Patricia1 aFeitosa, Mary, F1 aFeng, Ye1 aFreedman, Barry, I1 aGillanders, Elizabeth, M1 aGottesman, Omri1 aGuo, Xiuqing1 aHaritunians, Talin1 aHarris, Tamara1 aHarris, Curtis, C1 aHennis, Anselm, J M1 aHernandez, Dena, G1 aMcNeill, Lorna, H1 aHoward, Timothy, D1 aHoward, Barbara, V1 aHoward, Virginia, J1 aJohnson, Karen, C1 aKang, Sun, J1 aKeating, Brendan, J1 aKolb, Suzanne1 aKuller, Lewis, H1 aKutlar, Abdullah1 aLangefeld, Carl, D1 aLettre, Guillaume1 aLohman, Kurt1 aLotay, Vaneet1 aLyon, Helen1 aManson, JoAnn, E1 aMaixner, William1 aMeng, Yan, A1 aMonroe, Kristine, R1 aMorhason-Bello, Imran1 aMurphy, Adam, B1 aMychaleckyj, Josyf, C1 aNadukuru, Raj1 aNathanson, Katherine, L1 aNayak, Uma1 aN'diaye, Amidou1 aNemesure, Barbara1 aWu, Suh-Yuh1 aLeske, Cristina1 aNeslund-Dudas, Christine1 aNeuhouser, Marian1 aNyante, Sarah1 aOchs-Balcom, Heather1 aOgunniyi, Adesola1 aOgundiran, Temidayo, O1 aOjengbede, Oladosu1 aOlopade, Olufunmilayo, I1 aPalmer, Julie, R1 aRuiz-Narvaez, Edward, A1 aPalmer, Nicholette, D1 aPress, Michael, F1 aRampersaud, Evandine1 aRasmussen-Torvik, Laura, J1 aRodriguez-Gil, Jorge, L1 aSalako, Babatunde1 aSchadt, Eric, E1 aSchwartz, Ann, G1 aShriner, Daniel, A1 aSiscovick, David1 aSmith, Shad, B1 aWassertheil-Smoller, Sylvia1 aSpeliotes, Elizabeth, K1 aSpitz, Margaret, R1 aSucheston, Lara1 aTaylor, Herman1 aTayo, Bamidele, O1 aTucker, Margaret, A1 aVan Den Berg, David, J1 aEdwards, Digna, R Velez1 aWang, Zhaoming1 aWiencke, John, K1 aWinkler, Thomas, W1 aWitte, John, S1 aWrensch, Margaret1 aWu, Xifeng1 aYang, James, J1 aLevin, Albert, M1 aYoung, Taylor, R1 aZakai, Neil, A1 aCushman, Mary1 aZanetti, Krista, A1 aZhao, Jing Hua1 aZhao, Wei1 aZheng, Yonglan1 aZhou, Jie1 aZiegler, Regina, G1 aZmuda, Joseph, M1 aFernandes, Jyotika, K1 aGilkeson, Gary, S1 aKamen, Diane, L1 aHunt, Kelly, J1 aSpruill, Ida, J1 aAmbrosone, Christine, B1 aAmbs, Stefan1 aArnett, Donna, K1 aAtwood, Larry1 aBecker, Diane, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBorecki, Ingrid, B1 aBottinger, Erwin, P1 aBowden, Donald, W1 aBurke, Gregory1 aChanock, Stephen, J1 aCooper, Richard, S1 aDing, Jingzhong1 aDuggan, David1 aEvans, Michele, K1 aFox, Caroline1 aGarvey, Timothy1 aBradfield, Jonathan, P1 aHakonarson, Hakon1 aGrant, Struan, F A1 aHsing, Ann1 aChu, Lisa1 aHu, Jennifer, J1 aHuo, Dezheng1 aIngles, Sue, A1 aJohn, Esther, M1 aJordan, Joanne, M1 aKabagambe, Edmond, K1 aKardia, Sharon, L R1 aKittles, Rick, A1 aGoodman, Phyllis, J1 aKlein, Eric, A1 aKolonel, Laurence, N1 aLe Marchand, Loïc1 aLiu, Simin1 aMcKnight, Barbara1 aMillikan, Robert, C1 aMosley, Thomas, H1 aPadhukasahasram, Badri1 aWilliams, Keoki1 aPatel, Sanjay, R1 aPeters, Ulrike1 aPettaway, Curtis, A1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aRotimi, Charles, N1 aRybicki, Benjamin, A1 aSale, Michèle, M1 aSchreiner, Pamela, J1 aSignorello, Lisa, B1 aSingleton, Andrew, B1 aStanford, Janet, L1 aStrom, Sara, S1 aThun, Michael, J1 aVitolins, Mara1 aZheng, Wei1 aMoore, Jason, H1 