03572nas a2200745 4500008004100000022001400041245011600055210006900171260001300240300001100253490000700264520148800271653001501759653001001774653000901784653002201793653001001815653002001825653001901845653002801864653004001892653001101932653003201943653001901975653001101994653000902005653001602014653001202030653003602042653001302078653001802091653001602109100002202125700002502147700001502172700001802187700002102205700002202226700002202248700002402270700002402294700002202318700001602340700002102356700002102377700002302398700002102421700002502442700001902467700002402486700001902510700002002529700002002549700002302569700002802592700001902620700002102639700002302660700002002683700002202703700002702725700001902752700001902771856003602790 2013 eng d a1939-327X00aThe influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study.0 ainfluence of obesityrelated single nucleotide polymorphisms on B c2013 May a1763-70 v623 a
Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m², respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aAging10aBody Mass Index10aCohort Studies10aCross-Sectional Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aHealth Surveys10aHumans10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aProteins10aUnited States10aYoung Adult1 aGraff, Mariaelisa1 aGordon-Larsen, Penny1 aLim, Unhee1 aFowke, Jay, H1 aLove, Shelly-Ann1 aFesinmeyer, Megan1 aWilkens, Lynne, R1 aVertilus, Shawyntee1 aRitchie, Marilyn, D1 aPrentice, Ross, L1 aPankow, Jim1 aMonroe, Kristine1 aManson, JoAnn, E1 aLe Marchand, Loïc1 aKuller, Lewis, H1 aKolonel, Laurence, N1 aHong, Ching, P1 aHenderson, Brian, E1 aHaessler, Jeff1 aGross, Myron, D1 aGoodloe, Robert1 aFranceschini, Nora1 aCarlson, Christopher, S1 aBuyske, Steven1 aBůzková, Petra1 aHindorff, Lucia, A1 aMatise, Tara, C1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aPeters, Ulrike1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/663009008nas a2202809 4500008004100000022001400041245010800055210006900163260001300232300001000245490000700255520108900262653002201351653002001373653002501393653001901418653001701437653003801454653003401492653001101526653002701537653001201564653003601576100001901612700001801631700002001649700002001669700002101689700002101710700001901731700002601750700002401776700002401800700001801824700002201842700002501864700001801889700001201907700001701919700001701936700001801953700002201971700001601993700002402009700001902033700002402052700002202076700002502098700002202123700002102145700002002166700002102186700001602207700002202223700002202245700001802267700001802285700001802303700001502321700002102336700002802357700002402385700002002409700003202429700002002461700002202481700002102503700001302524700002302537700002902560700002002589700001702609700002302626700001902649700002202668700002402690700002302714700002202737700002302759700002302782700002402805700002202829700001702851700002402868700001802892700002102910700002102931700002302952700002202975700001702997700001803014700001603032700002103048700002103069700001703090700002403107700002603131700002003157700002603177700001803203700002803221700001503249700002003264700002203284700001603306700002003322700002903342700002203371700001803393700002503411700002203436700002703458700002303485700002903508700002103537700002803558700002603586700002203612700002503634700003103659700002803690700002203718700002003740700002103760700002303781700002103804700001903825700003203844700002803876700002303904700002003927700001903947700002203966700002403988700002704012700002804039700001904067700002104086700002304107700001904130700002204149700001504171700001904186700002104205700002104226700001904247700001804266700002304284700001904307700001404326700001904340700001404359700002304373700002104396700002604417700002204443700002004465700001904485700002004504700002804524700001704552700002104569700001804590700002104608700002104629700002204650700002104672700002304693700002404716700002204740700001904762700002404781700002304805700002004828700001804848700002204866700001804888700002004906700002704926700002204953700002304975700001504998700001405013700002005027700001705047700001905064700002005083700002205103700002505125700002405150700002105174700002405195700001905219700002505238700002305263700001505286700002205301700002405323700002205347700002705369700002005396700002105416700001905437700002405456700002405480700002005504700001905524700002305543700002505566700002205591700002505613700002405638700002505662700002305687700001905710700002105729700001905750700001505769700002005784700002305804700002005827700001805847700002305865700002405888700002805912700002405940700002005964700002405984700002006008700001906028700002706047710002106074710002106095710002606116710002006142856003606162 2013 eng d a1546-171800aA meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.0 ametaanalysis identifies new loci associated with body mass index c2013 Jun a690-60 v453 aGenome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
