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Genome-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/130110597nas a2203385 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2013 eng d a1546-171800aCommon variants associated with plasma triglycerides and risk for coronary artery disease.0 aCommon variants associated with plasma triglycerides and risk fo c2013 Nov a1345-520 v453 aTriglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
10aBiological Transport10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors10aTriglycerides1 aDo, Ron1 aWiller, Cristen, J1 aSchmidt, Ellen, M1 aSengupta, Sebanti1 aGao, Chi1 aPeloso, Gina, M1 aGustafsson, Stefan1 aKanoni, Stavroula1 aGanna, Andrea1 aChen, Jin1 aBuchkovich, Martin, L1 aMora, Samia1 aBeckmann, Jacques, S1 aBragg-Gresham, Jennifer, L1 aChang, Hsing-Yi1 aDemirkan, Ayse1 aHertog, Heleen, M Den1 aDonnelly, Louise, A1 aEhret, Georg, B1 aEsko, Tõnu1 aFeitosa, Mary, F1 aFerreira, Teresa1 aFischer, Krista1 aFontanillas, Pierre1 aFraser, Ross, M1 aFreitag, Daniel, F1 aGurdasani, Deepti1 aHeikkilä, Kauko1 aHyppönen, Elina1 aIsaacs, Aaron1 aJackson, Anne, U1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKettunen, Johannes1 aKleber, Marcus, E1 aLi, Xiaohui1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMihailov, Evelin1 aMontasser, May, E1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aPalmer, Cameron, D1 aPerola, Markus1 aPetersen, Ann-Kristin1 aSanna, Serena1 aSaxena, Richa1 aService, Susan, K1 aShah, Sonia1 aShungin, Dmitry1 aSidore, Carlo1 aSong, Ci1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTanaka, Toshiko1 aTeslovich, Tanya, M1 aThorleifsson, Gudmar1 avan den Herik, Evita, G1 aVoight, Benjamin, F1 aVolcik, Kelly, A1 aWaite, Lindsay, L1 aWong, Andrew1 aWu, Ying1 aZhang, Weihua1 aAbsher, Devin1 aAsiki, Gershim1 aBarroso, Inês1 aBeen, Latonya, F1 aBolton, Jennifer, L1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBurnett, Mary, S1 aCesana, Giancarlo1 aDimitriou, Maria1 aDoney, Alex, S F1 aDöring, Angela1 aElliott, Paul1 aEpstein, Stephen, E1 aEyjolfsson, Gudmundur, Ingi1 aGigante, Bruna1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGravito, Martha, L1 aGroves, Christopher, J1 aHallmans, Göran1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHernandez, Dena1 aHicks, Andrew, A1 aHolm, Hilma1 aHung, Yi-Jen1 aIllig, Thomas1 aJones, Michelle, R1 aKaleebu, Pontiano1 aKastelein, John, J P1 aKhaw, Kay-Tee1 aKim, Eric1 aKlopp, Norman1 aKomulainen, Pirjo1 aKumari, Meena1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLin, Shih-Yi1 aLindström, Jaana1 aLoos, Ruth, J F1 aMach, François1 aMcArdle, Wendy, L1 aMeisinger, Christa1 aMitchell, Braxton, D1 aMüller, Gabrielle1 aNagaraja, Ramaiah1 aNarisu, Narisu1 aNieminen, Tuomo, V M1 aNsubuga, Rebecca, N1 aOlafsson, Isleifur1 aOng, Ken, K1 aPalotie, Aarno1 aPapamarkou, Theodore1 aPomilla, Cristina1 aPouta, Anneli1 aRader, Daniel, J1 aReilly, Muredach, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRudan, Igor1 aRuokonen, Aimo1 aSamani, Nilesh1 aScharnagl, Hubert1 aSeeley, Janet1 aSilander, Kaisa1 aStančáková, Alena1 aStirrups, Kathleen1 aSwift, Amy, J1 aTiret, Laurence1 aUitterlinden, André, G1 avan Pelt, Joost1 aVedantam, Sailaja1 aWainwright, Nicholas1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWilson, James, F1 aYoung, Elizabeth, H1 aZhao, Jing Hua1 aAdair, Linda, S1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBennett, Franklyn1 aBochud, Murielle1 aBoehm, Bernhard, O1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aBornstein, Stefan, R1 aBovet, Pascal1 aBurnier, Michel1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChen, Yii-Der Ida1 aCollins, Francis, S1 aCooper, Richard, S1 aDanesh, John1 aDedoussis, George1 ade Faire, Ulf1 aFeranil, Alan, B1 aFerrieres, Jean1 aFerrucci, Luigi1 aFreimer, Nelson, B1 aGieger, Christian1 