aWilliams, Scott, M1 aKetkar, Shamika1 aZhu, Xiaofeng1 aZonderman, Alan, B1 aKooperberg, Charles1 aPapanicolaou, George, J1 aHenderson, Brian, E1 aReiner, Alex, P1 aHirschhorn, Joel, N1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aNABEC Consortium1 aUKBEC Consortium1 aBioBank Japan Project1 aAGEN Consortium uhttps://chs-nhlbi.org/node/607811004nas a2203505 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2013 eng d a1553-740400aSex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.0 aSexstratified genomewide association studies including 270000 in c2013 Jun ae10035000 v93 aGiven the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
10aAnthropometry10aBody Height10aBody Mass Index10aBody Weight10aBody Weights and Measures10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist Circumference10aWaist-Hip Ratio1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aKutalik, Zoltán1 aBerndt, Sonja, I1 aJackson, Anne, U1 aMonda, Keri, L1 aKilpeläinen, Tuomas, O1 aEsko, Tõnu1 aMägi, Reedik1 aLi, Shengxu1 aWorkalemahu, Tsegaselassie1 aFeitosa, Mary, F1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aFall, Tove1 aFerreira, Teresa1 aGustafsson, Stefan1 aLocke, Adam, E1 aMathieson, Iain1 aScherag, Andre1 aVedantam, Sailaja1 aWood, Andrew, R1 aLiang, Liming1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aDermitzakis, Emmanouil, T1 aDimas, Antigone, S1 aKarpe, Fredrik1 aMin, Josine, L1 aNicholson, George1 aClegg, Deborah, J1 aPerson, Thomas1 aKrohn, Jon, P1 aBauer, Sabrina1 aBuechler, Christa1 aEisinger, Kristina1 aBonnefond, Amélie1 aFroguel, Philippe1 aHottenga, Jouke-Jan1 aProkopenko, Inga1 aWaite, Lindsay, L1 aHarris, Tamara, B1 aSmith, Albert, Vernon1 aShuldiner, Alan, R1 aMcArdle, Wendy, L1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aGrönberg, Henrik1 aChen, Yii-Der Ida1 aLi, Guo1 aBeckmann, Jacques, S1 aJohnson, Toby1 aThorsteinsdottir, Unnur1 aTeder-Laving, Maris1 aKhaw, Kay-Tee1 aWareham, Nicholas, J1 aZhao, Jing Hua1 aAmin, Najaf1 aOostra, Ben, A1 aKraja, Aldi, T1 aProvince, Michael, A1 aCupples, Adrienne, L1 aHeard-Costa, Nancy, L1 aKaprio, Jaakko1 aRipatti, Samuli1 aSurakka, Ida1 aCollins, Francis, S1 aSaramies, Jouko1 aTuomilehto, Jaakko1 aJula, Antti1 aSalomaa, Veikko1 aErdmann, Jeanette1 aHengstenberg, Christian1 aLoley, Christina1 aSchunkert, Heribert1 aLamina, Claudia1 aWichmann, Erich, H1 aAlbrecht, Eva1 aGieger, Christian1 aHicks, Andrew, A1 aJohansson, Asa1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aSpeliotes, Elizabeth, K1 aPenninx, Brenda1 aHartikainen, Anna-Liisa1 aJarvelin, Marjo-Riitta1 aGyllensten, Ulf1 aBoomsma, Dorret, I1 aCampbell, Harry1 aWilson, James, F1 aChanock, Stephen, J1 aFarrall, Martin1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aRivadeneira, Fernando1 aEstrada, Karol1 aUitterlinden, André, G1 aHofman, Albert1 aZillikens, Carola, M1 aHeijer, Martin, den1 aKiemeney, Lambertus, A1 aMaschio, Andrea1 aHall, Per1 aTyrer, Jonathan1 aTeumer, Alexander1 aVölzke, Henry1 aKovacs, Peter1 aTönjes, Anke1 aMangino, Massimo1 aSpector, Tim, D1 aHayward, Caroline1 aRudan, Igor1 aHall, Alistair, S1 aSamani, Nilesh, J1 aAttwood, Antony, Paul1 aSambrook, Jennifer, G1 aHung, Joseph1 aPalmer, Lyle, J1 aLokki, Marja-Liisa1 aSinisalo, Juha1 aBoucher, Gabrielle1 aHuikuri, Heikki1 aLorentzon, Mattias1 aOhlsson, Claes1 aEklund, Niina1 aEriksson, Johan, G1 aBarlassina, Cristina1 aRivolta, Carlo1 aNolte, Ilja, M1 aSnieder, Harold1 avan der Klauw, Melanie, M1 avan Vliet-Ostaptchouk, Jana, V1 aGejman, Pablo, V1 aShi, Jianxin1 aJacobs, Kevin, B1 aWang, Zhaoming1 aBakker, Stephan, J L1 aLeach, Irene, Mateo1 aNavis, Gerjan1 aHarst, Pim1 aMartin, Nicholas, G1 aMedland, Sarah, E1 aMontgomery, Grant, W1 aYang, Jian1 aChasman, Daniel, I1 aRidker, Paul, M1 aRose, Lynda, M1 aLehtimäki, Terho1 aRaitakari, Olli1 aAbsher, Devin1 aIribarren, Carlos1 aBasart, Hanneke1 aHovingh, Kees, G1 aHyppönen, Elina1 aPower, Chris1 aAnderson, Denise1 aBeilby, John, P1 aHui, Jennie1 aJolley, Jennifer1 aSager, Hendrik1 aBornstein, Stefan, R1 aSchwarz, Peter, E H1 aKristiansson, Kati1 aPerola, Markus1 aLindström, Jaana1 aSwift, Amy, J1 aUusitupa, Matti1 aAtalay, Mustafa1 aLakka, Timo, A1 aRauramaa, Rainer1 aBolton, Jennifer, L1 aFowkes, Gerry1 aFraser, Ross, M1 aPrice, Jackie, F1 aFischer, Krista1 aKov, Kaarel, Krjutå1 aMetspalu, Andres1 aMihailov, Evelin1 aLangenberg, Claudia1 aLuan, Jian'an1 aOng, Ken, K1 aChines, Peter, S1 aKeinanen-Kiukaanniemi, Sirkka, M1 aSaaristo, Timo, E1 aEdkins, Sarah1 aFranks, Paul, W1 aHallmans, Göran1 aShungin, Dmitry1 aMorris, Andrew, David1 aPalmer, Colin, N A1 aErbel, Raimund1 aMoebus, Susanne1 aNöthen, Markus, M1 aPechlivanis, Sonali1 aHveem, Kristian1 aNarisu, Narisu1 aHamsten, Anders1 aHumphries, Steve, E1 aStrawbridge, Rona, J1 aTremoli, Elena1 aGrallert, Harald1 aThorand, Barbara1 aIllig, Thomas1 aKoenig, Wolfgang1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aBoehm, Bernhard, O1 aKleber, Marcus, E1 aMärz, Winfried1 aWinkelmann, Bernhard, R1 aKuusisto, Johanna1 aLaakso, Markku1 aArveiler, Dominique1 aCesana, Giancarlo1 aKuulasmaa, Kari1 aVirtamo, Jarmo1 aYarnell, John, W G1 aKuh, Diana1 aWong, Andrew1 aLind, Lars1 ade Faire, Ulf1 aGigante, Bruna1 aMagnusson, Patrik, K E1 aPedersen, Nancy, L1 aDedoussis, George1 aDimitriou, Maria1 aKolovou, Genovefa1 aKanoni, Stavroula1 aStirrups, Kathleen1 aBonnycastle, Lori, L1 aNjølstad, Inger1 aWilsgaard, Tom1 aGanna, Andrea1 aRehnberg, Emil1 aHingorani, Aroon1 aKivimaki, Mika1 aKumari, Meena1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David1 aIngelsson, Erik1 aKaplan, Robert1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aStrachan, David, P1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAbecasis, Goncalo, R1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aQi, Lu1 aLoos, Ruth, J F1 aLindgren, Cecilia, M1 aNorth, Kari, E1 aHeid, Iris, M1 aDIAGRAM Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/602806392nas a2201669 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2014 eng d a1460-208300aFTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.0 aFTO genetic variants dietary intake and body mass index insights c2014 Dec 20 a6961-720 v233 aFTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