10aAfrican Americans10aBody Mass Index10aCase-Control Studies10aGene Frequency10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aObesity10aPolymorphism, Single Nucleotide1 aMonda, Keri, L1 aChen, Gary, K1 aTaylor, Kira, C1 aPalmer, Cameron1 aEdwards, Todd, L1 aLange, Leslie, A1 aC Y Ng, Maggie1 aAdeyemo, Adebowale, A1 aAllison, Matthew, A1 aBielak, Lawrence, F1 aChen, Guanjie1 aGraff, Mariaelisa1 aIrvin, Marguerite, R1 aRhie, Suhn, K1 aLi, Guo1 aLiu, Yongmei1 aLiu, Youfang1 aLu, Yingchang1 aNalls, Michael, A1 aSun, Yan, V1 aWojczynski, Mary, K1 aYanek, Lisa, R1 aAldrich, Melinda, C1 aAdemola, Adeyinka1 aAmos, Christopher, I1 aBandera, Elisa, V1 aBock, Cathryn, H1 aBritton, Angela1 aBroeckel, Ulrich1 aCai, Quiyin1 aCaporaso, Neil, E1 aCarlson, Chris, S1 aCarpten, John1 aCasey, Graham1 aChen, Wei-Min1 aChen, Fang1 aChen, Yii-der, I1 aChiang, Charleston, W K1 aCoetzee, Gerhard, A1 aDemerath, Ellen1 aDeming-Halverson, Sandra, L1 aDriver, Ryan, W1 aDubbert, Patricia1 aFeitosa, Mary, F1 aFeng, Ye1 aFreedman, Barry, I1 aGillanders, Elizabeth, M1 aGottesman, Omri1 aGuo, Xiuqing1 aHaritunians, Talin1 aHarris, Tamara1 aHarris, Curtis, C1 aHennis, Anselm, J M1 aHernandez, Dena, G1 aMcNeill, Lorna, H1 aHoward, Timothy, D1 aHoward, Barbara, V1 aHoward, Virginia, J1 aJohnson, Karen, C1 aKang, Sun, J1 aKeating, Brendan, J1 aKolb, Suzanne1 aKuller, Lewis, H1 aKutlar, Abdullah1 aLangefeld, Carl, D1 aLettre, Guillaume1 aLohman, Kurt1 aLotay, Vaneet1 aLyon, Helen1 aManson, JoAnn, E1 aMaixner, William1 aMeng, Yan, A1 aMonroe, Kristine, R1 aMorhason-Bello, Imran1 aMurphy, Adam, B1 aMychaleckyj, Josyf, C1 aNadukuru, Raj1 aNathanson, Katherine, L1 aNayak, Uma1 aN'diaye, Amidou1 aNemesure, Barbara1 aWu, Suh-Yuh1 aLeske, Cristina1 aNeslund-Dudas, Christine1 aNeuhouser, Marian1 aNyante, Sarah1 aOchs-Balcom, Heather1 aOgunniyi, Adesola1 aOgundiran, Temidayo, O1 aOjengbede, Oladosu1 aOlopade, Olufunmilayo, I1 aPalmer, Julie, R1 aRuiz-Narvaez, Edward, A1 aPalmer, Nicholette, D1 aPress, Michael, F1 aRampersaud, Evandine1 aRasmussen-Torvik, Laura, J1 aRodriguez-Gil, Jorge, L1 aSalako, Babatunde1 aSchadt, Eric, E1 aSchwartz, Ann, G1 aShriner, Daniel, A1 aSiscovick, David1 aSmith, Shad, B1 aWassertheil-Smoller, Sylvia1 aSpeliotes, Elizabeth, K1 aSpitz, Margaret, R1 aSucheston, Lara1 aTaylor, Herman1 aTayo, Bamidele, O1 aTucker, Margaret, A1 aVan Den Berg, David, J1 aEdwards, Digna, R Velez1 aWang, Zhaoming1 aWiencke, John, K1 aWinkler, Thomas, W1 aWitte, John, S1 aWrensch, Margaret1 aWu, Xifeng1 aYang, James, J1 aLevin, Albert, M1 aYoung, Taylor, R1 aZakai, Neil, A1 aCushman, Mary1 aZanetti, Krista, A1 aZhao, Jing Hua1 aZhao, Wei1 aZheng, Yonglan1 aZhou, Jie1 aZiegler, Regina, G1 aZmuda, Joseph, M1 aFernandes, Jyotika, K1 aGilkeson, Gary, S1 aKamen, Diane, L1 aHunt, Kelly, J1 aSpruill, Ida, J1 aAmbrosone, Christine, B1 aAmbs, Stefan1 aArnett, Donna, K1 aAtwood, Larry1 aBecker, Diane, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBorecki, Ingrid, B1 aBottinger, Erwin, P1 aBowden, Donald, W1 aBurke, Gregory1 aChanock, Stephen, J1 aCooper, Richard, S1 aDing, Jingzhong1 aDuggan, David1 aEvans, Michele, K1 aFox, Caroline1 aGarvey, Timothy1 aBradfield, Jonathan, P1 aHakonarson, Hakon1 aGrant, Struan, F A1 aHsing, Ann1 aChu, Lisa1 aHu, Jennifer, J1 aHuo, Dezheng1 aIngles, Sue, A1 aJohn, Esther, M1 aJordan, Joanne, M1 aKabagambe, Edmond, K1 aKardia, Sharon, L R1 aKittles, Rick, A1 aGoodman, Phyllis, J1 aKlein, Eric, A1 aKolonel, Laurence, N1 aLe Marchand, Loïc1 aLiu, Simin1 aMcKnight, Barbara1 aMillikan, Robert, C1 aMosley, Thomas, H1 aPadhukasahasram, Badri1 aWilliams, Keoki1 aPatel, Sanjay, R1 aPeters, Ulrike1 aPettaway, Curtis, A1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aRotimi, Charles, N1 aRybicki, Benjamin, A1 aSale, Michèle, M1 aSchreiner, Pamela, J1 aSignorello, Lisa, B1 aSingleton, Andrew, B1 aStanford, Janet, L1 aStrom, Sara, S1 aThun, Michael, J1 aVitolins, Mara1 aZheng, Wei1 aMoore, Jason, H1 aWilliams, Scott, M1 aKetkar, Shamika1 aZhu, Xiaofeng1 aZonderman, Alan, B1 aKooperberg, Charles1 aPapanicolaou, George, J1 aHenderson, Brian, E1 aReiner, Alex, P1 aHirschhorn, Joel, N1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aNABEC Consortium1 aUKBEC Consortium1 aBioBank Japan Project1 aAGEN Consortium uhttps://chs-nhlbi.org/node/607810963nas 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/857006485nas a2201489 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2017 eng d a1553-740400aDiscovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium.0 aDiscovery and finemapping of adiposity loci using high density i c2017 Apr 21 ae10067190 v133 aGenome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
1 aC Y Ng, Maggie1 aGraff, Mariaelisa1 aLu, Yingchang1 aJustice, Anne, E1 aMudgal, Poorva1 aLiu, Ching-Ti1 aYoung, Kristin1 aYanek, Lisa, R1 aFeitosa, Mary, F1 aWojczynski, Mary, K1 aRand, Kristin1 aBrody, Jennifer, A1 aCade, Brian, E1 aDimitrov, Latchezar1 aDuan, Qing1 aGuo, Xiuqing1 aLange, Leslie, A1 aNalls, Michael, A1 aOkut, Hayrettin1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aVedantam, Sailaja1 aBradfield, Jonathan, P1 aChen, Guanjie1 aChen, Wei-Min1 aChesi, Alessandra1 aIrvin, Marguerite, R1 aPadhukasahasram, Badri1 aSmith, Jennifer, A1 aZheng, Wei1 aAllison, Matthew, A1 aAmbrosone, Christine, B1 aBandera, Elisa, V1 aBartz, Traci, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBottinger, Erwin, P1 aCarpten, John1 aChanock, Stephen, J1 aChen, Yii-Der Ida1 aConti, David, V1 aCooper, Richard, S1 aFornage, Myriam1 aFreedman, Barry, I1 aGarcia, Melissa1 aGoodman, Phyllis, J1 aHsu, Yu-Han, H1 aHu, Jennifer1 aHuff, Chad, D1 aIngles, Sue, A1 aJohn, Esther, M1 aKittles, Rick1 aKlein, Eric1 aLi, Jin1 aMcKnight, Barbara1 aNayak, Uma1 aNemesure, Barbara1 aOgunniyi, Adesola1 aOlshan, Andrew1 aPress, Michael, F1 aRohde, Rebecca1 aRybicki, Benjamin, A1 aSalako, Babatunde1 aSanderson, Maureen1 aShao, Yaming1 aSiscovick, David, S1 aStanford, Janet, L1 aStevens, Victoria, L1 aStram, Alex1 aStrom, Sara, S1 aVaidya, Dhananjay1 aWitte, John, S1 aYao, Jie1 aZhu, Xiaofeng1 aZiegler, Regina, G1 aZonderman, Alan, B1 aAdeyemo, Adebowale1 aAmbs, Stefan1 aCushman, Mary1 aFaul, Jessica, D1 aHakonarson, Hakon1 aLevin, Albert, M1 aNathanson, Katherine, L1 aWare, Erin, B1 aWeir, David, R1 aZhao, Wei1 aZhi, Degui1 aArnett, Donna, K1 aGrant, Struan, F A1 aKardia, Sharon, L R1 aOloapde, Olufunmilayo, I1 aRao, D, C1 aRotimi, Charles, N1 