aGroop, Leif, C1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHingorani, Aroon1 aHirschhorn, Joel, N1 aHofman, Albert1 aHovingh, Kees1 aHsiung, Chao, Agnes1 aHumphries, Steve, E1 aHunt, Steven, C1 aHveem, Kristian1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKaprio, Jaakko1 aKesäniemi, Antero1 aKivimaki, Mika1 aKooner, Jaspal, S1 aKoudstaal, Peter, J1 aKrauss, Ronald, M1 aKuh, Diana1 aKuusisto, Johanna1 aKyvik, Kirsten, O1 aLaakso, Markku1 aLakka, Timo, A1 aLind, Lars1 aLindgren, Cecilia, M1 aMartin, Nicholas, G1 aMärz, Winfried1 aMcCarthy, Mark, I1 aMcKenzie, Colin, A1 aMeneton, Pierre1 aMetspalu, Andres1 aMoilanen, Leena1 aMorris, Andrew, D1 aMunroe, Patricia, B1 aNjølstad, Inger1 aPedersen, Nancy, L1 aPower, Chris1 aPramstaller, Peter, P1 aPrice, Jackie, F1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRauramaa, Rainer1 aSaleheen, Danish1 aSalomaa, Veikko1 aSanghera, Dharambir, K1 aSaramies, Jouko1 aSchwarz, Peter, E H1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aSiegbahn, Agneta1 aSpector, Tim, D1 aStefansson, Kari1 aStrachan, David, P1 aTayo, Bamidele, O1 aTremoli, Elena1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aDuijn, Cornelia, M1 aVollenweider, Peter1 aWallentin, Lars1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWolffenbuttel, Bruce, H R1 aAltshuler, David1 aOrdovas, Jose, M1 aBoerwinkle, Eric1 aPalmer, Colin, N A1 aThorsteinsdottir, Unnur1 aChasman, Daniel, I1 aRotter, Jerome, I1 aFranks, Paul, W1 aRipatti, Samuli1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRich, Stephen, S1 aBoehnke, Michael1 aDeloukas, Panos1 aMohlke, Karen, L1 aIngelsson, Erik1 aAbecasis, Goncalo, R1 aDaly, Mark, J1 aNeale, Benjamin, M1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/801410661nas a2203397 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2013 eng d a1546-171800aDiscovery and refinement of loci associated with lipid levels.0 aDiscovery and refinement of loci associated with lipid levels c2013 Nov a1274-12830 v453 aLevels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
10aAfrican Continental Ancestry Group10aAsian Continental Ancestry Group10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLipids10aTriglycerides1 aWiller, Cristen, J1 aSchmidt, Ellen, M1 aSengupta, Sebanti1 aPeloso, Gina, M1 aGustafsson, Stefan1 aKanoni, Stavroula1 aGanna, Andrea1 aChen, Jin1 aBuchkovich, Martin, L1 aMora, Samia1 aBeckmann, Jacques, S1 aBragg-Gresham, Jennifer, L1 aChang, Hsing-Yi1 aDemirkan, Ayse1 aHertog, Heleen, M Den1 aDo, Ron1 aDonnelly, Louise, A1 aEhret, Georg, B1 aEsko, Tõnu1 aFeitosa, Mary, F1 aFerreira, Teresa1 aFischer, Krista1 aFontanillas, Pierre1 aFraser, Ross, M1 aFreitag, Daniel, F1 aGurdasani, Deepti1 aHeikkilä, Kauko1 aHyppönen, Elina1 aIsaacs, Aaron1 aJackson, Anne, U1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKettunen, Johannes1 aKleber, Marcus, E1 aLi, Xiaohui1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMihailov, Evelin1 aMontasser, May, E1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aPalmer, Cameron, D1 aPerola, Markus1 aPetersen, Ann-Kristin1 aSanna, Serena1 aSaxena, Richa1 aService, Susan, K1 aShah, Sonia1 aShungin, Dmitry1 aSidore, Carlo1 aSong, Ci1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTanaka, Toshiko1 aTeslovich, Tanya, M1 aThorleifsson, Gudmar1 avan den Herik, Evita, G1 aVoight, Benjamin, F1 aVolcik, Kelly, A1 aWaite, Lindsay, L1 aWong, Andrew1 aWu, Ying1 aZhang, Weihua1 aAbsher, Devin1 aAsiki, Gershim1 aBarroso, Inês1 aBeen, Latonya, F1 aBolton, Jennifer, L1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBurnett, Mary, S1 aCesana, Giancarlo1 aDimitriou, Maria1 aDoney, Alex, S F1 aDöring, Angela1 aElliott, Paul1 aEpstein, Stephen, E1 aEyjolfsson, Gudmundur, Ingi1 aGigante, Bruna1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGravito, Martha, L1 aGroves, Christopher, J1 aHallmans, Göran1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHernandez, Dena1 aHicks, Andrew, A1 aHolm, Hilma1 aHung, Yi-Jen1 aIllig, Thomas1 aJones, Michelle, R1 aKaleebu, Pontiano1 aKastelein, John, J P1 aKhaw, Kay-Tee1 aKim, Eric1 aKlopp, Norman1 aKomulainen, Pirjo1 aKumari, Meena1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLin, Shih-Yi1 aLindström, Jaana1 aLoos, Ruth, J F1 aMach, François1 aMcArdle, Wendy, L1 aMeisinger, Christa1 aMitchell, Braxton, D1 aMüller, Gabrielle1 aNagaraja, Ramaiah1 aNarisu, Narisu1 aNieminen, Tuomo, V M1 aNsubuga, Rebecca, N1 aOlafsson, Isleifur1 aOng, Ken, K1 aPalotie, Aarno1 aPapamarkou, Theodore1 aPomilla, Cristina1 aPouta, Anneli1 aRader, Daniel, J1 aReilly, Muredach, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRudan, Igor1 aRuokonen, Aimo1 aSamani, Nilesh1 aScharnagl, Hubert1 aSeeley, Janet1 aSilander, Kaisa1 aStančáková, Alena1 aStirrups, Kathleen1 aSwift, Amy, J1 aTiret, Laurence1 aUitterlinden, André, G1 avan Pelt, Joost1 aVedantam, Sailaja1 aWainwright, Nicholas1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWilson, James, F1 aYoung, Elizabeth, H1 aZhao, Jing Hua1 aAdair, Linda, S1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBennett, Franklyn1 aBochud, Murielle1 aBoehm, Bernhard, O1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aBornstein, Stefan, R1 aBovet, Pascal1 aBurnier, Michel1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChen, Yii-Der Ida1 aCollins, Francis, S1 aCooper, Richard, S1 aDanesh, John1 aDedoussis, George1 ade Faire, Ulf1 aFeranil, Alan, B1 aFerrieres, Jean1 aFerrucci, Luigi1 aFreimer, Nelson, B1 aGieger, Christian1 aGroop, Leif, C1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHingorani, Aroon1 aHirschhorn, Joel, N1 aHofman, Albert1 aHovingh, Kees1 aHsiung, Chao, Agnes1 aHumphries, Steve, E1 aHunt, Steven, C1 aHveem, Kristian1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKaprio, Jaakko1 aKesäniemi, Antero1 aKivimaki, Mika1 aKooner, Jaspal, S1 aKoudstaal, Peter, J1 aKrauss, Ronald, M1 aKuh, Diana1 aKuusisto, Johanna1 aKyvik, Kirsten, O1 aLaakso, Markku1 aLakka, Timo, A1 aLind, Lars1 aLindgren, Cecilia, M1 aMartin, Nicholas, G1 aMärz, Winfried1 aMcCarthy, Mark, I1 aMcKenzie, Colin, A1 aMeneton, Pierre1 aMetspalu, Andres1 aMoilanen, Leena1 aMorris, Andrew, D1 aMunroe, Patricia, B1 aNjølstad, Inger1 aPedersen, Nancy, L1 aPower, Chris1 aPramstaller, Peter, P1 aPrice, Jackie, F1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRauramaa, Rainer1 aSaleheen, Danish1 aSalomaa, Veikko1 aSanghera, Dharambir, K1 aSaramies, Jouko1 aSchwarz, Peter, E H1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aSiegbahn, Agneta1 aSpector, Tim, D1 aStefansson, Kari1 aStrachan, David, P1 aTayo, Bamidele, O1 aTremoli, Elena1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aDuijn, Cornelia, M1 aVollenweider, Peter1 aWallentin, Lars1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWolffenbuttel, Bruce, H R1 aOrdovas, Jose, M1 aBoerwinkle, Eric1 aPalmer, Colin, N A1 aThorsteinsdottir, Unnur1 aChasman, Daniel, I1 aRotter, Jerome, I1 aFranks, Paul, W1 aRipatti, Samuli1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRich, Stephen, S1 aBoehnke, Michael1 aDeloukas, Panos1 aKathiresan, Sekar1 aMohlke, Karen, L1 aIngelsson, Erik1 aAbecasis, Goncalo, R1 aGlobal Lipids Genetics Consortium uhttps://chs-nhlbi.org/node/615411009nas a2203553 4500008004100000022001400041245011100055210006900166260001300235300001100248490000700259520106100266653001201327653002501339653001901364653001701383653003401400653002801434653001501462653001101477653003601488653003601524653002801560100002201588700002201610700001601632700002701648700001901675700002001694700001901714700002301733700001601756700002501772700002101797700001801818700001801836700001501854700001901869700001901888700002001907700001601927700001901943700002101962700002301983700002502006700002502031700001802056700001502074700002202089700002402111700001602135700002102151700002102172700001802193700001802211700002302229700002102252700002302273700002202296700002002318700002202338700002502360700002302385700002002408700001702428700002002445700002502465700002202490700001902512700002102531700001802552700002502570700002102595700002202616700002202638700002102660700003102681700001302712700002302725700001602748700001602764700001802780700002502798700001902823700001902842700002502861700002102886700002502907700002002932700001902952700002502971700001802996700002403014700002103038700001603059700001903075700002003094700001803114700001803132700002203150700002003172700002703192700001903219700002203238700002403260700002203284700002803306700002203334700002303356700002103379700001903400700002203419700002803441700002403469700002203493700001903515700002103534700001903555700001603574700002003590700001803610700002303628700002203651700001703673700001803690700001703708700001803725700002303743700002403766700002103790700001703811700002103828700002403849700002103873700002603894700002503920700002403945700002203969700002503991700002204016700002304038700002504061700002404086700003004110700001704140700001604157700002604173700003004199700001604229700002004245700002004265700001904285700001804304700002604322700002004348700002004368700001904388700002504407700001704432700001804449700002104467700002004488700001904508700002004527700002504547700002104572700002004593700002004613700001804633700002604651700002304677700002804700700002404728700002004752700002304772700002004795700001904815700002304834700002104857700003004878700001704908700001704925700002004942700001904962700002304981700002305004700002305027700002305050700001705073700002105090700002205111700002105133700002005154700001905174700002405193700001505217700001505232700002405247700001905271700002305290700002405313700002205337700002205359700002905381700001705410700002305427700002005450700002905470700002505499700002105524700002305545700002105568700002505589700002205614700001705636700001805653700002005671700002005691700001905711700002105730700002505751700001605776700002005792700001905812700001705831700002305848700002105871700002205892700001505914700002705929700001605956700002005972700002705992700003006019700002206049700001706071700002206088700002206110700002606132700002506158700001806183700002406201700001906225700002106244700001106265700002306276700001806299700001906317700002006336700001606356700002006372700002006392700002206412700002306434700001906457700002206476700002106498700002306519700002406542700002806566700002206594700002806616700001906644700001906663700002406682700002006706700002106726700001906747700002106766700002306787700002006810700001706830700002206847700002206869700001806891700002206909700002906931700002406960700002606984700002107010700001907031700002507050700002407075700002107099700002507120700002407145700002007169700002007189700002007209700002207229700002007251710002807271710002607299710002307325710002407348710002207372710002507394856003607419 2013 eng d a1546-171800aIdentification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.0 aIdentification of heart rateassociated loci and their effects on c2013 Jun a621-310 v453 aElevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
10aAnimals10aArrhythmias, Cardiac10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHeart Rate10aHumans10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aHoed, Marcel, den1 aEijgelsheim, Mark1 aEsko, Tõnu1 aBrundel, Bianca, J J M1 aPeal, David, S1 aEvans, David, M1 aNolte, Ilja, M1 aSegrè, Ayellet, V1 aHolm, Hilma1 aHandsaker, Robert, E1 aWestra, Harm-Jan1 aJohnson, Toby1 aIsaacs, Aaron1 aYang, Jian1 aLundby, Alicia1 aZhao, Jing Hua1 aKim, Young, Jin1 aGo, Min Jin1 aAlmgren, Peter1 aBochud, Murielle1 aBoucher, Gabrielle1 aCornelis, Marilyn, C1 aGudbjartsson, Daniel1 aHadley, David1 aHarst, Pim1 aHayward, Caroline1 aHeijer, Martin, den1 aIgl, Wilmar1 aJackson, Anne, U1 aKutalik, Zoltán1 aLuan, Jian'an1 aKemp, John, P1 aKristiansson, Kati1 aLadenvall, Claes1 aLorentzon, Mattias1 aMontasser, May, E1 aNjajou, Omer, T1 aO'Reilly, Paul, F1 aPadmanabhan, Sandosh1 aSt Pourcain, Beate1 aRankinen, Tuomo1 aSalo, Perttu1 aTanaka, Toshiko1 aTimpson, Nicholas, J1 aVitart, Veronique1 aWaite, Lindsay1 aWheeler, William1 aZhang, Weihua1 aDraisma, Harmen, H M1 aFeitosa, Mary, F1 aKerr, Kathleen, F1 aLind, Penelope, A1 aMihailov, Evelin1 aOnland-Moret, Charlotte, N1 aSong, Ci1 aWeedon, Michael, N1 aXie, Weijia1 aYengo, Loic1 aAbsher, Devin1 aAlbert, Christine, M1 aAlonso, Alvaro1 aArking, Dan, E1 ade Bakker, Paul, I W1 aBalkau, Beverley1 aBarlassina, Cristina1 aBenaglio, Paola1 aBis, Joshua, C1 aBouatia-Naji, Nabila1 aBrage, Søren1 aChanock, Stephen, J1 aChines, Peter, S1 aChung, Mina1 aDarbar, Dawood1 aDina, Christian1 aDörr, Marcus1 aElliott, Paul1 aFelix, Stephan, B1 aFischer, Krista1 aFuchsberger, Christian1 aGeus, Eco, J C1 aGoyette, Philippe1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHicks, Andrew, A1 aHofman, Albert1 aHolewijn, Suzanne1 aHoogstra-Berends, Femke1 aHottenga, Jouke-Jan1 aJensen, Majken, K1 aJohansson, Asa1 aJunttila, Juhani1 aKääb, Stefan1 aKanon, Bart1 aKetkar, Shamika1 aKhaw, Kay-Tee1 aKnowles, Joshua, W1 aKooner, Angrad, S1 aKors, Jan, A1 aKumari, Meena1 aMilani, Lili1 aLaiho, Päivi1 aLakatta, Edward, G1 aLangenberg, Claudia1 aLeusink, Maarten1 aLiu, Yongmei1 aLuben, Robert, N1 aLunetta, Kathryn, L1 aLynch, Stacey, N1 aMarkus, Marcello, R P1 aMarques-Vidal, Pedro1 aLeach, Irene, Mateo1 aMcArdle, Wendy, L1 aMcCarroll, Steven, A1 aMedland, Sarah, E1 aMiller, Kathryn, A1 aMontgomery, Grant, W1 aMorrison, Alanna, C1 aMüller-Nurasyid, Martina1 aNavarro, Pau1 aNelis, Mari1 aO'Connell, Jeffrey, R1 aO'Donnell, Christopher, J1 aOng, Ken, K1 aNewman, Anne, B1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aRao, Dabeeru, C1 aRing, Susan, M1 aRossin, Elizabeth, J1 aRudan, Diana1 aSanna, Serena1 aScott, Robert, A1 aSehmi, Jaban, S1 aSharp, Stephen1 aShin, Jordan, T1 aSingleton, Andrew, B1 aSmith, Albert, V1 aSoranzo, Nicole1 aSpector, Tim, D1 aStewart, Chip1 aStringham, Heather, M1 aTarasov, Kirill, V1 aUitterlinden, André, G1 aVandenput, Liesbeth1 aHwang, Shih-Jen1 aWhitfield, John, B1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWitteman, Jacqueline, C M1 aWong, Andrew1 aWong, Quenna1 aJamshidi, Yalda1 aZitting, Paavo1 aBoer, Jolanda, M A1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aEkelund, Ulf1 aForouhi, Nita, G1 aFroguel, Philippe1 aHingorani, Aroon1 aIngelsson, Erik1 aKivimaki, Mika1 aKronmal, Richard, A1 aKuh, Diana1 aLind, Lars1 aMartin, Nicholas, G1 aOostra, Ben, A1 aPedersen, Nancy, L1 aQuertermous, Thomas1 aRotter, Jerome, I1 aSchouw, Yvonne, T1 aVerschuren, W, M Monique1 aWalker, Mark1 aAlbanes, Demetrius1 aArnar, David, O1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBoehnke, Michael1 ade Boer, Rudolf, A1 aBouchard, Claude1 aCaulfield, W, L Mark1 aChambers, John, C1 aCurhan, Gary1 aCusi, Daniele1 aEriksson, Johan1 aFerrucci, Luigi1 aGilst, Wiek, H1 aGlorioso, Nicola1 ade Graaf, Jacqueline1 aGroop, Leif1 aGyllensten, Ulf1 aHsueh, Wen-Chi1 aHu, Frank, B1 aHuikuri, Heikki, V1 aHunter, David, J1 aIribarren, Carlos1 aIsomaa, Bo1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKiemeney, Lambertus, A1 avan der Klauw, Melanie, M1 aKooner, Jaspal, S1 aKraft, Peter1 aIacoviello, Licia1 aLehtimäki, Terho1 aLokki, Marja-Liisa, L1 aMitchell, Braxton, D1 aNavis, Gerjan1 aNieminen, Markku, S1 aOhlsson, Claes1 aPoulter, Neil, R1 aQi, Lu1 aRaitakari, Olli, T1 aRimm, Eric, B1 aRioux, John, D1 aRizzi, Federica1 aRudan, Igor1 aSalomaa, Veikko1 aSever, Peter, S1 aShields, Denis, C1 aShuldiner, Alan, R1 aSinisalo, Juha1 aStanton, Alice, V1 aStolk, Ronald, P1 aStrachan, David, P1 aTardif, Jean-Claude1 aThorsteinsdottir, Unnur1 aTuomilehto, Jaako1 avan Veldhuisen, Dirk, J1 aVirtamo, Jarmo1 aViikari, Jorma1 aVollenweider, Peter1 aWaeber, Gérard1 aWiden, Elisabeth1 aCho, Yoon Shin1 aOlsen, Jesper, V1 aVisscher, Peter, M1 aWiller, Cristen1 aFranke, Lude1 aErdmann, Jeanette1 aThompson, John, R1 aPfeufer, Arne1 aSotoodehnia, Nona1 aNewton-Cheh, Christopher1 aEllinor, Patrick, T1 aStricker, Bruno, H Ch1 aMetspalu, Andres1 aPerola, Markus1 aBeckmann, Jacques, S1 aSmith, George Davey1 aStefansson, Kari1 aWareham, Nicholas, J1 aMunroe, Patricia, B1 aSibon, Ody, C M1 aMilan, David, J1 aSnieder, Harold1 aSamani, Nilesh, J1 aLoos, Ruth, J F1 aGlobal BPgen Consortium1 aCARDIoGRAM consortium1 aPR GWAS Consortium1 aQRS GWAS Consortium1 aQT-IGC consortium1 aCHARGE-AF Consortium uhttps://chs-nhlbi.org/node/801503066nas a2200577 4500008004100000022001400041245008100055210006900136260001300205300001300218490000700231520143400238653001101672653002301683653001801706653001101724653004301735653001901778653001701797653001801814653003401832653001101866653001901877653001801896653002001914653000901934653002301943653001401966653001601980653001901996653003602015653003302051653002102084653002302105653002702128100001802155700002302173700002002196700001302216700002502229700002102254700001802275700002002293700001802313700002302331700002502354700002202379700002502401710002602426856003602452 2017 eng d a1553-740400aRare coding variants pinpoint genes that control human hematological traits.0 aRare coding variants pinpoint genes that control human hematolog c2017 Aug ae10069250 v133 aThe identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.
10aAsthma10aDatabases, Genetic10aEndometriosis10aFemale10aFibrin Fibrinogen Degradation Products10aGene Frequency10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aInterleukin-3310aLinear Models10aLogistic Models10aMale10aMutation, Missense10aPhenotype10aPlasminogen10aPlatelet Count10aPolymorphism, Single Nucleotide10aPrincipal Component Analysis10aProtein Splicing10aRhinitis, Allergic10aSequence Analysis, DNA1 aMousas, Abdou1 aNtritsos, Georgios1 aChen, Ming-Huei1 aSong, Ci1 aHuffman, Jennifer, E1 aTzoulaki, Ioanna1 aElliott, Paul1 aPsaty, Bruce, M1 aAuer, Paul, L1 aJohnson, Andrew, D1 aEvangelou, Evangelos1 aLettre, Guillaume1 aReiner, Alexander, P1 aBlood-Cell Consortium uhttps://chs-nhlbi.org/node/757705032nas a2201033 4500008004100000022001400041245016100055210006900216260001600285520189700301100002502198700002502223700002202248700002102270700002802291700001302319700002102332700002802353700001902381700002002400700002502420700001702445700002002462700002602482700002002508700002502528700001802553700001902571700002102590700002002611700002002631700001802651700002002669700002002689700002202709700002402731700002102755700002502776700002202801700001602823700002302839700002002862700002202882700002502904700001902929700003002948700001902978700001802997700002003015700002203035700002203057700002003079700001603099700002103115700001503136700002603151700002803177700001903205700002103224700001803245700002003263700002903283700002203312700002203334700003003356700002103386700001903407700002403426700002103450700002203471700002003493700002003513700002403533700002403557700002103581700002003602700002003622700001903642700001903661700003203680700002403712700002303736700003003759700002303789700002703812700002303839710010003862856003603962 2018 eng d a1524-453900aGenome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.0 aGenomeWide Association TransEthnic MetaAnalyses Identifies Novel c2018 Nov 203 aBACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.
METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.
RESULTS: We identified 13 novel genome-wide significant (p≤2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.
CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
1 aSabater-Lleal, Maria1 aHuffman, Jennifer, E1 ade Vries, Paul, S1 aMarten, Jonathan1 aMastrangelo, Michael, A1 aSong, Ci1 aPankratz, Nathan1 aWard-Caviness, Cavin, K1 aYanek, Lisa, R1 aTrompet, Stella1 aDelgado, Graciela, E1 aGuo, Xiuqing1 aBartz, Traci, M1 aMartinez-Perez, Angel1 aGermain, Marine1 ade Haan, Hugoline, G1 aOzel, Ayse, B1 aPolasek, Ozren1 aSmith, Albert, V1 aEicher, John, D1 aReiner, Alex, P1 aTang, Weihong1 aDavies, Neil, M1 aStott, David, J1 aRotter, Jerome, I1 aTofler, Geoffrey, H1 aBoerwinkle, Eric1 ade Maat, Moniek, P M1 aKleber, Marcus, E1 aWelsh, Paul1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aVaidya, Dhananjay1 aSoria, José, Manuel1 aSuchon, Pierre1 aVlieg, Astrid, van Hylcka1 aDesch, Karl, C1 aKolcic, Ivana1 aJoshi, Peter, K1 aLauner, Lenore, J1 aHarris, Tamara, B1 aCampbell, Harry1 aRudan, Igor1 aBecker, Diane, M1 aLi, Jun, Z1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aCushman, Mary1 aPsaty, Bruce, M1 aMorange, Pierre-Emmanuel1 aMcKnight, Barbara1 aChong, Michael, R1 aFernandez-Cadenas, Israel1 aRosand, Jonathan1 aLindgren, Arne1 aGudnason, Vilmundur1 aWilson, James, F1 aHayward, Caroline1 aGinsburg, David1 aFornage, Myriam1 aRosendaal, Frits, R1 aSouto, Juan, Carlos1 aBecker, Lewis, C1 aJenny, Nancy, S1 aMärz, Winfried1 aJukema, Wouter1 aDehghan, Abbas1 aTrégouët, David-Alexandre1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aStrachan, David, P1 aLowenstein, Charles, J1 aSmith, Nicholas, L1 aINVENT Consortium; MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC) uhttps://chs-nhlbi.org/node/792403820nas a2200697 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520168300286100002201969700002501991700002502016700002102041700001302062700002102075700002002096700002502116700002502141700002002166700002602186700002802212700002302240700002002263700002502283700002302308700001902331700002202350700002602372700002502398700001802423700002402441700002802465700003002493700002002523700002102543700002002564700002302584700001802607700002302625700002202648700002002670700002002690700003302710700002002743700002002763700002002783700002002803700002402823700002402847700001902871700002302890700002402913700003002937700002302967710002202990710007403012856003603086 2019 eng d a1528-002000aA genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.0 agenomewide association study identifies new loci for factor VII c2019 Feb 28 a967-9770 v1333 aFactor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a -ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel ( and ) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing in HuH7 cells upregulated FVII, whereas silencing downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at and contribute to FVII activity by regulating expression levels. FVII activity appears to contribute to the etiology of IS in the general population.
1 ade Vries, Paul, S1 aSabater-Lleal, Maria1 aHuffman, Jennifer, E1 aMarten, Jonathan1 aSong, Ci1 aPankratz, Nathan1 aBartz, Traci, M1 ade Haan, Hugoline, G1 aDelgado, Graciela, E1 aEicher, John, D1 aMartinez-Perez, Angel1 aWard-Caviness, Cavin, K1 aBrody, Jennifer, A1 aChen, Ming-Huei1 ade Maat, Moniek, P M1 aFrånberg, Mattias1 aGill, Dipender1 aKleber, Marcus, E1 aRivadeneira, Fernando1 aSoria, José, Manuel1 aTang, Weihong1 aTofler, Geoffrey, H1 aUitterlinden, André, G1 aVlieg, Astrid, van Hylcka1 aSeshadri, Sudha1 aBoerwinkle, Eric1 aDavies, Neil, M1 aGiese, Anne-Katrin1 aIkram, Kamran1 aKittner, Steven, J1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aReiner, Alex, P1 aSargurupremraj, Muralidharan1 aTaylor, Kent, D1 aFornage, Myriam1 aHamsten, Anders1 aMärz, Winfried1 aRosendaal, Frits, R1 aSouto, Juan, Carlos1 aDehghan, Abbas1 aJohnson, Andrew, D1 aMorrison, Alanna, C1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aINVENT Consortium1 aMEGASTROKE Consortium of the International Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/798804639nas a2200829 4500008004100000022001400041245010700055210006900162260000900231300001300240490000700253520225600260100002802516700002202544700002202566700002502588700001902613700002402632700002302656700001702679700002202696700002002718700001802738700002202756700002502778700002502803700001702828700001902845700003002864700002402894700002102918700002602939700002202965700002102987700002103008700001803029700001603047700002303063700001303086700002503099700002803124700002103152700002303173700002203196700002203218700002003240700002303260700002103283700002403304700002303328700002603351700002003377700002003397700001303417700001903430700002203449700002003471700001903491700001903510700002103529700002403550700002203574700002003596700001803616700002303634700001903657700003003676700002303706700002003729700002403749856003603773 2019 eng d a1932-620300aMendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.0 aMendelian randomization evaluation of causal effects of fibrinog c2019 ae02162220 v143 aBACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.
METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.
CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.
1 aWard-Caviness, Cavin, K1 ade Vries, Paul, S1 aWiggins, Kerri, L1 aHuffman, Jennifer, E1 aYanek, Lisa, R1 aBielak, Lawrence, F1 aGiulianini, Franco1 aGuo, Xiuqing1 aKleber, Marcus, E1 aKacprowski, Tim1 aGroß, Stefan1 aPetersman, Astrid1 aSmith, George, Davey1 aHartwig, Fernando, P1 aBowden, Jack1 aHemani, Gibran1 aMüller-Nuraysid, Martina1 aStrauch, Konstantin1 aKoenig, Wolfgang1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aPankratz, Nathan1 aBoerwinkle, Eric1 aTang, Weihong1 aFu, Yi-Ping1 aJohnson, Andrew, D1 aSong, Ci1 ade Maat, Moniek, P M1 aUitterlinden, André, G1 aFranco, Oscar, H1 aBrody, Jennifer, A1 aMcKnight, Barbara1 aChen, Yii-Der Ida1 aPsaty, Bruce, M1 aMathias, Rasika, A1 aBecker, Diane, M1 aPeyser, Patricia, A1 aSmith, Jennifer, A1 aBielinski, Suzette, J1 aRidker, Paul, M1 aTaylor, Kent, D1 aYao, Jie1 aTracy, Russell1 aDelgado, Graciela1 aTrompet, Stella1 aSattar, Naveed1 aJukema, Wouter1 aBecker, Lewis, C1 aKardia, Sharon, L R1 aRotter, Jerome, I1 aMärz, Winfried1 aDörr, Marcus1 aChasman, Daniel, I1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aPeters, Annette1 aMorrison, Alanna, C uhttps://chs-nhlbi.org/node/805003927nas a2200709 4500008004100000022001400041245011200055210006900167260001600236520183400252100002102086700001302107700001702120700002902137700002002166700003002186700002202216700002502238700001702263700001302280700002002293700002202313700002302335700002202358700001802380700002302398700002402421700002902445700002702474700002102501700002902522700001902551700002102570700002302591700002102614700002302635700002802658700001802686700001902704700001902723700002102742700002002763700001802783700002502801700001902826700003202845700002902877700002002906700002102926700002302947700001902970700001802989700002203007700002203029700002403051700002103075700002403096700002003120700001803140700002303158856003603181 2021 eng d a1538-783600aFGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.0 aFGL1 as a modulator of plasma Ddimer levels Exomewide marker ana c2021 Apr 203 aBACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.
OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.
METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.
RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.
CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.
1 aThibord, Florian1 aSong, Ci1 aPattee, Jack1 aRodriguez, Benjamin, A T1 aChen, Ming-Huei1 aO'Donnell, Christopher, J1 aKleber, Marcus, E1 aDelgado, Graciela, E1 aGuo, Xiuqing1 aYao, Jie1 aTaylor, Kent, D1 aOzel, Ayse, Bilge1 aBrody, Jennifer, A1 aMcKnight, Barbara1 aGyorgy, Beata1 aSimonsick, Eleanor1 aLeonard, Hampton, L1 aCarrasquilla, Germán, D1 aGuindo-Martinez, Marta1 aSilveira, Angela1 aTemprano-Sagrera, Gerard1 aYanek, Lisa, R1 aBecker, Diane, M1 aMathias, Rasika, A1 aBecker, Lewis, C1 aRaffield, Laura, M1 aKilpeläinen, Tuomas, O1 aGrarup, Niels1 aPedersen, Oluf1 aHansen, Torben1 aLinneberg, Allan1 aHamsten, Anders1 aWatkins, Hugh1 aSabater-Lleal, Maria1 aNalls, Mike, A1 aTrégouët, David-Alexandre1 aMorange, Pierre-Emmanuel1 aPsaty, Bruce, M1 aTracy, Russel, P1 aSmith, Nicholas, L1 aDesch, Karl, C1 aCushman, Mary1 aRotter, Jerome, I1 ade Vries, Paul, S1 aPankratz, Nathan, D1 aFolsom, Aaron, R1 aMorrison, Alanna, C1 aMärz, Winfried1 aTang, Weihong1 aJohnson, Andrew, D uhttps://chs-nhlbi.org/node/8791