10aAdult10aAfrican Americans10aAged10aAlleles10aAsian Continental Ancestry Group10aBody Mass Index10aDietary Carbohydrates10aDietary Fats10aDietary Proteins10aEnergy Intake10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aHumans10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aProteins1 aQi, Qibin1 aKilpeläinen, Tuomas, O1 aDowner, Mary, K1 aTanaka, Toshiko1 aSmith, Caren, E1 aSluijs, Ivonne1 aSonestedt, Emily1 aChu, Audrey, Y1 aRenstrom, Frida1 aLin, Xiaochen1 aÄngquist, Lars, H1 aHuang, Jinyan1 aLiu, Zhonghua1 aLi, Yanping1 aAli, Muhammad, Asif1 aXu, Min1 aAhluwalia, Tarunveer, Singh1 aBoer, Jolanda, M A1 aChen, Peng1 aDaimon, Makoto1 aEriksson, Johan1 aPerola, Markus1 aFriedlander, Yechiel1 aGao, Yu-Tang1 aHeppe, Denise, H M1 aHolloway, John, W1 aHouston, Denise, K1 aKanoni, Stavroula1 aKim, Yu-Mi1 aLaaksonen, Maarit, A1 aJääskeläinen, Tiina1 aLee, Nanette, R1 aLehtimäki, Terho1 aLemaitre, Rozenn, N1 aLu, Wei1 aLuben, Robert, N1 aManichaikul, Ani1 aMännistö, Satu1 aMarques-Vidal, Pedro1 aMonda, Keri, L1 aNgwa, Julius, S1 aPerusse, Louis1 avan Rooij, Frank, J A1 aXiang, Yong-Bing1 aWen, Wanqing1 aWojczynski, Mary, K1 aZhu, Jingwen1 aBorecki, Ingrid, B1 aBouchard, Claude1 aCai, Qiuyin1 aCooper, Cyrus1 aDedoussis, George, V1 aDeloukas, Panos1 aFerrucci, Luigi1 aForouhi, Nita, G1 aHansen, Torben1 aChristiansen, Lene1 aHofman, Albert1 aJohansson, Ingegerd1 aJørgensen, Torben1 aKarasawa, Shigeru1 aKhaw, Kay-Tee1 aKim, Mi-Kyung1 aKristiansson, Kati1 aLi, Huaixing1 aLin, Xu1 aLiu, Yongmei1 aLohman, Kurt, K1 aLong, Jirong1 aMikkilä, Vera1 aMozaffarian, Dariush1 aNorth, Kari1 aPedersen, Oluf1 aRaitakari, Olli1 aRissanen, Harri1 aTuomilehto, Jaakko1 aSchouw, Yvonne, T1 aUitterlinden, André, G1 aZillikens, Carola, M1 aFranco, Oscar, H1 aTai, Shyong1 aShu, Xiao, Ou1 aSiscovick, David, S1 aToft, Ulla1 aVerschuren, W, M Monique1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWitteman, Jacqueline, C M1 aZheng, Wei1 aRidker, Paul, M1 aKang, Jae, H1 aLiang, Liming1 aJensen, Majken, K1 aCurhan, Gary, C1 aPasquale, Louis, R1 aHunter, David, J1 aMohlke, Karen, L1 aUusitupa, Matti1 aCupples, Adrienne, L1 aRankinen, Tuomo1 aOrho-Melander, Marju1 aWang, Tao1 aChasman, Daniel, I1 aFranks, Paul, W1 aSørensen, Thorkild, I A1 aHu, Frank, B1 aLoos, Ruth, J F1 aNettleton, Jennifer, A1 aQi, Lu uhttps://chs-nhlbi.org/node/693805300nas a2201225 4500008004100000022001400041245016600055210006900221260001600290300001300306490000700319520181200326653001402138653001002152653000902162653002202171653002002193653004002213653001102253653003402264653001102298653000902309653001602318653002402334653002002358653001602378100002202394700001502416700002502431700002302456700002102479700002602500700002502526700002102551700001802572700002302590700002402613700002302637700001902660700001602679700001402695700002902709700001802738700002202756700001402778700002002792700002302812700001802835700002402853700002302877700001902900700003102919700002702950700002602977700001803003700001603021700002003037700002203057700001803079700001603097700001903113700002103132700002103153700002903174700002003203700002103223700002403244700002203268700001503290700002203305700002303327700001803350700002203368700002003390700002103410700002403431700002203455700001903477700002503496700002103521700002103542700002503563700001903588700002103607700002203628700002403650700002203674700001903696700002303715700002103738700002003759700001703779700002203796700002103818700002303839700002103862700001903883700002003902700002103922700002003943710003003963710002103993710002404014856003604038 2014 eng d a1460-208300aGene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations.0 aGenecentric metaanalyses for central adiposity traits in up to 5 c2014 May 01 a2498-5100 v233 aWaist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
10aAdiposity10aAdult10aAged10aAged, 80 and over10aBody Mass Index10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aWaist Circumference10aWaist-Hip Ratio10aYoung Adult1 aYoneyama, Sachiko1 aGuo, Yiran1 aLanktree, Matthew, B1 aBarnes, Michael, R1 aElbers, Clara, C1 aKarczewski, Konrad, J1 aPadmanabhan, Sandosh1 aBauer, Florianne1 aBaumert, Jens1 aBeitelshees, Amber1 aBerenson, Gerald, S1 aBoer, Jolanda, M A1 aBurke, Gregory1 aCade, Brian1 aChen, Wei1 aCooper-Dehoff, Rhonda, M1 aGaunt, Tom, R1 aGieger, Christian1 aGong, Yan1 aGorski, Mathias1 aHeard-Costa, Nancy1 aJohnson, Toby1 aLamonte, Michael, J1 aMcDonough, Caitrin1 aMonda, Keri, L1 aOnland-Moret, Charlotte, N1 aNelson, Christopher, P1 aO'Connell, Jeffrey, R1 aOrdovas, Jose1 aPeter, Inga1 aPeters, Annette1 aShaffer, Jonathan1 aShen, Haiqinq1 aSmith, Erin1 aSpeilotes, Liz1 aThomas, Fridtjof1 aThorand, Barbara1 aVerschuren, W, M Monique1 aAnand, Sonia, S1 aDominiczak, Anna1 aDavidson, Karina, W1 aHegele, Robert, A1 aHeid, Iris1 aHofker, Marten, H1 aHuggins, Gordon, S1 aIllig, Thomas1 aJohnson, Julie, A1 aKirkland, Susan1 aKönig, Wolfgang1 aLangaee, Taimour, Y1 aMcCaffery, Jeanne1 aMelander, Olle1 aMitchell, Braxton, D1 aMunroe, Patricia1 aMurray, Sarah, S1 aPapanicolaou, George1 aRedline, Susan1 aReilly, Muredach1 aSamani, Nilesh, J1 aSchork, Nicholas, J1 aSchouw, Yvonne, T1 aShimbo, Daichi1 aShuldiner, Alan, R1 aTobin, Martin, D1 aWijmenga, Cisca1 aYusuf, Salim1 aHakonarson, Hakon1 aLange, Leslie, A1 aDemerath, Ellen, W1 aFox, Caroline, S1 aNorth, Kari, E1 aReiner, Alex, P1 aKeating, Brendan1 aTaylor, Kira, C1 aLook AHEAD Research Group1 aGIANT Consortium1 aCARe IBC Consortium uhttps://chs-nhlbi.org/node/636810963nas a2203529 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2016 eng d a2041-172300aA principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.0 aprincipal component metaanalysis on multiple anthropometric trai c2016 11 23 a133570 v73 aLarge consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
10aAnthropometry10aBody Size10aGenome-Wide Association Study10aGenotype10aHumans10aModels, Genetic10aPrincipal Component Analysis1 aRied, Janina, S1 aM, Janina, Jeff1 aChu, Audrey, Y1 aBragg-Gresham, Jennifer, L1 avan Dongen, Jenny1 aHuffman, Jennifer, E1 aAhluwalia, Tarunveer, S1 aCadby, Gemma1 aEklund, Niina1 aEriksson, Joel1 aEsko, Tõnu1 aFeitosa, Mary, F1 aGoel, Anuj1 aGorski, Mathias1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aJackson, Anne, U1 aJokinen, Eero1 aKanoni, Stavroula1 aKristiansson, Kati1 aKutalik, Zoltán1 aLahti, Jari1 aLuan, Jian'an1 aMägi, Reedik1 aMahajan, Anubha1 aMangino, Massimo1 aMedina-Gómez, Carolina1 aMonda, Keri, L1 aNolte, Ilja, M1 aPerusse, Louis1 aProkopenko, Inga1 aQi, Lu1 aRose, Lynda, M1 aSalvi, Erika1 aSmith, Megan, T1 aSnieder, Harold1 aStančáková, Alena1 aSung, Yun, Ju1 aTachmazidou, Ioanna1 aTeumer, Alexander1 aThorleifsson, Gudmar1 aHarst, Pim1 aWalker, Ryan, W1 aWang, Sophie, R1 aWild, Sarah, H1 aWillems, Sara, M1 aWong, Andrew1 aZhang, Weihua1 aAlbrecht, Eva1 aAlves, Alexessander, Couto1 aBakker, Stephan, J L1 aBarlassina, Cristina1 aBartz, Traci, M1 aBeilby, John1 aBellis, Claire1 aBergman, Richard, N1 aBergmann, Sven1 aBlangero, John1 aBlüher, Matthias1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBruinenberg, Marcel1 aCampbell, Harry1 aChen, Yii-Der Ida1 aChiang, Charleston, W K1 aChines, Peter, S1 aCollins, Francis, S1 aCucca, Fracensco1 aCupples, Adrienne, L1 aD'Avila, Francesca1 aGeus, Eco, J C1 aDedoussis, George1 aDimitriou, Maria1 aDöring, Angela1 aEriksson, Johan, G1 aFarmaki, Aliki-Eleni1 aFarrall, Martin1 aFerreira, Teresa1 aFischer, Krista1 aForouhi, Nita, G1 aFriedrich, Nele1 aGjesing, Anette, Prior1 aGlorioso, Nicola1 aGraff, Mariaelisa1 aGrallert, Harald1 aGrarup, Niels1 aGräßler, Jürgen1 aGrewal, Jagvir1 aHamsten, Anders1 aHarder, Marie, Neergaard1 aHartman, Catharina, A1 aHassinen, Maija1 aHastie, Nicholas1 aHattersley, Andrew, Tym1 aHavulinna, Aki, S1 aHeliövaara, Markku1 aHillege, Hans1 aHofman, Albert1 aHolmen, Oddgeir1 aHomuth, Georg1 aHottenga, Jouke-Jan1 aHui, Jennie1 aHusemoen, Lise, Lotte1 aHysi, Pirro, G1 aIsaacs, Aaron1 aIttermann, Till1 aJalilzadeh, Shapour1 aJames, Alan, L1 aJørgensen, Torben1 aJousilahti, Pekka1 aJula, Antti1 aJustesen, Johanne, Marie1 aJustice, Anne, E1 aKähönen, Mika1 aKaraleftheri, Maria1 aKhaw, Kay, Tee1 aKeinanen-Kiukaanniemi, Sirkka, M1 aKinnunen, Leena1 aKnekt, Paul, B1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooner, Ishminder, K1 aKoskinen, Seppo1 aKovacs, Peter1 aKyriakou, Theodosios1 aLaitinen, Tomi1 aLangenberg, Claudia1 aLewin, Alexandra, M1 aLichtner, Peter1 aLindgren, Cecilia, M1 aLindström, Jaana1 aLinneberg, Allan1 aLorbeer, Roberto1 aLorentzon, Mattias1 aLuben, Robert1 aLyssenko, Valeriya1 aMännistö, Satu1 aManunta, Paolo1 aLeach, Irene, Mateo1 aMcArdle, Wendy, L1 aMcKnight, Barbara1 aMohlke, Karen, L1 aMihailov, Evelin1 aMilani, Lili1 aMills, Rebecca1 aMontasser, May, E1 aMorris, Andrew, P1 aMüller, Gabriele1 aMusk, Arthur, W1 aNarisu, Narisu1 aOng, Ken, K1 aOostra, Ben, A1 aOsmond, Clive1 aPalotie, Aarno1 aPankow, James, S1 aPaternoster, Lavinia1 aPenninx, Brenda, W1 aPichler, Irene1 aPilia, Maria, G1 aPolasek, Ozren1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRankinen, Tuomo1 aRao, D, C1 aRayner, Nigel, W1 aRibel-Madsen, Rasmus1 aRice, Treva, K1 aRichards, Marcus1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRyan, Kathy, A1 aSanna, Serena1 aSarzynski, Mark, A1 aScholtens, Salome1 aScott, Robert, A1 aSebert, Sylvain1 aSoutham, Lorraine1 aSparsø, Thomas, Hempel1 aSteinthorsdottir, Valgerdur1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStrauch, Konstantin1 aStringham, Heather, M1 aSwertz, Morris, A1 aSwift, Amy, J1 aTönjes, Anke1 aTsafantakis, Emmanouil1 avan der Most, Peter, J1 avan Vliet-Ostaptchouk, Jana, V1 aVandenput, Liesbeth1 aVartiainen, Erkki1 aVenturini, Cristina1 aVerweij, Niek1 aViikari, Jorma, S1 aVitart, Veronique1 aVohl, Marie-Claude1 aVonk, Judith, M1 aWaeber, Gérard1 aWiden, Elisabeth1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWinkler, Thomas, W1 aWright, Alan, F1 aYerges-Armstrong, Laura, M1 aZhao, Jing, Hua1 aZillikens, Carola, M1 aBoomsma, Dorret, I1 aBouchard, Claude1 aChambers, John, C1 aChasman, Daniel, I1 aCusi, Daniele1 aGansevoort, Ron, T1 aGieger, Christian1 aHansen, Torben1 aHicks, Andrew, A1 aHu, Frank1 aHveem, Kristian1 aJarvelin, Marjo-Riitta1 aKajantie, Eero1 aKooner, Jaspal, S1 aKuh, Diana1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo, A1 aLehtimäki, Terho1 aMetspalu, Andres1 aNjølstad, Inger1 aOhlsson, Claes1 aOldehinkel, Albertine, J1 aPalmer, Lyle, J1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPsaty, Bruce, M1 aPuolijoki, Hannu1 aRauramaa, Rainer1 aRudan, Igor1 aSalomaa, Veikko1 aSchwarz, Peter, E H1 aShudiner, Alan, R1 aSmit, Jan, H1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStefansson, Kari1 aStumvoll, Michael1 aTremblay, Angelo1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 aUusitupa, Matti1 aVölker, Uwe1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWilson, James, F1 aZeggini, Eleftheria1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aDuijn, Cornelia, M1 aFox, Caroline1 aGroop, Leif, C1 aHeid, Iris, M1 aHunter, David, J1 aKaplan, Robert, C1 aMcCarthy, Mark, I1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aThorsteinsdottir, Unnur1 aStrachan, David, P1 aFrayling, Timothy1 aHirschhorn, Joel, N1 aMüller-Nurasyid, Martina1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/857009591nas a2202833 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2021 eng d a1537-660500aDiscovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.0 aDiscovery and finemapping of height loci via highdensity imputat c2021 Apr 01 a564-5820 v1083 aAlthough many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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