aSale, Michèle, M1 aWilliams, Keoki1 aZemel, Babette, S1 aBecker, Diane, M1 aBorecki, Ingrid, B1 aEvans, Michele, K1 aHarris, Tamara, B1 aHirschhorn, Joel, N1 aLi, Yun1 aPatel, Sanjay, R1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aWilson, James, G1 aBowden, Donald, W1 aCupples, Adrienne, L1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aNorth, Kari, E1 aBone Mineral Density in Childhood Study (BMDCS) Group uhttps://chs-nhlbi.org/node/735204016nas 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/758805566nas a2201489 4500008004100000022001400041245010700055210006900162260001600231300000800247490000600255520135700261100002001618700002001638700002801658700002001686700001701706700002601723700002001749700001901769700002601788700002501814700001401839700001901853700002101872700002901893700002101922700002301943700002301966700002201989700001402011700002802025700002002053700002002073700002102093700002002114700002502134700002502159700002202184700001902206700002402225700001902249700002102268700002402289700001902313700002402332700002102356700001602377700002102393700002402414700002102438700002302459700001702482700002102499700001402520700002602534700002002560700002202580700002102602700002402623700002302647700002002670700002002690700001802710700001502728700002102743700002302764700002402787700001902811700001802830700002502848700002202873700001702895700001502912700002502927700002402952700002602976700002003002700002603022700002203048700001803070700002203088700002003110700002003130700002003150700002303170700002203193700003503215700002603250700002303276700002303299700002403322700001803346700001803364700002303382700002303405700002203428700002203450700001903472700002703491700001803518700002003536700002403556700001903580700002103599700001703620700002003637700002303657700002103680700001903701700002403720700002803744700002303772700001903795700001903814700002103833700002303854700002203877700002003899700002403919700001903943700002003962700001603982700002103998700002104019856003604040 2017 eng d a2041-172300aGenome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.0 aGenomewide metaanalysis associates HLADQA1DRB1 and LPA and lifes c2017 Oct 13 a9100 v83 aGenomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
1 aJoshi, Peter, K1 aPirastu, Nicola1 aKentistou, Katherine, A1 aFischer, Krista1 aHofer, Edith1 aSchraut, Katharina, E1 aClark, David, W1 aNutile, Teresa1 aBarnes, Catriona, L K1 aTimmers, Paul, R H J1 aShen, Xia1 aGandin, Ilaria1 aMcDaid, Aaron, F1 aHansen, Thomas, Folkmann1 aGordon, Scott, D1 aGiulianini, Franco1 aBoutin, Thibaud, S1 aAbdellaoui, Abdel1 aZhao, Wei1 aMedina-Gómez, Carolina1 aBartz, Traci, M1 aTrompet, Stella1 aLange, Leslie, A1 aRaffield, Laura1 avan der Spek, Ashley1 aGalesloot, Tessel, E1 aProitsi, Petroula1 aYanek, Lisa, R1 aBielak, Lawrence, F1 aPayton, Antony1 aMurgia, Federico1 aConcas, Maria, Pina1 aBiino, Ginevra1 aTajuddin, Salman, M1 aSeppälä, Ilkka1 aAmin, Najaf1 aBoerwinkle, Eric1 aBørglum, Anders, D1 aCampbell, Archie1 aDemerath, Ellen, W1 aDemuth, Ilja1 aFaul, Jessica, D1 aFord, Ian1 aGialluisi, Alessandro1 aGögele, Martin1 aGraff, Mariaelisa1 aHingorani, Aroon1 aHottenga, Jouke-Jan1 aHougaard, David, M1 aHurme, Mikko, A1 aIkram, Arfan, M1 aJylhä, Marja1 aKuh, Diana1 aLigthart, Lannie1 aLill, Christina, M1 aLindenberger, Ulman1 aLumley, Thomas1 aMägi, Reedik1 aMarques-Vidal, Pedro1 aMedland, Sarah, E1 aMilani, Lili1 aNagy, Reka1 aOllier, William, E R1 aPeyser, Patricia, A1 aPramstaller, Peter, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRuggiero, Daniela1 aSaba, Yasaman1 aSchmidt, Reinhold1 aSchmidt, Helena1 aSlagboom, Eline1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aSteinhagen-Thiessen, Elisabeth1 avan Rooij, Frank, J A1 aVerbeek, André, L1 aVermeulen, Sita, H1 aVollenweider, Peter1 aWang, Yunpeng1 aWerge, Thomas1 aWhitfield, John, B1 aZonderman, Alan, B1 aLehtimäki, Terho1 aEvans, Michele, K1 aPirastu, Mario1 aFuchsberger, Christian1 aBertram, Lars1 aPendleton, Neil1 aKardia, Sharon, L R1 aCiullo, Marina1 aBecker, Diane, M1 aWong, Andrew1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWilson, James, G1 aJukema, Wouter1 aKiemeney, Lambertus1 aUitterlinden, André, G1 aFranceschini, Nora1 aNorth, Kari, E1 aWeir, David, R1 aMetspalu, Andres1 aBoomsma, Dorret, I1 aHayward, Caroline1 aChasman, Daniel1 aMartin, Nicholas, G1 aSattar, Naveed1 aCampbell, Harry1 aEsko, Tõnu1 aKutalik, Zoltán1 aWilson, James, F uhttps://chs-nhlbi.org/node/756804643nas a2200985 4500008004100000022001400041245023800055210006900293260001300362300001200375490000800387520178500395653002002180653001802200653002502218653001102243653001202254100003002266700001502296700002202311700002302333700002202356700002802378700001602406700002502422700002202447700002102469700002002490700002402510700001902534700001702553700002002570700002102590700001302611700001802624700002702642700002102669700002202690700002002712700001602732700001702748700002602765700001902791700001802810700002502828700001502853700002702868700002302895700002502918700001902943700001802962700002402980700002003004700002103024700001703045700001803062700001403080700001703094700001803111700001603129700002003145700001403165700001603179700002003195700002403215700002303239700002203262700002603284700002003310700002203330700001903352700002103371700002103392700002403413700002003437700002503457700002503482700001703507700002003524700001903544700002003563700001903583700001903602856003603621 2017 eng d a1432-120300aTrans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.0 aTransethnic finemapping of genetic loci for body mass index in t c2017 Jun a771-8000 v1363 aMost body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.
10aBody Mass Index10aEthnic Groups10aGenetics, Population10aHumans10aObesity1 aFernandez-Rhodes, Lindsay1 aGong, Jian1 aHaessler, Jeffrey1 aFranceschini, Nora1 aGraff, Mariaelisa1 aNishimura, Katherine, K1 aWang, Yujie1 aHighland, Heather, M1 aYoneyama, Sachiko1 aBush, William, S1 aGoodloe, Robert1 aRitchie, Marylyn, D1 aCrawford, Dana1 aGross, Myron1 aFornage, Myriam1 aBůzková, Petra1 aTao, Ran1 aIsasi, Carmen1 aAvilés-Santa, Larissa1 aDaviglus, Martha1 aMackey, Rachel, H1 aHouston, Denise1 aGu, Charles1 aEhret, Georg1 aNguyen, Khanh-Dung, H1 aLewis, Cora, E1 aLeppert, Mark1 aIrvin, Marguerite, R1 aLim, Unhee1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aSchumacher, Fredrick1 aWilkens, Lynne1 aLu, Yingchang1 aBottinger, Erwin, P1 aLoos, Ruth, J L1 aSheu, Wayne, H-H1 aGuo, Xiuqing1 aLee, Wen-Jane1 aHai, Yang1 aHung, Yi-Jen1 aAbsher, Devin1 aWu, I-Chien1 aTaylor, Kent, D1 aLee, I-Te1 aLiu, Yeheng1 aWang, Tzung-Dau1 aQuertermous, Thomas1 aJuang, Jyh-Ming, J1 aRotter, Jerome, I1 aAssimes, Themistocles1 aHsiung, Chao, A1 aChen, Yii-Der Ida1 aPrentice, Ross1 aKuller, Lewis, H1 aManson, JoAnn, E1 aKooperberg, Charles1 aSmokowski, Paul1 aRobinson, Whitney, R1 aGordon-Larsen, Penny1 aLi, Rongling1 aHindorff, Lucia1 aBuyske, Steven1 aMatise, Tara, C1 aPeters, Ulrike1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/746503699nas 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/777504963nas a2201357 4500008004100000022001400041245010700055210006900162260001600231300000900247490000600256520112300262100001901385700001701404700002001421700002301441700002401464700001901488700002601507700002601533700002001559700002101579700001301600700002801613700001601641700002701657700001501684700001701699700002401716700001801740700002101758700002901779700002501808700001901833700001901852700002001871700001901891700001901910700002401929700001601953700002101969700001801990700001802008700002202026700002202048700001702070700002302087700002502110700002402135700001702159700002702176700002102203700002002224700002202244700001702266700002302283700002902306700002202335700002702357700001902384700002102403700002202424700002202446700002402468700002402492700002202516700002802538700002102566700002302587700002202610700002202632700003402654700001802688700001702706700001202723700002302735700002302758700002202781700001702803700001702820700002502837700002402862700002002886700002102906700002002927700002502947700002402972700001602996700002403012700001903036700002003055700002003075700002203095700002103117700001903138700002103157700002503178700001703203700001803220700001903238700001803257700001903275700002403294700002103318700002903339700002703368700002803395700001903423700002003442700002203462700002003484700001903504700002103523700002503544856003603569 2018 eng d a2041-172300aMultiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.0 aMultiethnic metaanalysis identifies ancestryspecific and crossan c2018 Jul 30 a29760 v93 aNearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
1 aWyss, Annah, B1 aSofer, Tamar1 aLee, Mi, Kyeong1 aTerzikhan, Natalie1 aNguyen, Jennifer, N1 aLahousse, Lies1 aLatourelle, Jeanne, C1 aSmith, Albert, Vernon1 aBartz, Traci, M1 aFeitosa, Mary, F1 aGao, Wei1 aAhluwalia, Tarunveer, S1 aTang, Wenbo1 aOldmeadow, Christopher1 aDuan, Qing1 ade Jong, Kim1 aWojczynski, Mary, K1 aWang, Xin-Qun1 aNoordam, Raymond1 aHartwig, Fernando, Pires1 aJackson, Victoria, E1 aWang, Tianyuan1 aObeidat, Ma'en1 aHobbs, Brian, D1 aHuan, Tianxiao1 aGui, Hongsheng1 aParker, Margaret, M1 aHu, Donglei1 aMogil, Lauren, S1 aKichaev, Gleb1 aJin, Jianping1 aGraff, Mariaelisa1 aHarris, Tamara, B1 aKalhan, Ravi1 aHeckbert, Susan, R1 aPaternoster, Lavinia1 aBurkart, Kristin, M1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aWilson, James, G1 aVonk, Judith, M1 aSanders, Jason, L1 aBarr, Graham1 ade Mutsert, Renée1 aMenezes, Ana, Maria Bapt1 aAdams, Hieab, H H1 avan den Berge, Maarten1 aJoehanes, Roby1 aLevin, Albert, M1 aLiberto, Jennifer1 aLauner, Lenore, J1 aMorrison, Alanna, C1 aSitlani, Colleen, M1 aCeledón, Juan, C1 aKritchevsky, Stephen, B1 aScott, Rodney, J1 aChristensen, Kaare1 aRotter, Jerome, I1 aBonten, Tobias, N1 aWehrmeister, Fernando, César1 aBossé, Yohan1 aXiao, Shujie1 aOh, Sam1 aFranceschini, Nora1 aBrody, Jennifer, A1 aKaplan, Robert, C1 aLohman, Kurt1 aMcEvoy, Mark1 aProvince, Michael, A1 aRosendaal, Frits, R1 aTaylor, Kent, D1 aNickle, David, C1 aWilliams, Keoki1 aBurchard, Esteban, G1 aWheeler, Heather, E1 aSin, Don, D1 aGudnason, Vilmundur1 aNorth, Kari, E1 aFornage, Myriam1 aPsaty, Bruce, M1 aMyers, Richard, H1 aO'Connor, George1 aHansen, Torben1 aLaurie, Cathy, C1 aCassano, Patricia, A1 aSung, Joohon1 aKim, Woo, Jin1 aAttia, John, R1 aLange, Leslie1 aBoezen, Marike1 aThyagarajan, Bharat1 aRich, Stephen, S1 aMook-Kanamori, Dennis, O1 aHorta, Bernardo, Lessa1 aUitterlinden, André, G1 aIm, Hae, Kyung1 aCho, Michael, H1 aBrusselle, Guy, G1 aGharib, Sina, A1 aDupuis, Josée1 aManichaikul, Ani1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/781904010nas 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/777604864nas a2200733 4500008004100000022001400041245018700055210006900242260001300311300001200324490000700336520267100343100002303014700002203037700001603059700002403075700003203099700002003131700002003151700002203171700002403193700001703217700002103234700002803255700002903283700001603312700001903328700003103347700001903378700002203397700002403419700002503443700003203468700001703500700002003517700001503537700001903552700002003571700001803591700002003609700002003629700002003649700002403669700001903693700002003712700002003732700002203752700002803774700001903802700002403821700002103845700001903866700002503885700001903910700002503929700002103954700002303975700001103998700002204009700002104031700002204052700002004074856003604094 2018 eng d a1432-042800aSugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis.0 aSugarsweetened beverage intake associations with fasting glucose c2018 Feb a317-3300 v613 aAIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits.
METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway.
RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10-3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant.
CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.
TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study).
1 aMcKeown, Nicola, M1 aDashti, Hassan, S1 aMa, Jiantao1 aHaslam, Danielle, E1 ade Jong, Jessica, C Kiefte-1 aSmith, Caren, E1 aTanaka, Toshiko1 aGraff, Mariaelisa1 aLemaitre, Rozenn, N1 aRybin, Denis1 aSonestedt, Emily1 aFrazier-Wood, Alexis, C1 aMook-Kanamori, Dennis, O1 aLi, Yanping1 aWang, Carol, A1 aLeermakers, Elisabeth, T M1 aMikkilä, Vera1 aYoung, Kristin, L1 aMukamal, Kenneth, J1 aCupples, Adrienne, L1 aSchulz, Christina-Alexandra1 aChen, Tzu-An1 aLi-Gao, Ruifang1 aHuang, Tao1 aOddy, Wendy, H1 aRaitakari, Olli1 aRice, Kenneth1 aMeigs, James, B1 aEricson, Ulrika1 aSteffen, Lyn, M1 aRosendaal, Frits, R1 aHofman, Albert1 aKähönen, Mika1 aPsaty, Bruce, M1 aBrunkwall, Louise1 aUitterlinden, André, G1 aViikari, Jorma1 aSiscovick, David, S1 aSeppälä, Ilkka1 aNorth, Kari, E1 aMozaffarian, Dariush1 aDupuis, Josée1 aOrho-Melander, Marju1 aRich, Stephen, S1 ade Mutsert, Renée1 aQi, Lu1 aPennell, Craig, E1 aFranco, Oscar, H1 aLehtimäki, Terho1 aHerman, Mark, A 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2019 eng d a2041-172300aAssociations of autozygosity with a broad range of human phenotypes.0 aAssociations of autozygosity with a broad range of human phenoty c2019 Oct 31 a49570 v103 aIn many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
1 aClark, David, W1 aOkada, Yukinori1 aMoore, Kristjan, H S1 aMason, Dan1 aPirastu, Nicola1 aGandin, Ilaria1 aMattsson, Hannele1 aBarnes, Catriona, L K1 aLin, Kuang1 aZhao, Jing Hua1 aDeelen, Patrick1 aRohde, Rebecca1 aSchurmann, Claudia1 aGuo, Xiuqing1 aGiulianini, Franco1 aZhang, Weihua1 aMedina-Gómez, Carolina1 aKarlsson, Robert1 aBao, Yanchun1 aBartz, Traci, M1 aBaumbach, Clemens1 aBiino, Ginevra1 aBixley, Matthew, J1 aBrumat, Marco1 aChai, Jin-Fang1 aCorre, Tanguy1 aCousminer, Diana, L1 aDekker, Annelot, M1 aEccles, David, A1 avan Eijk, Kristel, R1 aFuchsberger, Christian1 aGao, He1 aGermain, Marine1 aGordon, Scott, D1 ade Haan, Hugoline, G1 aHarris, Sarah, E1 aHofer, Edith1 aHuerta-Chagoya, Alicia1 aIgartua, Catherine1 aJansen, Iris, E1 aJia, Yucheng1 aKacprowski, Tim1 aKarlsson, Torgny1 aKleber, Marcus, E1 aLi, Shengchao, Alfred1 aLi-Gao, Ruifang1 aMahajan, Anubha1 aMatsuda, Koichi1 aMeidtner, Karina1 aMeng, Weihua1 aMontasser, May, E1 avan der Most, Peter, J1 aMunz, Matthias1 aNutile, Teresa1 aPalviainen, Teemu1 aPrasad, Gauri1 aPrasad, Rashmi, B1 aPriyanka, Tallapragada, Divya Sri1 aRizzi, Federica1 aSalvi, Erika1 aSapkota, Bishwa, R1 aShriner, Daniel1 aSkotte, Line1 aSmart, Melissa, C1 aSmith, Albert, Vernon1 avan der Spek, Ashley1 aSpracklen, Cassandra, N1 aStrawbridge, Rona, J1 aTajuddin, Salman, M1 aTrompet, Stella1 aTurman, Constance1 aVerweij, Niek1 aViberti, Clara1 aWang, Lihua1 aWarren, Helen, R1 aWootton, Robyn, E1 aYanek, Lisa, R1 aYao, Jie1 aYousri, Noha, A1 aZhao, Wei1 aAdeyemo, Adebowale, A1 aAfaq, Saima1 aAguilar-Salinas, Carlos, Alberto1 aAkiyama, Masato1 aAlbert, Matthew, L1 aAllison, Matthew, A1 aAlver, Maris1 aAung, Tin1 aAzizi, Fereidoun1 aBentley, Amy, R1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBorja, Judith, B1 ade Borst, Gert, J1 aBottinger, Erwin, P1 aBroer, Linda1 aCampbell, Harry1 aChanock, Stephen1 aChee, Miao-Li1 aChen, Guanjie1 aChen, Yii-der, I1 aChen, Zhengming1 aChiu, Yen-Feng1 aCocca, Massimiliano1 aCollins, Francis, S1 aConcas, Maria, Pina1 aCorley, Janie1 aCugliari, Giovanni1 avan Dam, Rob, M1 aDamulina, Anna1 aDaneshpour, Maryam, S1 aDay, Felix, R1 aDelgado, Graciela, E1 aDhana, Klodian1 aDoney, Alexander, S F1 aDörr, Marcus1 aDoumatey, Ayo, P1 aDzimiri, Nduna1 aEbenesersdóttir, Sunna1 aElliott, Joshua1 aElliott, Paul1 aEwert, Ralf1 aFelix, Janine, F1 aFischer, Krista1 aFreedman, Barry, I1 aGirotto, Giorgia1 aGoel, Anuj1 aGögele, Martin1 aGoodarzi, Mark, O1 aGraff, Mariaelisa1 aGranot-Hershkovitz, Einat1 aGrodstein, Francine1 aGuarrera, Simonetta1 aGudbjartsson, Daniel, F1 aGuity, Kamran1 aGunnarsson, Bjarni1 aGuo, Yu1 aHagenaars, Saskia, P1 aHaiman, Christopher, A1 aHalevy, Avner1 aHarris, Tamara, B1 aHedayati, Mehdi1 avan Heel, David, A1 aHirata, Makoto1 aHöfer, Imo1 aHsiung, Chao, Agnes1 aHuang, Jinyan1 aHung, Yi-Jen1 aIkram, Arfan, M1 aJagadeesan, Anuradha1 aJousilahti, Pekka1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKerrison, Nicola, D1 aKessler, Thorsten1 aKhaw, Kay-Tee1 aKhor, Chiea, Chuen1 ade Kleijn, Dominique, P V1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKraft, Peter1 aKrämer, Bernhard, K1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLawlor, Deborah, A1 aLee, I-Te1 aLee, Wen-Jane1 aLerch, Markus, M1 aLi, Liming1 aLiu, Jianjun1 aLoh, Marie1 aLondon, Stephanie, J1 aLoomis, Stephanie1 aLu, Yingchang1 aLuan, Jian'an1 aMägi, Reedik1 aManichaikul, Ani, W1 aManunta, Paolo1 aMásson, Gísli1 aMatoba, Nana1 aMei, Xue, W1 aMeisinger, Christa1 aMeitinger, Thomas1 aMezzavilla, Massimo1 aMilani, Lili1 aMillwood, Iona, Y1 aMomozawa, Yukihide1 aMoore, Amy1 aMorange, Pierre-Emmanuel1 aMoreno-Macias, Hortensia1 aMori, Trevor, A1 aMorrison, Alanna, C1 aMuka, Taulant1 aMurakami, Yoshinori1 aMurray, Alison, D1 ade Mutsert, Renée1 aMychaleckyj, Josyf, C1 aNalls, Mike, A1 aNauck, Matthias1 aNeville, Matt, J1 aNolte, Ilja, M1 aOng, Ken, K1 aOrozco, Lorena1 aPadmanabhan, Sandosh1 aPálsson, Gunnar1 aPankow, James, S1 aPattaro, Cristian1 aPattie, Alison1 aPolasek, Ozren1 aPoulter, Neil1 aPramstaller, Peter, P1 aQuintana-Murci, Lluis1 aRäikkönen, Katri1 aRalhan, Sarju1 aRao, Dabeeru, C1 avan Rheenen, Wouter1 aRich, Stephen, S1 aRidker, Paul, M1 aRietveld, Cornelius, A1 aRobino, Antonietta1 avan Rooij, Frank, J A1 aRuggiero, Daniela1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSabater-Lleal, Maria1 aSala, Cinzia, Felicita1 aSalomaa, Veikko1 aSandow, Kevin1 aSchmidt, Helena1 aScott, Laura, J1 aScott, William, R1 aSedaghati-Khayat, Bahareh1 aSennblad, Bengt1 avan Setten, Jessica1 aSever, Peter, J1 aSheu, Wayne, H-H1 aShi, Yuan1 aShrestha, Smeeta1 aShukla, Sharvari, Rahul1 aSigurdsson, Jon, K1 aSikka, Timo, Tonis1 aSingh, Jai, Rup1 aSmith, Blair, H1 aStančáková, Alena1 aStanton, Alice1 aStarr, John, M1 aStefansdottir, Lilja1 aStraker, Leon1 aSulem, Patrick1 aSveinbjornsson, Gardar1 aSwertz, Morris, A1 aTaylor, Adele, M1 aTaylor, Kent, D1 aTerzikhan, Natalie1 aTham, Yih-Chung1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTillander, Annika1 aTracy, Russell, P1 aTusié-Luna, Teresa1 aTzoulaki, Ioanna1 aVaccargiu, Simona1 aVangipurapu, Jagadish1 aVeldink, Jan, H1 aVitart, Veronique1 aVölker, Uwe1 aVuoksimaa, Eero1 aWakil, Salma, M1 aWaldenberger, Melanie1 aWander, Gurpreet, S1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWild, Sarah1 aYajnik, Chittaranjan, S1 aYuan, Jian-Min1 aZeng, Lingyao1 aZhang, Liang1 aZhou, Jie1 aAmin, Najaf1 aAsselbergs, Folkert, W1 aBakker, Stephan, J L1 aBecker, Diane, M1 aLehne, Benjamin1 aBennett, David, A1 avan den Berg, Leonard, H1 aBerndt, Sonja, I1 aBharadwaj, Dwaipayan1 aBielak, Lawrence, F1 aBochud, Murielle1 aBoehnke, Mike1 aBouchard, Claude1 aBradfield, Jonathan, P1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarmi, Shai1 aCaulfield, Mark, J1 aCesarini, David1 aChambers, John, C1 aChandak, Giriraj, Ratan1 aCheng, Ching-Yu1 aCiullo, Marina1 aCornelis, Marilyn1 aCusi, Daniele1 aSmith, George Davey1 aDeary, Ian, J1 aDorajoo, Rajkumar1 aDuijn, Cornelia, M1 aEllinghaus, David1 aErdmann, Jeanette1 aEriksson, Johan, G1 aEvangelou, Evangelos1 aEvans, Michele, K1 aFaul, Jessica, D1 aFeenstra, Bjarke1 aFeitosa, Mary1 aFoisy, Sylvain1 aFranke, Andre1 aFriedlander, Yechiel1 aGasparini, Paolo1 aGieger, Christian1 aGonzalez, Clicerio1 aGoyette, Philippe1 aGrant, Struan, F A1 aGriffiths, Lyn, R1 aGroop, Leif1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHakonarson, Hakon1 aHamsten, Anders1 aHarst, Pim1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHochner, Hagit1 aHuikuri, Heikki1 aHunt, Steven, C1 aJaddoe, Vincent, W V1 aDe Jager, Philip, L1 aJohannesson, Magnus1 aJohansson, Asa1 aJonas, Jost, B1 aJukema, Wouter1 aJunttila, Juhani1 aKaprio, Jaakko1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKumari, Meena1 aLaakso, Markku1 avan der Laan, Sander, W1 aLahti, Jari1 aLaudes, Matthias1 aLea, Rodney, A1 aLieb, Wolfgang1 aLumley, Thomas1 aMartin, Nicholas, G1 aMärz, Winfried1 aMatullo, Giuseppe1 aMcCarthy, Mark, I1 aMedland, Sarah, E1 aMerriman, Tony, R1 aMetspalu, Andres1 aMeyer, Brian, F1 aMohlke, Karen, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis1 aMunroe, Patricia, B1 aNorth, Kari, E1 aNyholt, Dale, R1 aO'Connell, Jeffery, R1 aOber, Carole1 aOldehinkel, Albertine, J1 aPalmas, Walter1 aPalmer, Colin1 aPasterkamp, Gerard, G1 aPatin, Etienne1 aPennell, Craig, E1 aPerusse, Louis1 aPeyser, Patricia, A1 aPirastu, Mario1 aPolderman, Tinca, J C1 aPorteous, David, J1 aPosthuma, Danielle1 aPsaty, Bruce, M1 aRioux, John, D1 aRivadeneira, Fernando1 aRotimi, Charles1 aRotter, Jerome, I1 aRudan, Igor1 aRuijter, Hester, M den1 aSanghera, Dharambir, K1 aSattar, Naveed1 aSchmidt, Reinhold1 aSchulze, Matthias, B1 aSchunkert, Heribert1 aScott, Robert, A1 aShuldiner, Alan, R1 aSim, Xueling1 aSmall, Neil1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aTai, E-Shyong1 aTeumer, Alexander1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTrégouët, David-Alexandre1 aTuomi, Tiinamaija1 aVollenweider, Peter1 aWang, Carol, A1 aWeir, David, R1 aWhitfield, John, B1 aWijmenga, Cisca1 aWong, Tien-Yin1 aWright, John1 aYang, Jingyun1 aYu, Lei1 aZemel, Babette, S1 aZonderman, Alan, B1 aPerola, Markus1 aMagnusson, Patrik, K E1 aUitterlinden, André, G1 aKooner, Jaspal, S1 aChasman, Daniel, I1 aLoos, Ruth, J F1 aFranceschini, Nora1 aFranke, Lude1 aHaley, Chris, S1 aHayward, Caroline1 aWalters, Robin, G1 aPerry, John, R B1 aEsko, Tõnu1 aHelgason, Agnar1 aStefansson, Kari1 aJoshi, Peter, K1 aKubo, Michiaki1 aWilson, James, F uhttps://chs-nhlbi.org/node/819810550nas a2203325 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2019 eng d a1476-625600aMulti-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.0 aMultiAncestry GenomeWide Association Study of Lipid Levels Incor c2019 Jan 293 aAn individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.
1 ade Vries, Paul, S1 aBrown, Michael, R1 aBentley, Amy, R1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aSchwander, Karen1 aKraja, Aldi, T1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDeng, Xuan1 aDorajoo, Rajkumar1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aEvangelou, Evangelos1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLee, Joseph, H1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aRiaz, Muhammad1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBallantyne, Christie1 aBoerwinkle, Eric1 aBroeckel, Ulrich1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aConnell, John, M1 ade Faire, Ulf1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDing, Jingzhong1 aDominiczak, Anna, F1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFisher, Virginia1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGrabe, Hans, J1 aGrove, Megan, L1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJacobs, David, R1 aJohnson, Craig1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Steve, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLemaitre, Rozenn, N1 aLi, Yize1 aLiang, Jingjing1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMukamal, Kenneth, J1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRice, Treva, K1 aRich, Stephen, S1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTan, Nicholas1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 avan Heemst, Diana1 aVuckovic, Dragana1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Yujie1 aWang, Zhe1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aPenninx, Brenda1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aZheng, Wei1 aElliott, Paul1 aNorth, Kari, E1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aLiu, Ching-Ti1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aKardia, Sharon, L R1 aZhu, Xiaofeng1 aRotimi, Charles, N1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLiu, Jingmin1 aRotter, Jerome, I1 aGauderman, James1 aProvince, Michael, A1 aMunroe, Patricia, B1 aRice, Kenneth1 aChasman, Daniel, I1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aMorrison, Alanna, C1 aInterAct Consortium1 aLifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study) uhttps://chs-nhlbi.org/node/797011178nas a2203793 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2019 eng d a1546-171800aMulti-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.0 aMultiancestry genomewide genesmoking interaction study of 387272 c2019 Apr a636-6480 v513 aThe concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
1 aBentley, Amy, R1 aSung, Yun, J1 aBrown, Michael, R1 aWinkler, Thomas, W1 aKraja, Aldi, T1 aNtalla, Ioanna1 aSchwander, Karen1 aChasman, Daniel, I1 aLim, Elise1 aDeng, Xuan1 aGuo, Xiuqing1 aLiu, Jingmin1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aBaker, Jenna1 aChen, Guanjie1 aAschard, Hugues1 aBartz, Traci, M1 aDing, Jingzhong1 aDorajoo, Rajkumar1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aZhao, Wei1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aHung, Yi-Jen1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLeander, Karin1 aLin, Keng-Hung1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aPrins, Bram1 aRiaz, Muhammad1 aRobino, Antonietta1 aSaid, Abdullah1 aSchupf, Nicole1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Tzung-Dau1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aXiang, Yong-Bing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAdeyemo, Adebowale1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aArzumanyan, Zorayr1 aAung, Tin1 aBallantyne, Christie1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBroeckel, Ulrich1 aBrown, Morris1 aCade, Brian, E1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aChristensen, Kaare1 aConcas, Maria, Pina1 aConnell, John, M1 aFuentes, Lisa, de Las1 ade Silva, Janaka1 ade Vries, Paul, S1 aDoumatey, Ayo1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFloyd, James, S1 aForouhi, Nita, G1 aForrester, Terrence1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGharib, Sina, A1 aGigante, Bruna1 aGiulianini, Franco1 aGrabe, Hans, J1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aIkram, Arfan, M1 aJia, Yucheng1 aJoehanes, Roby1 aJohnson, Craig1 aJonas, Jost, Bruno1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLiang, Jingjing1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLohman, Kurt, K1 aLouie, Tin1 aLuzzi, Anna1 aMägi, Reedik1 aMahajan, Anubha1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMurray, Alison, D1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRenstrom, Frida1 aRice, Treva, K1 aRich, Stephen, S1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTiemeier, Henning1 aTurner, Stephen, T1 aUitterlinden, André, G1 avan Heemst, Diana1 aWaldenberger, Melanie1 aWang, Heming1 aWang, Lan1 aWang, Lihua1 aBin Wei, Wen1 aWilliams, Christine, A1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYoung, Kristin1 aYu, Caizheng1 aYuan, Jian-Min1 aZhou, Jie1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aCooper, Richard, S1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aJuang, Jyh-Ming, Jimmy1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLaurie, Cathy, C1 aLee, I-Te1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aRedline, Susan1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Jun-Sing1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZeggini, Eleftheria1 aZheng, Wei1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aProvince, Michael, A1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aFranceschini, Nora1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aCOGENT-Kidney Consortium1 aEPIC-InterAct Consortium1 aUnderstanding Society Scientific Group1 aLifelines Cohort uhttps://chs-nhlbi.org/node/800510097nas a2203265 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2019 eng d a2041-172300aMulti-ancestry study of blood lipid levels identifies four loci interacting with physical activity.0 aMultiancestry study of blood lipid levels identifies four loci i c2019 01 22 a3760 v103 aMany genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aBrazil10aCalcium-Binding Proteins10aCholesterol10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aExercise10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHispanic Americans10aHumans10aLIM-Homeodomain Proteins10aLipid Metabolism10aLipids10aMale10aMembrane Proteins10aMicrotubule-Associated Proteins10aMiddle Aged10aMuscle Proteins10aNerve Tissue Proteins10aTranscription Factors10aTriglycerides10aYoung Adult1 aKilpeläinen, Tuomas, O1 aBentley, Amy, R1 aNoordam, Raymond1 aSung, Yun, Ju1 aSchwander, Karen1 aWinkler, Thomas, W1 aJakupović, Hermina1 aChasman, Daniel, I1 aManning, Alisa1 aNtalla, Ioanna1 aAschard, Hugues1 aBrown, Michael, R1 aFuentes, Lisa, de Las1 aFranceschini, Nora1 aGuo, Xiuqing1 aVojinovic, Dina1 aAslibekyan, Stella1 aFeitosa, Mary, F1 aKho, Minjung1 aMusani, Solomon, K1 aRichard, Melissa1 aWang, Heming1 aWang, Zhe1 aBartz, Traci, M1 aBielak, Lawrence, F1 aCampbell, Archie1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLi, Changwei1 aLohman, Kurt, K1 aMarten, Jonathan1 aSim, Xueling1 aSmith, Albert, V1 aTajuddin, Salman, M1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGraff, Mariaelisa1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aZhao, Jing Hua1 aKraja, Aldi, T1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRobino, Antonietta1 aRueedi, Rico1 aStringham, Heather, M1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVerweij, Niek1 aWare, Erin, B1 aWen, Wanqing1 aLi, Xiaoyin1 aYanek, Lisa, R1 aAmin, Najaf1 aArnett, Donna, K1 aBoerwinkle, Eric1 aBrumat, Marco1 aCade, Brian1 aCanouil, Mickaël1 aChen, Yii-Der Ida1 aConcas, Maria, Pina1 aConnell, John1 ade Mutsert, Renée1 ade Silva, Janaka1 ade Vries, Paul, S1 aDemirkan, Ayse1 aDing, Jingzhong1 aEaton, Charles, B1 aFaul, Jessica, D1 aFriedlander, Yechiel1 aGabriel, Kelley, P1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGu, Chi, Charles1 aGu, Dongfeng1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHunt, Steven, C1 aIkram, Arfan, M1 aJonas, Jost, B1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLeander, Karin1 aLemaitre, Rozenn, N1 aLewis, Cora, E1 aLiang, Jingjing1 aLiu, Jianjun1 aMägi, Reedik1 aManichaikul, Ani1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMurray, Alison, D1 aNalls, Mike, A1 aNang, Ei-Ei, Khaing1 aNelson, Christopher, P1 aNona, