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/123405042nas a2201093 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2010 eng d a1935-554800aInteractions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.0 aInteractions of dietary wholegrain intake with fasting glucose a c2010 Dec a2684-910 v333 aOBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.
RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.
RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.
CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
10aAdult10aAged10aBlood Glucose10aEdible Grain10aEuropean Continental Ancestry Group10aFasting10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aNettleton, Jennifer, A1 aMcKeown, Nicola, M1 aKanoni, Stavroula1 aLemaitre, Rozenn, N1 aHivert, Marie-France1 aNgwa, Julius1 avan Rooij, Frank, J A1 aSonestedt, Emily1 aWojczynski, Mary, K1 aYe, Zheng1 aTanaka, Tosh1 aGarcia, Melissa1 aAnderson, Jennifer, S1 aFollis, Jack, L1 aDjoussé, Luc1 aMukamal, Kenneth1 aPapoutsakis, Constantina1 aMozaffarian, Dariush1 aZillikens, Carola, M1 aBandinelli, Stefania1 aBennett, Amanda, J1 aBorecki, Ingrid, B1 aFeitosa, Mary, F1 aFerrucci, Luigi1 aForouhi, Nita, G1 aGroves, Christopher, J1 aHallmans, Göran1 aHarris, Tamara1 aHofman, Albert1 aHouston, Denise, K1 aHu, Frank, B1 aJohansson, Ingegerd1 aKritchevsky, Stephen, B1 aLangenberg, Claudia1 aLauner, Lenore1 aLiu, Yongmei1 aLoos, Ruth, J1 aNalls, Michael1 aOrho-Melander, Marju1 aRenstrom, Frida1 aRice, Kenneth1 aRiserus, Ulf1 aRolandsson, Olov1 aRotter, Jerome, I1 aSaylor, Georgia1 aSijbrands, Eric, J G1 aSjogren, Per1 aSmith, Albert1 aSteingrímsdóttir, Laufey1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aProkopenko, Inga1 aPankow, James, S1 aDuijn, Cornelia, M1 aFlorez, Jose, C1 aWitteman, Jacqueline, C M1 aDupuis, Josée1 aDedoussis, George, V1 aOrdovas, Jose, M1 aIngelsson, Erik1 aCupples, Adrienne, L1 aSiscovick, David, S1 aFranks, Paul, W1 aMeigs, James, B1 aMAGIC investigators uhttps://chs-nhlbi.org/node/122211930nas 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/123612636nas a2204069 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2010 eng d a1546-171800aNew genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.0 aNew genetic loci implicated in fasting glucose homeostasis and t c2010 Feb a105-160 v423 aLevels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
10aAdolescent10aAdult10aAlleles10aBlood Glucose10aChild10aDatabases, Genetic10aDiabetes Mellitus, Type 210aDNA Copy Number Variations10aFasting10aGene Expression Regulation10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHomeostasis10aHumans10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aReproducibility of Results1 aDupuis, Josée1 aLangenberg, Claudia1 aProkopenko, Inga1 aSaxena, Richa1 aSoranzo, Nicole1 aJackson, Anne, U1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aGloyn, Anna, L1 aLindgren, Cecilia, M1 aMägi, Reedik1 aMorris, Andrew, P1 aRandall, Joshua1 aJohnson, Toby1 aElliott, Paul1 aRybin, Denis1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aHenneman, Peter1 aGrallert, Harald1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aFranklin, Christopher, S1 aNavarro, Pau1 aSong, Kijoung1 aGoel, Anuj1 aPerry, John, R B1 aEgan, Josephine, M1 aLajunen, Taina1 aGrarup, Niels1 aSparsø, Thomas1 aDoney, Alex1 aVoight, Benjamin, F1 aStringham, Heather, M1 aLi, Man1 aKanoni, Stavroula1 aShrader, Peter1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aQi, Lu1 aTimpson, Nicholas, J1 aGieger, Christian1 aZabena, Carina1 aRocheleau, Ghislain1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aPayne, Felicity1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aArdlie, Kristin1 aAriyurek, Yavuz1 aBalkau, Beverley1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBonnefond, Amélie1 aBonnycastle, Lori, L1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aCharpentier, Guillaume1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCornelis, Marilyn1 aCrawford, Gabe1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, Eco, J C1 aDelplanque, Jerome1 aDina, Christian1 aErdos, Michael, R1 aFedson, Annette, C1 aFischer-Rosinsky, Antje1 aForouhi, Nita, G1 aFox, Caroline, S1 aFrants, Rune1 aFranzosi, Maria Grazia1 aGalan, Pilar1 aGoodarzi, Mark, O1 aGraessler, Jürgen1 aGroves, Christopher, J1 aGrundy, Scott1 aGwilliam, Rhian1 aGyllensten, Ulf1 aHadjadj, Samy1 aHallmans, Göran1 aHammond, Naomi1 aHan, Xijing1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHayward, Caroline1 aHeath, Simon, C1 aHercberg, Serge1 aHerder, Christian1 aHicks, Andrew, A1 aHillman, David, R1 aHingorani, Aroon, D1 aHofman, Albert1 aHui, Jennie1 aHung, Joe1 aIsomaa, Bo1 aJohnson, Paul, R V1 aJørgensen, Torben1 aJula, Antti1 aKaakinen, Marika1 aKaprio, Jaakko1 aKesaniemi, Antero, Y1 aKivimaki, Mika1 aKnight, Beatrice1 aKoskinen, Seppo1 aKovacs, Peter1 aKyvik, Kirsten Ohm1 aLathrop, Mark, G1 aLawlor, Debbie, A1 aLe Bacquer, Olivier1 aLecoeur, Cécile1 aLi, Yun1 aLyssenko, Valeriya1 aMahley, Robert1 aMangino, Massimo1 aManning, Alisa, K1 aMartínez-Larrad, María Teresa1 aMcAteer, Jarred, B1 aMcCulloch, Laura, J1 aMcPherson, Ruth1 aMeisinger, Christa1 aMelzer, David1 aMeyre, David1 aMitchell, Braxton, D1 aMorken, Mario, A1 aMukherjee, Sutapa1 aNaitza, Silvia1 aNarisu, Narisu1 aNeville, Matthew, J1 aOostra, Ben, A1 aOrrù, Marco1 aPakyz, Ruth1 aPalmer, Colin, N A1 aPaolisso, Giuseppe1 aPattaro, Cristian1 aPearson, Daniel1 aPeden, John, F1 aPedersen, Nancy, L1 aPerola, Markus1 aPfeiffer, Andreas, F H1 aPichler, Irene1 aPolasek, Ozren1 aPosthuma, Danielle1 aPotter, Simon, C1 aPouta, Anneli1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRathmann, Wolfgang1 aRayner, Nigel, W1 aRice, Kenneth1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRoden, Michael1 aRolandsson, Olov1 aSandbaek, Annelli1 aSandhu, Manjinder1 aSanna, Serena1 aSayer, Avan Aihie1 aScheet, Paul1 aScott, Laura, J1 aSeedorf, Udo1 aSharp, Stephen, J1 aShields, Beverley1 aSigurethsson, Gunnar1 aSijbrands, Eric, J G1 aSilveira, Angela1 aSimpson, Laila1 aSingleton, Andrew1 aSmith, Nicholas, L1 aSovio, Ulla1 aSwift, Amy1 aSyddall, Holly1 aSyvänen, Ann-Christine1 aTanaka, Toshiko1 aThorand, Barbara1 aTichet, Jean1 aTönjes, Anke1 aTuomi, Tiinamaija1 aUitterlinden, André, G1 aDijk, Ko Willems1 aHoek, Mandy1 aVarma, Dhiraj1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogelzangs, Nicole1 aWaeber, Gérard1 aWagner, Peter, J1 aWalley, Andrew1 aWalters, Bragi, G1 aWard, Kim, L1 aWatkins, Hugh1 aWeedon, Michael, N1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitteman, Jaqueline, C M1 aYarnell, John, W G1 aZeggini, Eleftheria1 aZelenika, Diana1 aZethelius, Björn1 aZhai, Guangju1 aZhao, Jing Hua1 aZillikens, Carola, M1 aBorecki, Ingrid, B1 aLoos, Ruth, J F1 aMeneton, Pierre1 aMagnusson, Patrik, K E1 aNathan, David, M1 aWilliams, Gordon, H1 aHattersley, Andrew, T1 aSilander, Kaisa1 aSalomaa, Veikko1 aSmith, George Davey1 aBornstein, Stefan, R1 aSchwarz, Peter1 aSpranger, Joachim1 aKarpe, Fredrik1 aShuldiner, Alan, R1 aCooper, Cyrus1 aDedoussis, George, V1 aSerrano-Ríos, Manuel1 aMorris, Andrew, D1 aLind, Lars1 aPalmer, Lyle, J1 aHu, Frank, B1 aFranks, Paul, W1 aEbrahim, Shah1 aMarmot, Michael1 aKao, Linda, W H1 aPankow, James, S1 aSampson, Michael, J1 aKuusisto, Johanna1 aLaakso, Markku1 aHansen, Torben1 aPedersen, Oluf1 aPramstaller, Peter Paul1 aWichmann, Erich, H1 aIllig, Thomas1 aRudan, Igor1 aWright, Alan, F1 aStumvoll, Michael1 aCampbell, Harry1 aWilson, James, F1 aBergman, Richard, N1 aBuchanan, Thomas, A1 aCollins, Francis, S1 aMohlke, Karen, L1 aTuomilehto, Jaakko1 aValle, Timo, T1 aAltshuler, David1 aRotter, Jerome, I1 aSiscovick, David, S1 aPenninx, Brenda, W J H1 aBoomsma, Dorret, I1 aDeloukas, Panos1 aSpector, Timothy, D1 aFrayling, Timothy, M1 aFerrucci, Luigi1 aKong, Augustine1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAulchenko, Yurii, S1 aCao, Antonio1 aScuteri, Angelo1 aSchlessinger, David1 aUda, Manuela1 aRuokonen, Aimo1 aJarvelin, Marjo-Riitta1 aWaterworth, Dawn, M1 aVollenweider, Peter1 aPeltonen, Leena1 aMooser, Vincent1 aAbecasis, Goncalo, R1 aWareham, Nicholas, J1 aSladek, Robert1 aFroguel, Philippe1 aWatanabe, Richard, M1 aMeigs, James, B1 aGroop, Leif1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aFlorez, Jose, C1 aBarroso, Inês1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal BPgen Consortium1 aAnders Hamsten on behalf of Procardis Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/116006326nas a2201873 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2010 eng d a1546-171800aNew loci associated with kidney function and chronic kidney disease.0 aNew loci associated with kidney function and chronic kidney dise c2010 May a376-840 v423 aChronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
10aCohort Studies10aCreatinine10aCystatin C10aDiet10aEurope10aGenetic Markers10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aModels, Genetic10aRisk Factors1 aKöttgen, Anna1 aPattaro, Cristian1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aGlazer, Nicole, L1 aParsa, Afshin1 aGao, Xiaoyi1 aYang, Qiong1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aLi, Man1 aSchmidt, Helena1 aTanaka, Toshiko1 aIsaacs, Aaron1 aKetkar, Shamika1 aHwang, Shih-Jen1 aJohnson, Andrew, D1 aDehghan, Abbas1 aTeumer, Alexander1 aParé, Guillaume1 aAtkinson, Elizabeth, J1 aZeller, Tanja1 aLohman, Kurt1 aCornelis, Marilyn, C1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aTönjes, Anke1 aHayward, Caroline1 aAspelund, Thor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aRampersaud, Evadnie1 aMitchell, Braxton, D1 aArking, Dan, E1 aBoerwinkle, Eric1 aStruchalin, Maksim1 aCavalieri, Margherita1 aSingleton, Andrew1 aGiallauria, Francesco1 aMetter, Jeffrey1 ade Boer, Ian, H1 aHaritunians, Talin1 aLumley, Thomas1 aSiscovick, David1 aPsaty, Bruce, M1 aZillikens, Carola, M1 aOostra, Ben, A1 aFeitosa, Mary1 aProvince, Michael1 ade Andrade, Mariza1 aTurner, Stephen, T1 aSchillert, Arne1 aZiegler, Andreas1 aWild, Philipp, S1 aSchnabel, Renate, B1 aWilde, Sandra1 aMunzel, Thomas, F1 aLeak, Tennille, S1 aIllig, Thomas1 aKlopp, Norman1 aMeisinger, Christa1 aWichmann, H-Erich1 aKoenig, Wolfgang1 aZgaga, Lina1 aZemunik, Tatijana1 aKolcic, Ivana1 aMinelli, Cosetta1 aHu, Frank, B1 aJohansson, Asa1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aSchreiber, Stefan1 aAulchenko, Yurii, S1 aFelix, Janine, F1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aImboden, Medea1 aNitsch, Dorothea1 aBrandstätter, Anita1 aKollerits, Barbara1 aKedenko, Lyudmyla1 aMägi, Reedik1 aStumvoll, Michael1 aKovacs, Peter1 aBoban, Mladen1 aCampbell, Susan1 aEndlich, Karlhans1 aVölzke, Henry1 aKroemer, Heyo, K1 aNauck, Matthias1 aVölker, Uwe1 aPolasek, Ozren1 aVitart, Veronique1 aBadola, Sunita1 aParker, Alexander, N1 aRidker, Paul, M1 aKardia, Sharon, L R1 aBlankenberg, Stefan1 aLiu, Yongmei1 aCurhan, Gary, C1 aFranke, Andre1 aRochat, Thierry1 aPaulweber, Bernhard1 aProkopenko, Inga1 aWang, Wei1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aShlipak, Michael, G1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKrämer, Bernhard, K1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aWitteman, Jacqueline, C1 aPramstaller, Peter, P1 aRettig, Rainer1 aHastie, Nick1 aChasman, Daniel, I1 aKao, W H1 aHeid, Iris, M1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/118306039nas a2201765 4500008004100000022001400041245010100055210006900156260001600225300001100241490000700252520104700259653001601306653001401322653001201336653002601348653002001374653001601394653001101410653002201421653003401443653001101477653004001488653005001528653000901578653002201587653002701609653001501636653001201651653003601663653002101699100002801720700002501748700002501773700002501798700002001823700002401843700001801867700002501885700001801910700002401928700002601952700001701978700002601995700001902021700001602040700002202056700001802078700002302096700001202119700002102131700001802152700002702170700001902197700002102216700002202237700001302259700002102272700002402293700001902317700002002336700002502356700002202381700002002403700002402423700001902447700003502466700002002501700002202521700002202543700002202565700001902587700002402606700001502630700002202645700001602667700001902683700002402702700001802726700001902744700001902763700001802782700002102800700002202821700001702843700002102860700002302881700002102904700002202925700002002947700002502967700002002992700002503012700002103037700002603058700001803084700002003102700001803122700001903140700002003159700002003179700002103199700002203220700002603242700002303268700002103291700002403312700002803336700002403364700002503388700002803413700002803441700002303469700002403492700001903516700002003535700002203555700001703577700002103594700001603615700002003631700002303651700002303674700002003697700002303717700002203740700002403762700002203786700001603808700002103824700002603845700001703871700001903888700002403907700002003931700002203951700002203973700002003995700002404015700002104039700002204060700001904082700002304101700002504124700002804149700002104177700001904198700002004217856003604237 2011 eng d a1546-171800aGenetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.0 aGenetic variation near IRS1 associates with reduced adiposity an c2011 Jun 26 a753-600 v433 aGenome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
10aAdiponectin10aAdiposity10aAlleles10aBody Fat Distribution10aBody Mass Index10aBody Weight10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aInsulin Receptor Substrate Proteins10aIntracellular Signaling Peptides and Proteins10aMale10aMembrane Proteins10aMeta-Analysis as Topic10aMetabolome10aObesity10aPolymorphism, Single Nucleotide10aSubcutaneous Fat1 aKilpeläinen, Tuomas, O1 aZillikens, Carola, M1 aStančáková, Alena1 aFinucane, Francis, M1 aRied, Janina, S1 aLangenberg, Claudia1 aZhang, Weihua1 aBeckmann, Jacques, S1 aLuan, Jian'an1 aVandenput, Liesbeth1 aStyrkarsdottir, Unnur1 aZhou, Yanhua1 aSmith, Albert, Vernon1 aZhao, Jing-Hua1 aAmin, Najaf1 aVedantam, Sailaja1 aShin, So-Youn1 aHaritunians, Talin1 aFu, Mao1 aFeitosa, Mary, F1 aKumari, Meena1 aHalldorsson, Bjarni, V1 aTikkanen, Emmi1 aMangino, Massimo1 aHayward, Caroline1 aSong, Ci1 aArnold, Alice, M1 aAulchenko, Yurii, S1 aOostra, Ben, A1 aCampbell, Harry1 aCupples, Adrienne, L1 aDavis, Kathryn, E1 aDöring, Angela1 aEiriksdottir, Gudny1 aEstrada, Karol1 aFernández-Real, José, Manuel1 aGarcia, Melissa1 aGieger, Christian1 aGlazer, Nicole, L1 aGuiducci, Candace1 aHofman, Albert1 aHumphries, Steve, E1 aIsomaa, Bo1 aJacobs, Leonie, C1 aJula, Antti1 aKarasik, David1 aKarlsson, Magnus, K1 aKhaw, Kay-Tee1 aKim, Lauren, J1 aKivimaki, Mika1 aKlopp, Norman1 aKuhnel, Brigitte1 aKuusisto, Johanna1 aLiu, Yongmei1 aLjunggren, Osten1 aLorentzon, Mattias1 aLuben, Robert, N1 aMcKnight, Barbara1 aMellström, Dan1 aMitchell, Braxton, D1 aMooser, Vincent1 aMoreno, José, Maria1 aMännistö, Satu1 aO'Connell, Jeffery, R1 aPascoe, Laura1 aPeltonen, Leena1 aPeral, Belén1 aPerola, Markus1 aPsaty, Bruce, M1 aSalomaa, Veikko1 aSavage, David, B1 aSemple, Robert, K1 aSkaric-Juric, Tatjana1 aSigurdsson, Gunnar1 aSong, Kijoung, S1 aSpector, Timothy, D1 aSyvänen, Ann-Christine1 aTalmud, Philippa, J1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVidal-Puig, Antonio1 aWild, Sarah, H1 aWright, Alan, F1 aClegg, Deborah, J1 aSchadt, Eric1 aWilson, James, F1 aRudan, Igor1 aRipatti, Samuli1 aBorecki, Ingrid, B1 aShuldiner, Alan, R1 aIngelsson, Erik1 aJansson, John-Olov1 aKaplan, Robert, C1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aGroop, Leif1 aKiel, Douglas, P1 aRivadeneira, Fernando1 aWalker, Mark1 aBarroso, Inês1 aVollenweider, Peter1 aWaeber, Gérard1 aChambers, John, C1 aKooner, Jaspal, S1 aSoranzo, Nicole1 aHirschhorn, Joel, N1 aStefansson, Kari1 aWichmann, H-Erich1 aOhlsson, Claes1 aO'Rahilly, Stephen1 aWareham, Nicholas, J1 aSpeliotes, Elizabeth, K1 aFox, Caroline, S1 aLaakso, Markku1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/130103421nas a2200829 4500008004100000022001400041245004600055210004200101260001300143300001600156490000700172520116200179653001001341653003801351653003401389653001301423653001101436653001401447100001901461700001601480700002301496700002301519700002201542700001801564700002401582700002101606700002001627700002301647700001701670700001201687700001801699700002401717700001901741700002101760700002101781700001801802700002401820700002001844700002201864700002301886700001901909700001901928700002101947700001901968700002001987700002202007700002002029700002202049700002202071700002302093700002002116700002002136700002202156700002002178700002602198700002102224700002002245700002002265700002502285700002502310700002902335700002202364700002002386700002402406700001902430700001702449700002402466700002002490700002202510700002302532856003602555 2011 eng d a1558-149700aA genome-wide association study of aging.0 agenomewide association study of aging c2011 Nov a2109.e15-280 v323 aHuman longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.
10aAging10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLongevity1 aWalter, Stefan1 aAtzmon, Gil1 aDemerath, Ellen, W1 aGarcia, Melissa, E1 aKaplan, Robert, C1 aKumari, Meena1 aLunetta, Kathryn, L1 aMilaneschi, Yuri1 aTanaka, Toshiko1 aTranah, Gregory, J1 aVölker, Uwe1 aYu, Lei1 aArnold, Alice1 aBenjamin, Emelia, J1 aBiffar, Reiner1 aBuchman, Aron, S1 aBoerwinkle, Eric1 aCouper, David1 aDe Jager, Philip, L1 aEvans, Denis, A1 aHarris, Tamara, B1 aHoffmann, Wolfgang1 aHofman, Albert1 aKarasik, David1 aKiel, Douglas, P1 aKocher, Thomas1 aKuningas, Maris1 aLauner, Lenore, J1 aLohman, Kurt, K1 aLutsey, Pamela, L1 aMackenbach, Johan1 aMarciante, Kristin1 aPsaty, Bruce, M1 aReiman, Eric, M1 aRotter, Jerome, I1 aSeshadri, Sudha1 aShardell, Michelle, D1 aSmith, Albert, V1 aDuijn, Cornelia1 aWalston, Jeremy1 aZillikens, Carola, M1 aBandinelli, Stefania1 aBaumeister, Sebastian, E1 aBennett, David, A1 aFerrucci, Luigi1 aGudnason, Vilmundur1 aKivimaki, Mika1 aLiu, Yongmei1 aMurabito, Joanne, M1 aNewman, Anne, B1 aTiemeier, Henning1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/130704525nas a2200901 4500008004100000022001400041245012800055210006900183260001300252300001200265490000700277520189900284653001802183653003002201653001902231653001102250653003602261653000902297653002302306100002202329700002702351700002502378700001402403700002602417700002002443700002102463700002002484700002402504700002402528700002302552700002602575700002002601700001802621700002002639700002002659700002302679700002302702700002002725700002102745700001902766700002202785700002302807700001702830700002102847700002402868700001502892700001702907700002002924700001802944700002102962700002502983700002803008700002803036700002203064700002503086700002103111700002103132700002503153700002103178700002503199700001803224700002103242700001903263700002403282700002003306700002803326700002203354700002003376700002303396700003003419700002503449700002403474700002003498700002003518700002503538710002403563856003603587 2011 eng d a1939-327X00aTotal zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.0 aTotal zinc intake may modify the glucoseraising effect of a zinc c2011 Sep a2407-160 v603 aOBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.
RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.
RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.
CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.
10aBlood Glucose10aCation Transport Proteins10aCohort Studies10aHumans10aPolymorphism, Single Nucleotide10aZinc10aZinc Transporter 81 aKanoni, Stavroula1 aNettleton, Jennifer, A1 aHivert, Marie-France1 aYe, Zheng1 avan Rooij, Frank, J A1 aShungin, Dmitry1 aSonestedt, Emily1 aNgwa, Julius, S1 aWojczynski, Mary, K1 aLemaitre, Rozenn, N1 aGustafsson, Stefan1 aAnderson, Jennifer, S1 aTanaka, Toshiko1 aHindy, George1 aSaylor, Georgia1 aRenstrom, Frida1 aBennett, Amanda, J1 aDuijn, Cornelia, M1 aFlorez, Jose, C1 aFox, Caroline, S1 aHofman, Albert1 aHoogeveen, Ron, C1 aHouston, Denise, K1 aHu, Frank, B1 aJacques, Paul, F1 aJohansson, Ingegerd1 aLind, Lars1 aLiu, Yongmei1 aMcKeown, Nicola1 aOrdovas, Jose1 aPankow, James, S1 aSijbrands, Eric, J G1 aSyvänen, Ann-Christine1 aUitterlinden, André, G1 aYannakoulia, Mary1 aZillikens, Carola, M1 aWareham, Nick, J1 aProkopenko, Inga1 aBandinelli, Stefania1 aForouhi, Nita, G1 aCupples, Adrienne, L1 aLoos, Ruth, J1 aHallmans, Göran1 aDupuis, Josée1 aLangenberg, Claudia1 aFerrucci, Luigi1 aKritchevsky, Stephen, B1 aMcCarthy, Mark, I1 aIngelsson, Erik1 aBorecki, Ingrid, B1 aWitteman, Jacqueline, C M1 aOrho-Melander, Marju1 aSiscovick, David, S1 aMeigs, James, B1 aFranks, Paul, W1 aDedoussis, George, V1 aMAGIC investigators uhttps://chs-nhlbi.org/node/130805540nas a2201357 4500008004100000022001400041245007400055210006900129260001300198300001200211490000700223520169700230653001701927653001901944653001101963653001001974653003401984653001102018653000902029653002702038653003602065653002802101653003102129653002402160100001802184700001902202700003102221700001602252700002502268700001202293700002102305700002402326700002502350700001402375700001702389700001802406700001802424700001902442700002802461700001902489700002502508700002402533700002302557700002502580700002102605700001602626700002602642700001902668700002102687700001902708700002002727700002102747700002102768700002402789700001702813700002002830700001302850700002102863700002502884700001802909700002002927700003002947700002102977700002702998700002203025700002903047700002103076700002303097700001603120700002003136700001903156700002003175700002303195700002203218700002403240700002003264700001703284700002703301700003103328700002303359700002003382700002103402700001503423700002803438700001903466700002303485700002503508700002403533700001903557700001903576700001703595700002503612700002603637700001903663700002203682700002103704700002703725700002603752700002803778700002503806700002403831700002003855700002203875700002403897700002003921700002103941700002503962700002603987700002304013700001904036700002604055700002104081700002504102700001904127856003604146 2012 eng d a1523-468100aAssessment of gene-by-sex interaction effect on bone mineral density.0 aAssessment of genebysex interaction effect on bone mineral densi c2012 Oct a2051-640 v273 aSexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.
10aBone Density10aCohort Studies10aFemale10aGenes10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aReproducibility of Results10aSex Characteristics1 aLiu, Ching-Ti1 aEstrada, Karol1 aYerges-Armstrong, Laura, M1 aAmin, Najaf1 aEvangelou, Evangelos1 aLi, Guo1 aMinster, Ryan, L1 aCarless, Melanie, A1 aKammerer, Candace, M1 aOei, Ling1 aZhou, Yanhua1 aAlonso, Nerea1 aDailiana, Zoe1 aEriksson, Joel1 aGarcía-Giralt, Natalia1 aGiroux, Sylvie1 aHusted, Lise, Bjerre1 aKhusainova, Rita, I1 aKoromila, Theodora1 aKung, Annie, Waichee1 aLewis, Joshua, R1 aMasi, Laura1 aMencej-Bedrac, Simona1 aNogues, Xavier1 aPatel, Millan, S1 aPrezelj, Janez1 aRichards, Brent1 aSham, Pak, Chung1 aSpector, Timothy1 aVandenput, Liesbeth1 aXiao, Su-Mei1 aZheng, Hou-Feng1 aZhu, Kun1 aBalcells, Susana1 aBrandi, Maria, Luisa1 aFrost, Morten1 aGoltzman, David1 aGonzález-Macías, Jesús1 aKarlsson, Magnus1 aKhusnutdinova, Elza, K1 aKollia, Panagoula1 aLangdahl, Bente, Lomholt1 aLjunggren, Osten1 aLorentzon, Mattias1 aMarc, Janja1 aMellström, Dan1 aOhlsson, Claes1 aOlmos, José, M1 aRalston, Stuart, H1 aRiancho, José, A1 aRousseau, François1 aUrreizti, Roser1 aVan Hul, Wim1 aZarrabeitia, María, T1 aCastano-Betancourt, Martha1 aDemissie, Serkalem1 aGrundberg, Elin1 aHerrera, Lizbeth1 aKwan, Tony1 aMedina-Gómez, Carolina1 aPastinen, Tomi1 aSigurdsson, Gunnar1 aThorleifsson, Gudmar1 aVanmeurs, Joyce, Bj1 aBlangero, John1 aHofman, Albert1 aLiu, Yongmei1 aMitchell, Braxton, D1 aO'Connell, Jeffrey, R1 aOostra, Ben, A1 aRotter, Jerome, I1 aStefansson, Kari1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aThorsteinsdottir, Unnur1 aTylavsky, Frances, A1 aUitterlinden, Andre1 aCauley, Jane, A1 aHarris, Tamara, B1 aIoannidis, John, Pa1 aPsaty, Bruce, M1 aRobbins, John, A1 aZillikens, Carola, M1 aVanduijn, Cornelia, M1 aPrince, Richard, L1 aKarasik, David1 aRivadeneira, Fernando1 aKiel, Douglas, P1 aCupples, Adrienne, L1 aHsu, Yi-Hsiang uhttps://chs-nhlbi.org/node/155603509nas a2200493 4500008004100000022001400041245019600055210006900251260001300320300001100333490000700344520201000351653000902361653002002370653001602390653002802406653001102434653001102445653000902456653001402465653001402479653001502493653003102508653002002539653002402559100002702583700002502610700002702635700002002662700002502682700003002707700001902737700002502756700002202781700002002803700002202823700002102845700001902866700001502885700002202900700002802922710002902950856003602979 2012 eng d a1464-368500aThe association between waist circumference and risk of mortality considering body mass index in 65- to 74-year-olds: a meta-analysis of 29 cohorts involving more than 58 000 elderly persons.0 aassociation between waist circumference and risk of mortality co c2012 Jun a805-170 v413 aBACKGROUND: For the elderly, the association between waist circumference (WC) and mortality considering body mass index (BMI) remains unclear, and thereby also the evidence base for using these anthropometric measures in clinical practice. This meta-analysis examined the association between WC categories and (cause-specific) mortality within BMI categories. Furthermore, the association of continuous WC with lowest and increased mortality risks was examined.
METHODS: Age- and smoking-adjusted relative risks (RRs) of mortality associated with WC-BMI categories and continuous WC (including WC and WC(2)) were calculated by the investigators and pooled by means of random-effects models.
RESULTS: During a 5-year-follow-up of 32 678 men and 25 931 women, we ascertained 3318 and 1480 deaths, respectively. A large WC (men: ≥102 cm, women: ≥88 cm) was associated with increased all-cause mortality RRs for those in the 'healthy' weight {1.7 [95% confidence interval (CI): 1.2-2.2], 1.7 (95% CI: 1.3-2.3)}, overweight [1.1(95% CI: 1.0-1.3), 1.4 (95%: 1.1-1.7)] and obese [1.1 (95% CI: 1.0-1.3), 1.6 (95% CI: 1.3-1.9)] BMI category compared with the 'healthy' weight (20-24.9 kg/m(2)) and a small WC (<94 cm, men; <80 cm, women) category. Underweight was associated with highest all-cause mortality RRs in men [2.2 (95% CI: 1.8-2.8)] and women [2.3 (95% CI: 1.8-3.1]. We found a J-shaped association for continuous WC with all-cause, cardiovascular (CVD) and cancer, and a U-shaped association with respiratory disease mortality (P < 0.05). An all-cause (CVD) mortality RR of 2.0 was associated with a WC of 132 cm (123 cm) in men and 116 cm (105 cm) in women.
CONCLUSIONS: Our results showed increased mortality risks for elderly people with an increased WC-even across BMI categories- and for those who were classified as 'underweight' using BMI. The results provide a solid basis for re-evaluation of WC cut-points in ageing populations.
10aAged10aBody Mass Index10aBody Weight10aCardiovascular Diseases10aFemale10aHumans10aMale10aMortality10aNeoplasms10aOverweight10aRespiratory Tract Diseases10aRisk Assessment10aWaist Circumference1 ade Hollander, Ellen, L1 aBemelmans, Wanda, Je1 aBoshuizen, Hendriek, C1 aFriedrich, Nele1 aWallaschofski, Henri1 aGuallar-Castillón, Pilar1 aWalter, Stefan1 aZillikens, Carola, M1 aRosengren, Annika1 aLissner, Lauren1 aBassett, Julie, K1 aGiles, Graham, G1 aOrsini, Nicola1 aHeim, Noor1 aVisser, Marjolein1 ade Groot, Lisette, Cpgm1 aWC elderly collaborators uhttps://chs-nhlbi.org/node/137608598nas a2202365 4500008004100000022001400041245007900055210006900134260001600203300001100219490000800230520193500238653005002173653001602223653002002239653002602259653001102285653002202296653003402318653001102352653000902363653002602372653001402398653003602412653001302448653002302461100001502484700002002499700002202519700002202541700002802563700002302591700001902614700002502633700003202658700001802690700001902708700002602727700003102753700001902784700001802803700002002821700001202841700001702853700002202870700002502892700002002917700002002937700001602957700002002973700001902993700001903012700001803031700002103049700001803070700002603088700001903114700002103133700002003154700002103174700001903195700002103214700002003235700001903255700003503274700002403309700002103333700001803354700001503372700002803387700001903415700003403434700001803468700001803486700002003504700002203524700002103546700002103567700002503588700002903613700002303642700001603665700002003681700002203701700001403723700002303737700001603760700001803776700001903794700002203813700001903835700002103854700002203875700002203897700002003919700002103939700002303960700002003983700002004003700001804023700002104041700002304062700002404085700001904109700001804128700002704146700001804173700001704191700002204208700001904230700001904249700002404268700002604292700002104318700001704339700002004356700001904376700002004395700002004415700002004435700002504455700002004480700002404500700002204524700002004546700001604566700001904582700002104601700001904622700002304641700002304664700002504687700002504712700002404737700002304761700002504784700002104809700002104830700002104851700002404872700002104896700002204917700002404939700002804963700001704991700002305008700001905031700001805050700002105068700003005089700002605119700002205145700002405167700002005191700002705211700001905238700002305257700002005280700002105300700002005321700002405341700001505365700002005380700001805400700001905418700002805437700002505465700002805490700002605518700002505544700002705569700002305596700002505619700002405644700001905668700002205687700001805709700002005727700001905747700002205766700002205788700002105810700002105831700002405852700002005876700002505896700002405921700002205945700002305967700002105990700002006011700002006031700002806051700002106079700002506100700002406125700002406149700002306173856003606196 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/617508678nas a2202593 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2012 eng d a1546-171800aGenome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.0 aGenomewide metaanalysis identifies 56 bone mineral density loci c2012 Apr 15 a491-5010 v443 aBone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
10aBone Density10aComputational Biology10aEuropean Continental Ancestry Group10aExtracellular Matrix Proteins10aFemale10aFemur Neck10aFractures, Bone10aGene Expression Profiling10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGlycoproteins10aHumans10aIntercellular Signaling Peptides and Proteins10aLow Density Lipoprotein Receptor-Related Protein-510aLumbar Vertebrae10aMale10aMitochondrial Membrane Transport Proteins10aOsteoporosis10aPhosphoproteins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors10aSpectrin1 aEstrada, Karol1 aStyrkarsdottir, Unnur1 aEvangelou, Evangelos1 aHsu, Yi-Hsiang1 aDuncan, Emma, L1 aNtzani, Evangelia, E1 aOei, Ling1 aAlbagha, Omar, M E1 aAmin, Najaf1 aKemp, John, P1 aKoller, Daniel, L1 aLi, Guo1 aLiu, Ching-Ti1 aMinster, Ryan, L1 aMoayyeri, Alireza1 aVandenput, Liesbeth1 aWillner, Dana1 aXiao, Su-Mei1 aYerges-Armstrong, Laura, M1 aZheng, Hou-Feng1 aAlonso, Nerea1 aEriksson, Joel1 aKammerer, Candace, M1 aKaptoge, Stephen, K1 aLeo, Paul, J1 aThorleifsson, Gudmar1 aWilson, Scott, G1 aWilson, James, F1 aAalto, Ville1 aAlen, Markku1 aAragaki, Aaron, K1 aAspelund, Thor1 aCenter, Jacqueline, R1 aDailiana, Zoe1 aDuggan, David, J1 aGarcia, Melissa1 aGarcía-Giralt, Natalia1 aGiroux, Sylvie1 aHallmans, Göran1 aHocking, Lynne, J1 aHusted, Lise, Bjerre1 aJameson, Karen, A1 aKhusainova, Rita1 aKim, Ghi, Su1 aKooperberg, Charles1 aKoromila, Theodora1 aKruk, Marcin1 aLaaksonen, Marika1 aLaCroix, Andrea, Z1 aLee, Seung, Hun1 aLeung, Ping, C1 aLewis, Joshua, R1 aMasi, Laura1 aMencej-Bedrac, Simona1 aNguyen, Tuan, V1 aNogues, Xavier1 aPatel, Millan, S1 aPrezelj, Janez1 aRose, Lynda, M1 aScollen, Serena1 aSiggeirsdottir, Kristin1 aSmith, Albert, V1 aSvensson, Olle1 aTrompet, Stella1 aTrummer, Olivia1 avan Schoor, Natasja, M1 aWoo, Jean1 aZhu, Kun1 aBalcells, Susana1 aBrandi, Maria, Luisa1 aBuckley, Brendan, M1 aCheng, Sulin1 aChristiansen, Claus1 aCooper, Cyrus1 aDedoussis, George1 aFord, Ian1 aFrost, Morten1 aGoltzman, David1 aGonzález-Macías, Jesús1 aKähönen, Mika1 aKarlsson, Magnus1 aKhusnutdinova, Elza1 aKoh, Jung-Min1 aKollia, Panagoula1 aLangdahl, Bente, Lomholt1 aLeslie, William, D1 aLips, Paul1 aLjunggren, Osten1 aLorenc, Roman, S1 aMarc, Janja1 aMellström, Dan1 aObermayer-Pietsch, Barbara1 aOlmos, José, M1 aPettersson-Kymmer, Ulrika1 aReid, David, M1 aRiancho, José, A1 aRidker, Paul, M1 aRousseau, François1 aSlagboom, Eline1 aTang, Nelson, L S1 aUrreizti, Roser1 aVan Hul, Wim1 aViikari, Jorma1 aZarrabeitia, María, T1 aAulchenko, Yurii, S1 aCastano-Betancourt, Martha1 aGrundberg, Elin1 aHerrera, Lizbeth1 aIngvarsson, Thorvaldur1 aJohannsdottir, Hrefna1 aKwan, Tony1 aLi, Rui1 aLuben, Robert1 aMedina-Gómez, Carolina1 aPalsson, Stefan, Th1 aReppe, Sjur1 aRotter, Jerome, I1 aSigurdsson, Gunnar1 avan Meurs, Joyce, B J1 aVerlaan, Dominique1 aWilliams, Frances, M K1 aWood, Andrew, R1 aZhou, Yanhua1 aGautvik, Kaare, M1 aPastinen, Tomi1 aRaychaudhuri, Soumya1 aCauley, Jane, A1 aChasman, Daniel, I1 aClark, Graeme, R1 aCummings, Steven, R1 aDanoy, Patrick1 aDennison, Elaine, M1 aEastell, Richard1 aEisman, John, A1 aGudnason, Vilmundur1 aHofman, Albert1 aJackson, Rebecca, D1 aJones, Graeme1 aJukema, Wouter1 aKhaw, Kay-Tee1 aLehtimäki, Terho1 aLiu, Yongmei1 aLorentzon, Mattias1 aMcCloskey, Eugene1 aMitchell, Braxton, D1 aNandakumar, Kannabiran1 aNicholson, Geoffrey, C1 aOostra, Ben, A1 aPeacock, Munro1 aPols, Huibert, A P1 aPrince, Richard, L1 aRaitakari, Olli1 aReid, Ian, R1 aRobbins, John1 aSambrook, Philip, N1 aSham, Pak, Chung1 aShuldiner, Alan, R1 aTylavsky, Frances, A1 aDuijn, Cornelia, M1 aWareham, Nick, J1 aCupples, Adrienne, L1 aEcons, Michael, J1 aEvans, David, M1 aHarris, Tamara, B1 aKung, Annie, Wai Chee1 aPsaty, Bruce, M1 aReeve, Jonathan1 aSpector, Timothy, D1 aStreeten, Elizabeth, A1 aZillikens, Carola, M1 aThorsteinsdottir, Unnur1 aOhlsson, Claes1 aKarasik, David1 aRichards, Brent1 aBrown, Matthew, A1 aStefansson, Kari1 aUitterlinden, André, G1 aRalston, Stuart, H1 aIoannidis, John, P A1 aKiel, Douglas, P1 aRivadeneira, Fernando uhttps://chs-nhlbi.org/node/801607748nas a2202497 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2012 eng d a1546-171800aMeta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.0 aMetaanalyses identify 13 loci associated with age at menopause a c2012 Jan 22 a260-80 v443 aTo newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
10aAge Factors10aDNA Helicases10aDNA Polymerase gamma10aDNA Primase10aDNA Repair10aDNA Repair Enzymes10aDNA-Directed DNA Polymerase10aEuropean Continental Ancestry Group10aExodeoxyribonucleases10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aImmunity10aMenopause10aPolymorphism, Single Nucleotide10aProteins1 aStolk, Lisette1 aPerry, John, R B1 aChasman, Daniel, I1 aHe, Chunyan1 aMangino, Massimo1 aSulem, Patrick1 aBarbalic, Maja1 aBroer, Linda1 aByrne, Enda, M1 aErnst, Florian1 aEsko, Tõnu1 aFranceschini, Nora1 aGudbjartsson, Daniel, F1 aHottenga, Jouke-Jan1 aKraft, Peter1 aMcArdle, Patrick, F1 aPorcu, Eleonora1 aShin, So-Youn1 aSmith, Albert, V1 avan Wingerden, Sophie1 aZhai, Guangju1 aZhuang, Wei, V1 aAlbrecht, Eva1 aAlizadeh, Behrooz, Z1 aAspelund, Thor1 aBandinelli, Stefania1 aLauc, Lovorka, Barac1 aBeckmann, Jacques, S1 aBoban, Mladen1 aBoerwinkle, Eric1 aBroekmans, Frank, J1 aBurri, Andrea1 aCampbell, Harry1 aChanock, Stephen, J1 aChen, Constance1 aCornelis, Marilyn, C1 aCorre, Tanguy1 aCoviello, Andrea, D1 aD'Adamo, Pio1 aDavies, Gail1 ade Faire, Ulf1 aGeus, Eco, J C1 aDeary, Ian, J1 aDedoussis, George, V Z1 aDeloukas, Panagiotis1 aEbrahim, Shah1 aEiriksdottir, Gudny1 aEmilsson, Valur1 aEriksson, Johan, G1 aFauser, Bart, C J M1 aFerreli, Liana1 aFerrucci, Luigi1 aFischer, Krista1 aFolsom, Aaron, R1 aGarcia, Melissa, E1 aGasparini, Paolo1 aGieger, Christian1 aGlazer, Nicole1 aGrobbee, Diederick, E1 aHall, Per1 aHaller, Toomas1 aHankinson, Susan, E1 aHass, Merli1 aHayward, Caroline1 aHeath, Andrew, C1 aHofman, Albert1 aIngelsson, Erik1 aJanssens, Cecile, J W1 aJohnson, Andrew, D1 aKarasik, David1 aKardia, Sharon, L R1 aKeyzer, Jules1 aKiel, Douglas, P1 aKolcic, Ivana1 aKutalik, Zoltán1 aLahti, Jari1 aLai, Sandra1 aLaisk, Triin1 aLaven, Joop, S E1 aLawlor, Debbie, A1 aLiu, Jianjun1 aLopez, Lorna, M1 aLouwers, Yvonne, V1 aMagnusson, Patrik, K E1 aMarongiu, Mara1 aMartin, Nicholas, G1 aKlaric, Irena, Martinovic1 aMasciullo, Corrado1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMelzer, David1 aMooser, Vincent1 aNavarro, Pau1 aNewman, Anne, B1 aNyholt, Dale, R1 aOnland-Moret, Charlotte, N1 aPalotie, Aarno1 aParé, Guillaume1 aParker, Alex, N1 aPedersen, Nancy, L1 aPeeters, Petra, H M1 aPistis, Giorgio1 aPlump, Andrew, S1 aPolasek, Ozren1 aPop, Victor, J M1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRehnberg, Emil1 aRotter, Jerome, I1 aRudan, Igor1 aSala, Cinzia1 aSalumets, Andres1 aScuteri, Angelo1 aSingleton, Andrew1 aSmith, Jennifer, A1 aSnieder, Harold1 aSoranzo, Nicole1 aStacey, Simon, N1 aStarr, John, M1 aStathopoulou, Maria, G1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStyrkarsdottir, Unnur1 aSun, Yan, V1 aTenesa, Albert1 aThorand, Barbara1 aToniolo, Daniela1 aTryggvadottir, Laufey1 aTsui, Kim1 aUlivi, Sheila1 avan Dam, Rob, M1 aSchouw, Yvonne, T1 avan Gils, Carla, H1 avan Nierop, Peter1 aVink, Jacqueline, M1 aVisscher, Peter, M1 aVoorhuis, Marlies1 aWaeber, Gérard1 aWallaschofski, Henri1 aWichmann, Erich, H1 aWiden, Elisabeth1 avan Gent, Colette, J M Wijnan1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWright, Alan, F1 aYerges-Armstrong, Laura, M1 aZemunik, Tatijana1 aZgaga, Lina1 aZillikens, Carola, M1 aZygmunt, Marek1 aArnold, Alice, M1 aBoomsma, Dorret, I1 aBuring, Julie, E1 aCrisponi, Laura1 aDemerath, Ellen, W1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHu, Frank, B1 aHunter, David, J1 aLauner, Lenore, J1 aMetspalu, Andres1 aMontgomery, Grant, W1 aOostra, Ben, A1 aRidker, Paul, M1 aSanna, Serena1 aSchlessinger, David1 aSpector, Tim, D1 aStefansson, Kari1 aStreeten, Elizabeth, A1 aThorsteinsdottir, Unnur1 aUda, Manuela1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aMurray, Anna1 aMurabito, Joanne, M1 aVisser, Jenny, A1 aLunetta, Kathryn, L1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/136021848nas a2207177 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2012 eng d a1553-740400aNovel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.0 aNovel loci for adiponectin levels and their influence on type 2 c2012 ae10026070 v83 aCirculating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
10aAdiponectin10aAfrican Americans10aAsian Continental Ancestry Group10aCholesterol, HDL10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGene Expression10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlucose Tolerance Test10aHumans10aInsulin Resistance10aMale10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aWaist-Hip Ratio1 aDastani, Zari1 aHivert, Marie-France1 aTimpson, Nicholas1 aPerry, John, R B1 aYuan, Xin1 aScott, Robert, A1 aHenneman, Peter1 aHeid, Iris, M1 aKizer, Jorge, R1 aLyytikäinen, Leo-Pekka1 aFuchsberger, Christian1 aTanaka, Toshiko1 aMorris, Andrew, P1 aSmall, Kerrin1 aIsaacs, Aaron1 aBeekman, Marian1 aCoassin, Stefan1 aLohman, Kurt1 aQi, Lu1 aKanoni, Stavroula1 aPankow, James, S1 aUh, Hae-Won1 aWu, Ying1 aBidulescu, Aurelian1 aRasmussen-Torvik, Laura, J1 aGreenwood, Celia, M T1 aLadouceur, Martin1 aGrimsby, Jonna1 aManning, Alisa, K1 aLiu, Ching-Ti1 aKooner, Jaspal1 aMooser, Vincent, E1 aVollenweider, Peter1 aKapur, Karen, A1 aChambers, John1 aWareham, Nicholas, J1 aLangenberg, Claudia1 aFrants, Rune1 aWillems-Vandijk, Ko1 aOostra, Ben, A1 aWillems, Sara, M1 aLamina, Claudia1 aWinkler, Thomas, W1 aPsaty, Bruce, M1 aTracy, Russell, P1 aBrody, Jennifer1 aChen, Ida1 aViikari, Jorma1 aKähönen, Mika1 aPramstaller, Peter, P1 aEvans, David, M1 aSt Pourcain, Beate1 aSattar, Naveed1 aWood, Andrew, R1 aBandinelli, Stefania1 aCarlson, Olga, D1 aEgan, Josephine, M1 aBöhringer, Stefan1 avan Heemst, Diana1 aKedenko, Lyudmyla1 aKristiansson, Kati1 aNuotio, Marja-Liisa1 aLoo, Britt-Marie1 aHarris, Tamara1 aGarcia, Melissa1 aKanaya, Alka1 aHaun, Margot1 aKlopp, Norman1 aWichmann, H-Erich1 aDeloukas, Panos1 aKatsareli, Efi1 aCouper, David, J1 aDuncan, Bruce, B1 aKloppenburg, Margreet1 aAdair, Linda, S1 aBorja, Judith, B1 aWilson, James, G1 aMusani, Solomon1 aGuo, Xiuqing1 aJohnson, Toby1 aSemple, Robert1 aTeslovich, Tanya, M1 aAllison, Matthew, A1 aRedline, Susan1 aBuxbaum, Sarah, G1 aMohlke, Karen, L1 aMeulenbelt, Ingrid1 aBallantyne, Christie, M1 aDedoussis, George, V1 aHu, Frank, B1 aLiu, Yongmei1 aPaulweber, Bernhard1 aSpector, Timothy, D1 aSlagboom, Eline1 aFerrucci, Luigi1 aJula, Antti1 aPerola, Markus1 aRaitakari, Olli1 aFlorez, Jose, C1 aSalomaa, Veikko1 aEriksson, Johan, G1 aFrayling, Timothy, M1 aHicks, Andrew, A1 aLehtimäki, Terho1 aSmith, George Davey1 aSiscovick, David, S1 aKronenberg, Florian1 aDuijn, Cornelia1 aLoos, Ruth, J F1 aWaterworth, Dawn, M1 aMeigs, James, B1 aDupuis, Josée1 aRichards, Brent1 aVoight, Benjamin, F1 aScott, Laura, J1 aSteinthorsdottir, Valgerdur1 aDina, Christian1 aWelch, Ryan, P1 aZeggini, Eleftheria1 aHuth, Cornelia1 aAulchenko, Yurii, S1 aThorleifsson, Gudmar1 aMcCulloch, Laura, J1 aFerreira, Teresa1 aGrallert, Harald1 aAmin, Najaf1 aWu, Guanming1 aWiller, Cristen, J1 aRaychaudhuri, Soumya1 aMcCarroll, Steve, A1 aHofmann, Oliver, M1 aSegrè, Ayellet, V1 aHoek, Mandy1 aNavarro, Pau1 aArdlie, Kristin1 aBalkau, Beverley1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBlagieva, Roza1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBoström, Kristina, Bengtsson1 aBravenboer, Bert1 aBumpstead, Suzannah1 aBurtt, Noel, P1 aCharpentier, Guillaume1 aChines, Peter, S1 aCornelis, Marilyn1 aCrawford, Gabe1 aDoney, Alex, S F1 aElliott, Katherine, S1 aElliott, Amanda, L1 aErdos, Michael, R1 aFox, Caroline, S1 aFranklin, Christopher, S1 aGanser, Martha1 aGieger, Christian1 aGrarup, Niels1 aGreen, Todd1 aGriffin, Simon1 aGroves, Christopher, J1 aGuiducci, Candace1 aHadjadj, Samy1 aHassanali, Neelam1 aHerder, Christian1 aIsomaa, Bo1 aJackson, Anne, U1 aJohnson, Paul, R V1 aJørgensen, Torben1 aKao, Wen, H L1 aKong, Augustine1 aKraft, Peter1 aKuusisto, Johanna1 aLauritzen, Torsten1 aLi, Man1 aLieverse, Aloysius1 aLindgren, Cecilia, M1 aLyssenko, Valeriya1 aMarre, Michel1 aMeitinger, Thomas1 aMidthjell, Kristian1 aMorken, Mario, A1 aNarisu, Narisu1 aNilsson, Peter1 aOwen, Katharine, R1 aPayne, Felicity1 aPetersen, Ann-Kristin1 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aStrachan, David, P1 aReilly, Muredach, P1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRidker, Paul, M1 aRader, Daniel, J1 aKathiresan, Sekar1 aDIAGRAM+ Consortium1 aMAGIC Consortium1 aGLGC Investigators1 aMuTHER Consortium1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal B Pgen Consortium1 aProcardis Consortium1 aMAGIC investigators1 aGLGC Consortium uhttps://chs-nhlbi.org/node/137812626nas 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/615205845nas a2201189 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2013 eng d a1938-320700aGenome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake.0 aGenomewide metaanalysis of observational studies shows common ge c2013 Jun a1395-4020 v973 aBACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)).
CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
10aAlleles10aAtherosclerosis10aBody Mass Index10aDietary Carbohydrates10aDietary Fats10aDietary Proteins10aEnergy Intake10aEuropean Continental Ancestry Group10aFibroblast Growth Factors10aFollow-Up Studies10aGene-Environment Interaction10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLife Style10aObesity10aPolymorphism, Single Nucleotide10aProspective Studies10aQuantitative Trait Loci10aSurveys and Questionnaires1 aTanaka, Toshiko1 aNgwa, Julius, S1 avan Rooij, Frank, J A1 aZillikens, Carola, M1 aWojczynski, Mary, K1 aFrazier-Wood, Alexis, C1 aHouston, Denise, K1 aKanoni, Stavroula1 aLemaitre, Rozenn, N1 aLuan, Jian'an1 aMikkilä, Vera1 aRenstrom, Frida1 aSonestedt, Emily1 aZhao, Jing Hua1 aChu, Audrey, Y1 aQi, Lu1 aChasman, Daniel, I1 aOtto, Marcia, C de Olive1 aDhurandhar, Emily, J1 aFeitosa, Mary, F1 aJohansson, Ingegerd1 aKhaw, Kay-Tee1 aLohman, Kurt, K1 aManichaikul, Ani1 aMcKeown, Nicola, M1 aMozaffarian, Dariush1 aSingleton, Andrew1 aStirrups, Kathleen1 aViikari, Jorma1 aYe, Zheng1 aBandinelli, Stefania1 aBarroso, Inês1 aDeloukas, Panos1 aForouhi, Nita, G1 aHofman, Albert1 aLiu, Yongmei1 aLyytikäinen, Leo-Pekka1 aNorth, Kari, E1 aDimitriou, Maria1 aHallmans, Göran1 aKähönen, Mika1 aLangenberg, Claudia1 aOrdovas, Jose, M1 aUitterlinden, André, G1 aHu, Frank, B1 aKalafati, Ioanna-Panagiota1 aRaitakari, Olli1 aFranco, Oscar, H1 aJohnson, Andrew1 aEmilsson, Valur1 aSchrack, Jennifer, A1 aSemba, Richard, D1 aSiscovick, David, S1 aArnett, Donna, K1 aBorecki, Ingrid, B1 aFranks, Paul, W1 aKritchevsky, Stephen, B1 aLehtimäki, Terho1 aLoos, Ruth, J F1 aOrho-Melander, Marju1 aRotter, Jerome, I1 aWareham, Nicholas, J1 aWitteman, Jacqueline, C M1 aFerrucci, Luigi1 aDedoussis, George1 aCupples, Adrienne, L1 aNettleton, Jennifer, A uhttps://chs-nhlbi.org/node/616304700nas a2200961 4500008004100000022001400041245019200055210006900247260001300316300001100329490000800340520188800348653001802236653001102254653001702265653001102282653001202293653001402305653000902319653003602328653001902364653002502383100001702408700002002425700002002445700002402465700001802489700002102507700002302528700002102551700002202572700002202594700002402616700002102640700001902661700001902680700002102699700002002720700002602740700002502766700001802791700001902809700002402828700002002852700002102872700002302893700001702916700002202933700002502955700002202980700001703002700002503019700002903044700002803073700002803101700001903129700002703148700001903175700001503194700002203209700001903231700002103250700002103271700002303292700002503315700002503340700002003365700001703385700002003402700002003422700002003442700002803462700002503490700002103515700002203536700002403558700003003582700002003612700002003632700002303652700002703675856003603702 2013 eng d a1541-610000aHigher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies.0 aHigher magnesium intake is associated with lower fasting glucose c2013 Mar a345-530 v1433 aFavorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.
10aBlood Glucose10aFemale10aGenetic Loci10aHumans10aInsulin10aMagnesium10aMale10aPolymorphism, Single Nucleotide10aTrace Elements10aTRPM Cation Channels1 aHruby, Adela1 aNgwa, Julius, S1 aRenstrom, Frida1 aWojczynski, Mary, K1 aGanna, Andrea1 aHallmans, Göran1 aHouston, Denise, K1 aJacques, Paul, F1 aKanoni, Stavroula1 aLehtimäki, Terho1 aLemaitre, Rozenn, N1 aManichaikul, Ani1 aNorth, Kari, E1 aNtalla, Ioanna1 aSonestedt, Emily1 aTanaka, Toshiko1 avan Rooij, Frank, J A1 aBandinelli, Stefania1 aDjoussé, Luc1 aGrigoriou, Efi1 aJohansson, Ingegerd1 aLohman, Kurt, K1 aPankow, James, S1 aRaitakari, Olli, T1 aRiserus, Ulf1 aYannakoulia, Mary1 aZillikens, Carola, M1 aHassanali, Neelam1 aLiu, Yongmei1 aMozaffarian, Dariush1 aPapoutsakis, Constantina1 aSyvänen, Ann-Christine1 aUitterlinden, André, G1 aViikari, Jorma1 aGroves, Christopher, J1 aHofman, Albert1 aLind, Lars1 aMcCarthy, Mark, I1 aMikkilä, Vera1 aMukamal, Kenneth1 aFranco, Oscar, H1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aDedoussis, George, V1 aFerrucci, Luigi1 aHu, Frank, B1 aIngelsson, Erik1 aKähönen, Mika1 aKao, Linda, W H1 aKritchevsky, Stephen, B1 aOrho-Melander, Marju1 aProkopenko, Inga1 aRotter, Jerome, I1 aSiscovick, David, S1 aWitteman, Jacqueline, C M1 aFranks, Paul, W1 aMeigs, James, B1 aMcKeown, Nicola, M1 aNettleton, Jennifer, A uhttps://chs-nhlbi.org/node/587911004nas a2203505 4500008004100000022001400041245014700055210006900202260001300271300001300284490000600297520115200303653001801455653001601473653002001489653001601509653003001525653001101555653001701566653001801583653003401601653001101635653000901646653003601655653002401691653002401715653002001739100002301759700002301782700002101805700002101826700002101847700001901868700002801887700001601915700001801931700001601949700003101965700002101996700003002017700001802047700001502065700002102080700002302101700001902124700002002143700001902163700002202182700002002204700001802224700003202242700002502274700003002299700002302329700001902352700001902371700002202390700002202412700001902434700001802453700001902471700002202490700002302512700002302535700002202558700002402580700002102604700002202625700002202647700002602669700002302695700002202718700002302740700002402763700002202787700002202809700001202831700002502843700001802868700002802886700002402914700001802938700002502956700001902981700001603000700001903016700001903035700002503054700002503079700002603104700001903130700002003149700001703169700002403186700002003210700002303230700001603253700002003269700002203289700002803311700002103339700002403360700002003384700002303404700001803427700002203445700002103467700001903488700002603507700002203533700002803555700002003583700002803603700002703631700002003658700002303678700002003701700002103721700002403742700002003766700001503786700002803801700002603829700001903855700002803874700001903902700002503921700002403946700002703970700002003997700001404017700002004031700002204051700001904073700001804092700001804110700002104128700002004149700002204169700001604191700002204207700002204229700002604251700002604277700001704303700002004320700002304340700001904363700002304382700002004405700002304425700001904448700001804467700002304485700002504508700001904533700001904552700002004571700003004591700003504621700002104656700001704677700002104694700001904715700002504734700002404759700001804783700001504801700002404816700002204840700002504862700001504887700002304902700002004925700001904945700002204964700002004986700001805006700002205024700002005046700002105066700002105087700001705108700002105125700002005146700001605166700002105182700001905203700002505222700002405247700002305271700001905294700002205313700001805335700002005353700002005373700001905393700002105412700002405433700001805457700002005475700002105495700002005516700002505536700002105561700002105582700002405603700001805627700001605645700002105661700003705682700002205719700001805741700002005759700002105779700002005800700002605820700002305846700001905869700002005888700002305908700002405931700002005955700001905975700002005994700002406014700002506038700001906063700002106082700002106103700001806124700002106142700003006163700002006193700002306213700002206236700002006258700002806278700002206306700001906328700002406347700002206371700002006393700001906413700002306432700001506455700001706470700001506487700001806502700001906520700002706539700002306566700002206589700002106611700002206632700002206654700002306676700002506699700002106724700001906745700001806764700001906782700002106801700001906822700001806841700002906859700001906888700002106907700002306928700002006951700002106971700002206992700001907014700002307033700001807056700002007074700001907094700002107113700002607134700002407160700002307184700002107207700002307228700002507251700002207276700002407298700001107322700002007333700002507353700001907378700001807397710002307415710002407438856003607462 2013 eng d a1553-740400aSex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.0 aSexstratified genomewide association studies including 270000 in c2013 Jun ae10035000 v93 aGiven the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
10aAnthropometry10aBody Height10aBody Mass Index10aBody Weight10aBody Weights and Measures10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist Circumference10aWaist-Hip Ratio1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aKutalik, Zoltán1 aBerndt, Sonja, I1 aJackson, Anne, U1 aMonda, Keri, L1 aKilpeläinen, Tuomas, O1 aEsko, Tõnu1 aMägi, Reedik1 aLi, Shengxu1 aWorkalemahu, Tsegaselassie1 aFeitosa, Mary, F1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aFall, Tove1 aFerreira, Teresa1 aGustafsson, Stefan1 aLocke, Adam, E1 aMathieson, Iain1 aScherag, Andre1 aVedantam, Sailaja1 aWood, Andrew, R1 aLiang, Liming1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aDermitzakis, Emmanouil, T1 aDimas, Antigone, S1 aKarpe, Fredrik1 aMin, Josine, L1 aNicholson, George1 aClegg, Deborah, J1 aPerson, Thomas1 aKrohn, Jon, P1 aBauer, Sabrina1 aBuechler, Christa1 aEisinger, Kristina1 aBonnefond, Amélie1 aFroguel, Philippe1 aHottenga, Jouke-Jan1 aProkopenko, Inga1 aWaite, Lindsay, L1 aHarris, Tamara, B1 aSmith, Albert, Vernon1 aShuldiner, Alan, R1 aMcArdle, Wendy, L1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aGrönberg, Henrik1 aChen, Yii-Der Ida1 aLi, Guo1 aBeckmann, Jacques, S1 aJohnson, Toby1 aThorsteinsdottir, Unnur1 aTeder-Laving, Maris1 aKhaw, Kay-Tee1 aWareham, Nicholas, J1 aZhao, Jing Hua1 aAmin, Najaf1 aOostra, Ben, A1 aKraja, Aldi, T1 aProvince, Michael, A1 aCupples, Adrienne, L1 aHeard-Costa, Nancy, L1 aKaprio, Jaakko1 aRipatti, Samuli1 aSurakka, Ida1 aCollins, Francis, S1 aSaramies, Jouko1 aTuomilehto, Jaakko1 aJula, Antti1 aSalomaa, Veikko1 aErdmann, Jeanette1 aHengstenberg, Christian1 aLoley, Christina1 aSchunkert, Heribert1 aLamina, Claudia1 aWichmann, Erich, H1 aAlbrecht, Eva1 aGieger, Christian1 aHicks, Andrew, A1 aJohansson, Asa1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aSpeliotes, Elizabeth, K1 aPenninx, Brenda1 aHartikainen, Anna-Liisa1 aJarvelin, Marjo-Riitta1 aGyllensten, Ulf1 aBoomsma, Dorret, I1 aCampbell, Harry1 aWilson, James, F1 aChanock, Stephen, J1 aFarrall, Martin1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aRivadeneira, Fernando1 aEstrada, Karol1 aUitterlinden, André, G1 aHofman, Albert1 aZillikens, Carola, M1 aHeijer, Martin, den1 aKiemeney, Lambertus, A1 aMaschio, Andrea1 aHall, Per1 aTyrer, Jonathan1 aTeumer, Alexander1 aVölzke, Henry1 aKovacs, Peter1 aTönjes, Anke1 aMangino, Massimo1 aSpector, Tim, D1 aHayward, Caroline1 aRudan, Igor1 aHall, Alistair, S1 aSamani, Nilesh, J1 aAttwood, Antony, Paul1 aSambrook, Jennifer, G1 aHung, Joseph1 aPalmer, Lyle, J1 aLokki, Marja-Liisa1 aSinisalo, Juha1 aBoucher, Gabrielle1 aHuikuri, Heikki1 aLorentzon, Mattias1 aOhlsson, Claes1 aEklund, Niina1 aEriksson, Johan, G1 aBarlassina, Cristina1 aRivolta, Carlo1 aNolte, Ilja, M1 aSnieder, Harold1 avan der Klauw, Melanie, M1 avan Vliet-Ostaptchouk, Jana, V1 aGejman, Pablo, V1 aShi, Jianxin1 aJacobs, Kevin, B1 aWang, Zhaoming1 aBakker, Stephan, J L1 aLeach, Irene, Mateo1 aNavis, Gerjan1 aHarst, Pim1 aMartin, Nicholas, G1 aMedland, Sarah, E1 aMontgomery, Grant, W1 aYang, Jian1 aChasman, Daniel, I1 aRidker, Paul, M1 aRose, Lynda, M1 aLehtimäki, Terho1 aRaitakari, Olli1 aAbsher, Devin1 aIribarren, Carlos1 aBasart, Hanneke1 aHovingh, Kees, G1 aHyppönen, Elina1 aPower, Chris1 aAnderson, Denise1 aBeilby, John, P1 aHui, Jennie1 aJolley, Jennifer1 aSager, Hendrik1 aBornstein, Stefan, R1 aSchwarz, Peter, E H1 aKristiansson, Kati1 aPerola, Markus1 aLindström, Jaana1 aSwift, Amy, J1 aUusitupa, Matti1 aAtalay, Mustafa1 aLakka, Timo, A1 aRauramaa, Rainer1 aBolton, Jennifer, L1 aFowkes, Gerry1 aFraser, Ross, M1 aPrice, Jackie, F1 aFischer, Krista1 aKov, Kaarel, Krjutå1 aMetspalu, Andres1 aMihailov, Evelin1 aLangenberg, Claudia1 aLuan, Jian'an1 aOng, Ken, K1 aChines, Peter, S1 aKeinanen-Kiukaanniemi, Sirkka, M1 aSaaristo, Timo, E1 aEdkins, Sarah1 aFranks, Paul, W1 aHallmans, Göran1 aShungin, Dmitry1 aMorris, Andrew, David1 aPalmer, Colin, N A1 aErbel, Raimund1 aMoebus, Susanne1 aNöthen, Markus, M1 aPechlivanis, Sonali1 aHveem, Kristian1 aNarisu, Narisu1 aHamsten, Anders1 aHumphries, Steve, E1 aStrawbridge, Rona, J1 aTremoli, Elena1 aGrallert, Harald1 aThorand, Barbara1 aIllig, Thomas1 aKoenig, Wolfgang1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aBoehm, Bernhard, O1 aKleber, Marcus, E1 aMärz, Winfried1 aWinkelmann, Bernhard, R1 aKuusisto, Johanna1 aLaakso, Markku1 aArveiler, Dominique1 aCesana, Giancarlo1 aKuulasmaa, Kari1 aVirtamo, Jarmo1 aYarnell, John, W G1 aKuh, Diana1 aWong, Andrew1 aLind, Lars1 ade Faire, Ulf1 aGigante, Bruna1 aMagnusson, Patrik, K E1 aPedersen, Nancy, L1 aDedoussis, George1 aDimitriou, Maria1 aKolovou, Genovefa1 aKanoni, Stavroula1 aStirrups, Kathleen1 aBonnycastle, Lori, L1 aNjølstad, Inger1 aWilsgaard, Tom1 aGanna, Andrea1 aRehnberg, Emil1 aHingorani, Aroon1 aKivimaki, Mika1 aKumari, Meena1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David1 aIngelsson, Erik1 aKaplan, Robert1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aStrachan, David, P1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAbecasis, Goncalo, R1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aQi, Lu1 aLoos, Ruth, J F1 aLindgren, Cecilia, M1 aNorth, Kari, E1 aHeid, Iris, M1 aDIAGRAM Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/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/693804825nas a2201141 4500008004100000022001400041245010700055210007000162260001600232300001200248490000700260520164000267653001001907653002001917653002501937653001801962653002301980653004002003653001102043653001702054653003402071653001102105653000902116653001202125653003602137100002702173700002002200700002002220700002002240700001902260700002002279700002402299700002002323700002402343700002302367700002402390700002302414700002402437700001402461700002102475700002102496700002202517700001802539700001902557700001902576700002402595700001902619700002302638700002402661700002002685700001702705700001602722700001702738700002502755700001502780700001802795700001902813700002002832700001402852700002002866700002102886700002102907700002102928700001602949700002002965700002102985700002603006700002003032700001703052700002003069700001803089700001903107700001903126700001903145700002303164700001903187700002803206700002403234700002103258700002503279700002003304700002303324700001603347700002803363700002303391700002503414700001103439700002003450700002503470700002503495700002003520700002203540700002003562700002503582700002003607700002003627856003603647 2015 eng d a1460-208300aGene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry.0 aGene × dietary pattern interactions in obesity analysis of up to c2015 Aug 15 a4728-380 v243 aObesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.
10aAdult10aBody Mass Index10aCase-Control Studies10aDiet, Western10aEpistasis, Genetic10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aObesity10aPolymorphism, Single Nucleotide1 aNettleton, Jennifer, A1 aFollis, Jack, L1 aNgwa, Julius, S1 aSmith, Caren, E1 aAhmad, Shafqat1 aTanaka, Toshiko1 aWojczynski, Mary, K1 aVoortman, Trudy1 aLemaitre, Rozenn, N1 aKristiansson, Kati1 aNuotio, Marja-Liisa1 aHouston, Denise, K1 aPerälä, Mia-Maria1 aQi, Qibin1 aSonestedt, Emily1 aManichaikul, Ani1 aKanoni, Stavroula1 aGanna, Andrea1 aMikkilä, Vera1 aNorth, Kari, E1 aSiscovick, David, S1 aHarald, Kennet1 aMcKeown, Nicola, M1 aJohansson, Ingegerd1 aRissanen, Harri1 aLiu, Yongmei1 aLahti, Jari1 aHu, Frank, B1 aBandinelli, Stefania1 aRukh, Gull1 aRich, Stephen1 aBooij, Lisanne1 aDmitriou, Maria1 aAx, Erika1 aRaitakari, Olli1 aMukamal, Kenneth1 aMännistö, Satu1 aHallmans, Göran1 aJula, Antti1 aEricson, Ulrika1 aJacobs, David, R1 avan Rooij, Frank, J A1 aDeloukas, Panos1 aSjogren, Per1 aKähönen, Mika1 aDjoussé, Luc1 aPerola, Markus1 aBarroso, Inês1 aHofman, Albert1 aStirrups, Kathleen1 aViikari, Jorma1 aUitterlinden, André, G1 aKalafati, Ioanna, P1 aFranco, Oscar, H1 aMozaffarian, Dariush1 aSalomaa, Veikko1 aBorecki, Ingrid, B1 aKnekt, Paul1 aKritchevsky, Stephen, B1 aEriksson, Johan, G1 aDedoussis, George, V1 aQi, Lu1 aFerrucci, Luigi1 aOrho-Melander, Marju1 aZillikens, Carola, M1 aIngelsson, Erik1 aLehtimäki, Terho1 aRenstrom, Frida1 aCupples, Adrienne, L1 aLoos, Ruth, J F1 aFranks, Paul, W uhttps://chs-nhlbi.org/node/680204458nas a2200937 4500008004100000022001400041245009600055210006900151260001300220300001200233490000700245520181500252100002102067700002002088700001902108700001602127700001802143700002002161700002302181700002102204700002602225700001702251700002102268700002202289700001702311700002402328700002102352700002102373700002302394700002202417700001202439700001902451700002102470700002202491700002402513700002002537700002102557700002302578700002702601700002402628700001902652700001902671700002002690700001902710700002202729700001702751700001702768700002602785700002202811700002802833700001902861700002102880700002302901700002802924700001702952700001902969700001902988700002003007700001403027700002403041700002103065700002203086700002403108700001803132700002003150700002203170700002403192700001903216700002803235700002003263700002003283700002403303700002603327700001803353700002503371700002003396700002303416700002103439700002403460856003603484 2016 eng d a1474-972600aGWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.0 aGWAS analysis of handgrip and lower body strength in older adult c2016 Oct a792-8000 v153 aDecline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
1 aMatteini, Amy, M1 aTanaka, Toshiko1 aKarasik, David1 aAtzmon, Gil1 aChou, Wen-Chi1 aEicher, John, D1 aJohnson, Andrew, D1 aArnold, Alice, M1 aCallisaya, Michele, L1 aDavies, Gail1 aEvans, Daniel, S1 aHoltfreter, Birte1 aLohman, Kurt1 aLunetta, Kathryn, L1 aMangino, Massimo1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTeumer, Alexander1 aYu, Lei1 aArking, Dan, E1 aBuchman, Aron, S1 aChibinik, Lori, B1 aDe Jager, Philip, L1 aEvans, Denis, A1 aFaul, Jessica, D1 aGarcia, Melissa, E1 aGillham-Nasenya, Irina1 aGudnason, Vilmundur1 aHofman, Albert1 aHsu, Yi-Hsiang1 aIttermann, Till1 aLahousse, Lies1 aLiewald, David, C1 aLiu, Yongmei1 aLopez, Lorna1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSiggeirsdottir, Kristin1 aStarr, John, M1 aThomson, Russell1 aTranah, Gregory, J1 aUitterlinden, André, G1 aVölker, Uwe1 aVölzke, Henry1 aWeir, David, R1 aYaffe, Kristine1 aZhao, Wei1 aZhuang, Wei, Vivian1 aZmuda, Joseph, M1 aBennett, David, A1 aCummings, Steven, R1 aDeary, Ian, J1 aFerrucci, Luigi1 aHarris, Tamara, B1 aKardia, Sharon, L R1 aKocher, Thomas1 aKritchevsky, Stephen, B1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aSpector, Timothy, D1 aSrikanth, Velandai, K1 aWindham, Gwen1 aZillikens, Carola, M1 aNewman, Anne, B1 aWalston, Jeremy, D1 aKiel, Douglas, P1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/714210963nas 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/857004016nas a2200865 4500008004100000022001400041245009800055210006900153260001600222520147500238100002001713700002001733700002201753700002001775700002201795700002201817700002801839700002401867700002101891700001901912700003201931700001701963700002801980700002402008700001602032700002202048700001902070700001902089700002002108700001902128700002102147700002002168700002302188700001902211700002002230700001402250700002302264700001902287700002502306700002102331700002102352700002402373700002902397700002502426700002502451700002302476700002502499700002502524700002102549700002402570700002202594700003202616700002002648700002202668700001902690700002302709700002202732700002902754700002502783700002302808700001902831700001702850700002102867700001902888700002202907700002202929700002802951700002602979700002103005700001803026700002403044700002503068700002103093856003603114 2017 eng d a1613-413300aGenome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent.0 aGenomeWide Interactions with Dairy Intake for Body Mass Index in c2017 Sep 213 aSCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.
METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure.
CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.
1 aSmith, Caren, E1 aFollis, Jack, L1 aDashti, Hassan, S1 aTanaka, Toshiko1 aGraff, Mariaelisa1 aFretts, Amanda, M1 aKilpeläinen, Tuomas, O1 aWojczynski, Mary, K1 aRichardson, Kris1 aNalls, Mike, A1 aSchulz, Christina-Alexandra1 aLiu, Yongmei1 aFrazier-Wood, Alexis, C1 avan Eekelen, Esther1 aWang, Carol1 ade Vries, Paul, S1 aMikkilä, Vera1 aRohde, Rebecca1 aPsaty, Bruce, M1 aHansen, Torben1 aFeitosa, Mary, F1 aLai, Chao-Qiang1 aHouston, Denise, K1 aFerruci, Luigi1 aEricson, Ulrika1 aWang, Zhe1 ade Mutsert, Renée1 aOddy, Wendy, H1 ade Jonge, Ester, A L1 aSeppälä, Ilkka1 aJustice, Anne, E1 aLemaitre, Rozenn, N1 aSørensen, Thorkild, I A1 aProvince, Michael, A1 aParnell, Laurence, D1 aGarcia, Melissa, E1 aBandinelli, Stefania1 aOrho-Melander, Marju1 aRich, Stephen, S1 aRosendaal, Frits, R1 aPennell, Craig, E1 ade Jong, Jessica, C Kiefte-1 aKähönen, Mika1 aYoung, Kristin, L1 aPedersen, Oluf1 aAslibekyan, Stella1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aZillikens, Carola, M1 aRaitakari, Olli, T1 aNorth, Kari, E1 aOvervad, Kim1 aArnett, Donna, K1 aHofman, Albert1 aLehtimäki, Terho1 aTjønneland, Anne1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aFranco, Oscar, H1 aGerman, Bruce1 aSiscovick, David, S1 aCupples, Adrienne, L1 aOrdovas, Jose, M uhttps://chs-nhlbi.org/node/758808180nas a2202449 4500008004100000022001400041245010000055210006900155260001600224300000700240490000600247520139100253100002501644700002301669700001901692700003101711700001801742700001901760700002201779700001701801700001801818700002201836700002101858700001801879700001601897700002001913700002101933700002501954700002401979700002002003700001802023700001802041700002302059700001602082700002102098700001902119700002202138700001802160700001902178700002102197700002102218700002302239700002102262700001802283700002002301700002802321700002002349700002202369700002102391700001502412700001602427700002102443700002502464700002102489700002402510700002402534700001702558700003502575700002102610700002402631700002102655700001602676700002302692700001902715700001902734700002102753700002102774700001202795700002002807700002202827700001802849700002202867700002102889700001902910700001802929700002202947700002202969700001902991700002103010700001803031700001903049700002103068700001803089700002003107700002003127700001803147700002003165700002003185700002303205700002203228700001603250700002103266700001803287700002803305700001803333700002703351700002503378700002203403700002503425700002103450700002203471700001903493700001603512700001703528700002303545700002203568700002003590700002103610700002103631700001503652700002203667700001703689700001403706700001703720700002103737700002303758700002103781700002103802700002303823700002803846700002203874700001903896700002003915700001703935700002303952700002503975700002204000700002004022700001704042700002304059700002604082700001904108700002004127700001904147700002504166700001904191700001904210700002004229700001904249700002304268700002304291700002304314700002004337700002104357700002204378700001604400700002004416700002504436700002004461700001904481700001704500700001704517700001504534700002004549700002304569700001604592700002004608700002504628700003504653700002704688700002604715700002204741700002004763700002504783700002304808700002404831700002804855700001904883700002304902700002304925700002704948700001704975700002404992700001905016700002605035700001705061700002305078700001605101700002205117700002105139700002705160700002105187700002205208700001605230700001205246700001705258700002205275700002005297700002305317700002205340700002405362700002205386700002005408700002405428700002105452700002605473700002805499700002505527700002005552700002105572700002005593700001905613700002205632700001905654700002105673856003605694 2017 eng d a2041-172300aLarge meta-analysis of genome-wide association studies identifies five loci for lean body mass.0 aLarge metaanalysis of genomewide association studies identifies c2017 Jul 19 a800 v83 aLean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.
1 aZillikens, Carola, M1 aDemissie, Serkalem1 aHsu, Yi-Hsiang1 aYerges-Armstrong, Laura, M1 aChou, Wen-Chi1 aStolk, Lisette1 aLivshits, Gregory1 aBroer, Linda1 aJohnson, Toby1 aKoller, Daniel, L1 aKutalik, Zoltán1 aLuan, Jian'an1 aMalkin, Ida1 aRied, Janina, S1 aSmith, Albert, V1 aThorleifsson, Gudmar1 aVandenput, Liesbeth1 aZhao, Jing, Hua1 aZhang, Weihua1 aAghdassi, Ali1 aÅkesson, Kristina1 aAmin, Najaf1 aBaier, Leslie, J1 aBarroso, Inês1 aBennett, David, A1 aBertram, Lars1 aBiffar, Rainer1 aBochud, Murielle1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aBuchman, Aron, S1 aByberg, Liisa1 aCampbell, Harry1 aObanda, Natalia, Campos1 aCauley, Jane, A1 aCawthon, Peggy, M1 aCederberg, Henna1 aChen, Zhao1 aCho, Nam, H1 aChoi, Hyung, Jin1 aClaussnitzer, Melina1 aCollins, Francis1 aCummings, Steven, R1 aDe Jager, Philip, L1 aDemuth, Ilja1 aDhonukshe-Rutten, Rosalie, A M1 aDiatchenko, Luda1 aEiriksdottir, Gudny1 aEnneman, Anke, W1 aErdos, Mike1 aEriksson, Johan, G1 aEriksson, Joel1 aEstrada, Karol1 aEvans, Daniel, S1 aFeitosa, Mary, F1 aFu, Mao1 aGarcia, Melissa1 aGieger, Christian1 aGirke, Thomas1 aGlazer, Nicole, L1 aGrallert, Harald1 aGrewal, Jagvir1 aHan, Bok-Ghee1 aHanson, Robert, L1 aHayward, Caroline1 aHofman, Albert1 aHoffman, Eric, P1 aHomuth, Georg1 aHsueh, Wen-Chi1 aHubal, Monica, J1 aHubbard, Alan1 aHuffman, Kim, M1 aHusted, Lise, B1 aIllig, Thomas1 aIngelsson, Erik1 aIttermann, Till1 aJansson, John-Olov1 aJordan, Joanne, M1 aJula, Antti1 aKarlsson, Magnus1 aKhaw, Kay-Tee1 aKilpeläinen, Tuomas, O1 aKlopp, Norman1 aKloth, Jacqueline, S L1 aKoistinen, Heikki, A1 aKraus, William, E1 aKritchevsky, Stephen1 aKuulasmaa, Teemu1 aKuusisto, Johanna1 aLaakso, Markku1 aLahti, Jari1 aLang, Thomas1 aLangdahl, Bente, L1 aLauner, Lenore, J1 aLee, Jong-Young1 aLerch, Markus, M1 aLewis, Joshua, R1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLiu, Tian1 aLiu, Youfang1 aLjunggren, Osten1 aLorentzon, Mattias1 aLuben, Robert, N1 aMaixner, William1 aMcGuigan, Fiona, E1 aMedina-Gómez, Carolina1 aMeitinger, Thomas1 aMelhus, Håkan1 aMellström, Dan1 aMelov, Simon1 aMichaëlsson, Karl1 aMitchell, Braxton, D1 aMorris, Andrew, P1 aMosekilde, Leif1 aNewman, Anne1 aNielson, Carrie, M1 aO'Connell, Jeffrey, R1 aOostra, Ben, A1 aOrwoll, Eric, S1 aPalotie, Aarno1 aParker, Stephen, C J1 aPeacock, Munro1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPrince, Richard, L1 aRäikkönen, Katri1 aRalston, Stuart, H1 aRipatti, Samuli1 aRobbins, John, A1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSatterfield, Suzanne1 aSchadt, Eric, E1 aSchipf, Sabine1 aScott, Laura1 aSehmi, Joban1 aShen, Jian1 aShin, Chan, Soo1 aSigurdsson, Gunnar1 aSmith, Shad1 aSoranzo, Nicole1 aStančáková, Alena1 aSteinhagen-Thiessen, Elisabeth1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aSwart, Karin, M A1 aTan, Sian-Tsung1 aTarnopolsky, Mark, A1 aThompson, Patricia1 aThomson, Cynthia, A1 aThorsteinsdottir, Unnur1 aTikkanen, Emmi1 aTranah, Gregory, J1 aTuomilehto, Jaakko1 avan Schoor, Natasja, M1 aVerma, Arjun1 aVollenweider, Peter1 aVölzke, Henry1 aWactawski-Wende, Jean1 aWalker, Mark1 aWeedon, Michael, N1 aWelch, Ryan1 aWichmann, H-Erich1 aWiden, Elisabeth1 aWilliams, Frances, M K1 aWilson, James, F1 aWright, Nicole, C1 aXie, Weijia1 aYu, Lei1 aZhou, Yanhua1 aChambers, John, C1 aDöring, Angela1 aDuijn, Cornelia, M1 aEcons, Michael, J1 aGudnason, Vilmundur1 aKooner, Jaspal, S1 aPsaty, Bruce, M1 aSpector, Timothy, D1 aStefansson, Kari1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aOssowski, Vicky1 aWaterworth, Dawn1 aLoos, Ruth, J F1 aKarasik, David1 aHarris, Tamara, B1 aOhlsson, Claes1 aKiel, Douglas, P uhttps://chs-nhlbi.org/node/760004416nas a2200913 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520169200286653003701978653002902015653001902044653003802063653001802101653003402119653001102153653002302164653003602187653001702223653001402240653002502254100002402279700001702303700001902320700001902339700001802358700002802376700002002404700002802424700001902452700003002471700002402501700002102525700002402546700002102570700002302591700002602614700001902640700002002659700002202679700002202701700002602723700001802749700002302767700002102790700002502811700002202836700002702858700002102885700002602906700001702932700002702949700002102976700002002997700001903017700002303036700002403059700002403083700002003107700001503127700002003142700002903162700002303191700002203214700001903236700002003255700003103275700002303306700002103329700002503350700002603375700002003401700002503421700002003446856003603466 2017 eng d a1537-660500aLow-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.0 aLowFrequency Synonymous Coding Variation in CYP2R1 Has Large Eff c2017 Aug 03 a227-2380 v1013 aVitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
10aCholestanetriol 26-Monooxygenase10aCytochrome P450 Family 210aGene Frequency10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMultiple Sclerosis10aPolymorphism, Single Nucleotide10aRisk Factors10aVitamin D10aVitamin D Deficiency1 aManousaki, Despoina1 aDudding, Tom1 aHaworth, Simon1 aHsu, Yi-Hsiang1 aLiu, Ching-Ti1 aMedina-Gómez, Carolina1 aVoortman, Trudy1 avan der Velde, Nathalie1 aMelhus, Håkan1 aRobinson-Cohen, Cassianne1 aCousminer, Diana, L1 aNethander, Maria1 aVandenput, Liesbeth1 aNoordam, Raymond1 aForgetta, Vincenzo1 aGreenwood, Celia, M T1 aBiggs, Mary, L1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aZemel, Babette, S1 aMitchell, Jonathan, A1 aTaylor, Bruce1 aLorentzon, Mattias1 aKarlsson, Magnus1 aJaddoe, Vincent, V W1 aTiemeier, Henning1 aCampos-Obando, Natalia1 aFranco, Oscar, H1 aUtterlinden, Andre, G1 aBroer, Linda1 avan Schoor, Natasja, M1 aHam, Annelies, C1 aIkram, Arfan, M1 aKarasik, David1 ade Mutsert, Renée1 aRosendaal, Frits, R1 aHeijer, Martin, den1 aWang, Thomas, J1 aLind, Lars1 aOrwoll, Eric, S1 aMook-Kanamori, Dennis, O1 aMichaëlsson, Karl1 aKestenbaum, Bryan1 aOhlsson, Claes1 aMellström, Dan1 ade Groot, Lisette, C P G M1 aGrant, Struan, F A1 aKiel, Douglas, P1 aZillikens, Carola, M1 aRivadeneira, Fernando1 aSawcer, Stephen1 aTimpson, Nicholas, J1 aRichards, Brent uhttps://chs-nhlbi.org/node/748705033nas a2201381 4500008004100000022001400041245013800055210006900193260001600262300000800278490000600286520112300292100001501415700002201430700002001452700001901472700002001491700001901511700002001530700001901550700001701569700001701586700002201603700001901625700001701644700002501661700002701686700002301713700002201736700001201758700001801770700002201788700002501810700001901835700001401854700001701868700002201885700002001907700002101927700002801948700002201976700001801998700002702016700002802043700003102071700001802102700002502120700002002145700002702165700001802192700001702210700002002227700001902247700002402266700002302290700002302313700001502336700002302351700002802374700001702402700002002419700002002439700001902459700002202478700002002500700002002520700001802540700002202558700002202580700002002602700002002622700002002642700002202662700002102684700003002705700002402735700002702759700002002786700002002806700002102826700002202847700001502869700002302884700002002907700002502927700002802952700002602980700001703006700001603023700002003039700002403059700002503083700002103108700002303129700001903152700001903171700002203190700002803212700002003240700002303260700001903283700002003302700001903322700001903341700002503360700002403385700002103409700002503430700001803455700002503473700001703498700002103515700002003536700002103556700001703577700002103594856003603615 2018 eng d a2041-172300aGenome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.0 aGenomewide association study in 79366 Europeanancestry individua c2018 Jan 17 a2600 v93 aVitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
1 aJiang, Xia1 aO'Reilly, Paul, F1 aAschard, Hugues1 aHsu, Yi-Hsiang1 aRichards, Brent1 aDupuis, Josée1 aIngelsson, Erik1 aKarasik, David1 aPilz, Stefan1 aBerry, Diane1 aKestenbaum, Bryan1 aZheng, Jusheng1 aLuan, Jianan1 aSofianopoulou, Eleni1 aStreeten, Elizabeth, A1 aAlbanes, Demetrius1 aLutsey, Pamela, L1 aYao, Lu1 aTang, Weihong1 aEcons, Michael, J1 aWallaschofski, Henri1 aVölzke, Henry1 aZhou, Ang1 aPower, Chris1 aMcCarthy, Mark, I1 aMichos, Erin, D1 aBoerwinkle, Eric1 aWeinstein, Stephanie, J1 aFreedman, Neal, D1 aHuang, Wen-Yi1 avan Schoor, Natasja, M1 avan der Velde, Nathalie1 ade Groot, Lisette, C P G M1 aEnneman, Anke1 aCupples, Adrienne, L1 aBooth, Sarah, L1 aVasan, Ramachandran, S1 aLiu, Ching-Ti1 aZhou, Yanhua1 aRipatti, Samuli1 aOhlsson, Claes1 aVandenput, Liesbeth1 aLorentzon, Mattias1 aEriksson, Johan, G1 aShea, Kyla1 aHouston, Denise, K1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aLohman, Kurt, K1 aFerrucci, Luigi1 aPeacock, Munro1 aGieger, Christian1 aBeekman, Marian1 aSlagboom, Eline1 aDeelen, Joris1 avan Heemst, Diana1 aKleber, Marcus, E1 aMärz, Winfried1 ade Boer, Ian, H1 aWood, Alexis, C1 aRotter, Jerome, I1 aRich, Stephen, S1 aRobinson-Cohen, Cassianne1 aHeijer, Martin, den1 aJarvelin, Marjo-Riitta1 aCavadino, Alana1 aJoshi, Peter, K1 aWilson, James, F1 aHayward, Caroline1 aLind, Lars1 aMichaëlsson, Karl1 aTrompet, Stella1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aBroer, Linda1 aZgaga, Lina1 aCampbell, Harry1 aTheodoratou, Evropi1 aFarrington, Susan, M1 aTimofeeva, Maria1 aDunlop, Malcolm, G1 aValdes, Ana, M1 aTikkanen, Emmi1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aKähönen, Mika1 aRaitakari, Olli, T1 aMikkilä, Vera1 aIkram, Arfan, M1 aSattar, Naveed1 aJukema, Wouter1 aWareham, Nicholas, J1 aLangenberg, Claudia1 aForouhi, Nita, G1 aGundersen, Thomas, E1 aKhaw, Kay-Tee1 aButterworth, Adam, S1 aDanesh, John1 aSpector, Timothy1 aWang, Thomas, J1 aHyppönen, Elina1 aKraft, Peter1 aKiel, Douglas, P uhttps://chs-nhlbi.org/node/766703699nas a2200673 4500008004100000022001400041245018700055210006900242260001600311300000900327520167400336100001402010700002002024700002102044700002402065700002402089700001602113700002302129700001402152700002002166700002202186700002002208700002002228700002802248700002202276700002402298700002202322700001902344700001602363700002302379700002102402700002802423700002302451700002402474700002202498700002102520700002602541700002102567700002002588700002202608700002102630700002202651700002002673700002302693700002202716700002002738700002502758700001702783700001902800700002002819700001902839700002502858700001902883700002102902700002002923700002102943700002502964856003602989 2018 eng d a1475-266200aMeta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.0 aMetaanalysis across Cohorts for Heart and Aging Research in Geno c2018 Sep 12 a1-123 aThe role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
1 aXu, Jiayi1 aBartz, Traci, M1 aChittoor, Geetha1 aEiriksdottir, Gudny1 aManichaikul, Ani, W1 aSun, Fangui1 aTerzikhan, Natalie1 aZhou, Xia1 aBooth, Sarah, L1 aBrusselle, Guy, G1 ade Boer, Ian, H1 aFornage, Myriam1 aFrazier-Wood, Alexis, C1 aGraff, Mariaelisa1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHofman, Albert1 aHou, Ruixue1 aHouston, Denise, K1 aJacobs, David, R1 aKritchevsky, Stephen, B1 aLatourelle, Jeanne1 aLemaitre, Rozenn, N1 aLutsey, Pamela, L1 aO'Connor, George1 aOelsner, Elizabeth, C1 aPankow, James, S1 aPsaty, Bruce, M1 aRohde, Rebecca, R1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Lewis, J1 aStricker, Bruno, H1 aVoruganti, Saroja1 aWang, Thomas, J1 aZillikens, Carola, M1 aBarr, Graham1 aDupuis, Josée1 aGharib, Sina, A1 aLahousse, Lies1 aLondon, Stephanie, J1 aNorth, Kari, E1 aSmith, Albert, V1 aSteffen, Lyn, M1 aHancock, Dana, B1 aCassano, Patricia, A uhttps://chs-nhlbi.org/node/777504010nas a2200709 4500008004100000022001400041245010600055210006900161260001600230520196000246100001402206700002202220700002002242700001602262700002402278700002102302700002102323700001602344700002302360700002702383700002302410700001802433700002002451700002202471700002402493700001402517700002002531700002202551700002202573700002002595700002102615700002202636700002402658700002102682700002602703700002002729700002702749700002202776700002102798700002202819700002002841700002002861700002202881700002102903700002802924700002202952700001502974700002102989700002003010700002503030700002503055700001703080700001903097700002003116700002403136700001903160700001903179700002003198700002503218700002103243856003603264 2018 eng d a1535-497000aOmega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.0 aOmega3 Fatty Acids and Genomewide Interaction Analyses Reveal DP c2018 Sep 103 aRATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.
OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.
METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs.
RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P=9.4×10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80%) was associated with lower FVC (P=2.1×10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1×10; β=36.2mL).
CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.
1 aXu, Jiayi1 aGaddis, Nathan, C1 aBartz, Traci, M1 aHou, Ruixue1 aManichaikul, Ani, W1 aPankratz, Nathan1 aSmith, Albert, V1 aSun, Fangui1 aTerzikhan, Natalie1 aMarkunas, Christina, A1 aPatchen, Bonnie, K1 aSchu, Matthew1 aBeydoun, May, A1 aBrusselle, Guy, G1 aEiriksdottir, Gudny1 aZhou, Xia1 aWood, Alexis, C1 aGraff, Mariaelisa1 aHarris, Tamara, B1 aIkram, Arfan, M1 aJacobs, David, R1 aLauner, Lenore, J1 aLemaitre, Rozenn, N1 aO'Connor, George1 aOelsner, Elizabeth, C1 aPsaty, Bruce, M1 aRamachandran, Vasan, S1 aRohde, Rebecca, R1 aRich, Stephen, S1 aRotter, Jerome, I1 aSeshadri, Sudha1 aSmith, Lewis, J1 aTiemeier, Henning1 aTsai, Michael, Y1 aUitterlinden, André, G1 aVoruganti, Saroja1 aXu, Hanfei1 aZilhão, Nuno, R1 aFornage, Myriam1 aZillikens, Carola, M1 aLondon, Stephanie, J1 aBarr, Graham1 aDupuis, Josée1 aGharib, Sina, A1 aGudnason, Vilmundur1 aLahousse, Lies1 aNorth, Kari, E1 aSteffen, Lyn, M1 aCassano, Patricia, A1 aHancock, Dana, B uhttps://chs-nhlbi.org/node/777607560nas a2202017 4500008004100000022001400041245004500055210004400100260001600144300001200160490000800172520198400180100001902164700002502183700001902208700001802227700002302245700001602268700001902284700002202303700001802325700002102343700002302364700001702387700002102404700001802425700002002443700002702463700002002490700002202510700002202532700001502554700001602569700002102585700001802606700002402624700003102648700002502679700001702704700002102721700002202742700002402764700002102788700001902809700002302828700001902851700002102870700002102891700001202912700002202924700002102946700002402967700002202991700002203013700001903035700001803054700002003072700002003092700001803112700002003130700002003150700002303170700001803193700001903211700002203230700001603252700002103268700001803289700002803307700001803335700002703353700002203380700002203402700002203424700002503446700002103471700002103492700002203513700001903535700001603554700001703570700002303587700002103610700002103631700002003652700001503672700002203687700001703709700002203726700002103748700002003769700002303789700001803812700002103830700001603851700002303867700002803890700002203918700001903940700002003959700002303979700002504002700002204027700002004049700002104069700002004090700002604110700001904136700002004155700001904175700001904194700001904213700002004232700002304252700002004275700002304295700002304318700002004341700002604361700002104387700002204408700001604430700002004446700002504466700001904491700002004510700002104530700001904551700002004570700002404590700002504614700002104639700003504660700001904695700002704714700002604741700002204767700002304789700002404812700002504836700002804861700001904889700002304908700002804931700002304959700002704982700002405009700002405033700001905057700002605076700001705102700002505119700002105144700002305165700002205188700002105210700002705231700002105258700002205279700003105301700001205332700001805344700001905362700001705381700002305398700002205421700002305443700002105466700001905487856003605506 2019 eng d a1938-320700aDisentangling the genetics of lean mass.0 aDisentangling the genetics of lean mass c2019 Feb 01 a276-2870 v1093 aBackground: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.
Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.
Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).
Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.
Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
1 aKarasik, David1 aZillikens, Carola, M1 aHsu, Yi-Hsiang1 aAghdassi, Ali1 aÅkesson, Kristina1 aAmin, Najaf1 aBarroso, Inês1 aBennett, David, A1 aBertram, Lars1 aBochud, Murielle1 aBorecki, Ingrid, B1 aBroer, Linda1 aBuchman, Aron, S1 aByberg, Liisa1 aCampbell, Harry1 aCampos-Obando, Natalia1 aCauley, Jane, A1 aCawthon, Peggy, M1 aChambers, John, C1 aChen, Zhao1 aCho, Nam, H1 aChoi, Hyung, Jin1 aChou, Wen-Chi1 aCummings, Steven, R1 ade Groot, Lisette, C P G M1 aDe Jager, Phillip, L1 aDemuth, Ilja1 aDiatchenko, Luda1 aEcons, Michael, J1 aEiriksdottir, Gudny1 aEnneman, Anke, W1 aEriksson, Joel1 aEriksson, Johan, G1 aEstrada, Karol1 aEvans, Daniel, S1 aFeitosa, Mary, F1 aFu, Mao1 aGieger, Christian1 aGrallert, Harald1 aGudnason, Vilmundur1 aLenore, Launer, J1 aHayward, Caroline1 aHofman, Albert1 aHomuth, Georg1 aHuffman, Kim, M1 aHusted, Lise, B1 aIllig, Thomas1 aIngelsson, Erik1 aIttermann, Till1 aJansson, John-Olov1 aJohnson, Toby1 aBiffar, Reiner1 aJordan, Joanne, M1 aJula, Antti1 aKarlsson, Magnus1 aKhaw, Kay-Tee1 aKilpeläinen, Tuomas, O1 aKlopp, Norman1 aKloth, Jacqueline, S L1 aKoller, Daniel, L1 aKooner, Jaspal, S1 aKraus, William, E1 aKritchevsky, Stephen1 aKutalik, Zoltán1 aKuulasmaa, Teemu1 aKuusisto, Johanna1 aLaakso, Markku1 aLahti, Jari1 aLang, Thomas1 aLangdahl, Bente, L1 aLerch, Markus, M1 aLewis, Joshua, R1 aLill, Christina1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLivshits, Gregory1 aLjunggren, Osten1 aLoos, Ruth, J F1 aLorentzon, Mattias1 aLuan, Jian'an1 aLuben, Robert, N1 aMalkin, Ida1 aMcGuigan, Fiona, E1 aMedina-Gómez, Carolina1 aMeitinger, Thomas1 aMelhus, Håkan1 aMellström, Dan1 aMichaëlsson, Karl1 aMitchell, Braxton, D1 aMorris, Andrew, P1 aMosekilde, Leif1 aNethander, Maria1 aNewman, Anne, B1 aO'Connell, Jeffery, R1 aOostra, Ben, A1 aOrwoll, Eric, S1 aPalotie, Aarno1 aPeacock, Munro1 aPerola, Markus1 aPeters, Annette1 aPrince, Richard, L1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRalston, Stuart, H1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRobbins, John, A1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSatterfield, Suzanne1 aSchipf, Sabine1 aShin, Chan, Soo1 aSmith, Albert, V1 aSmith, Shad, B1 aSoranzo, Nicole1 aSpector, Timothy, D1 aStančáková, Alena1 aStefansson, Kari1 aSteinhagen-Thiessen, Elisabeth1 aStolk, Lisette1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aSwart, Karin, M A1 aThompson, Patricia1 aThomson, Cynthia, A1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTikkanen, Emmi1 aTranah, Gregory, J1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 avan Schoor, Natasja, M1 aVandenput, Liesbeth1 aVollenweider, Peter1 aVölzke, Henry1 aWactawski-Wende, Jean1 aWalker, Mark1 aWareham, Nicholas, J1 aWaterworth, Dawn1 aWeedon, Michael, N1 aWichmann, H-Erich1 aWiden, Elisabeth1 aWilliams, Frances, M K1 aWilson, James, F1 aWright, Nicole, C1 aYerges-Armstrong, Laura, M1 aYu, Lei1 aZhang, Weihua1 aZhao, Jing Hua1 aZhou, Yanhua1 aNielson, Carrie, M1 aHarris, Tamara, B1 aDemissie, Serkalem1 aKiel, Douglas, P1 aOhlsson, Claes uhttps://chs-nhlbi.org/node/7974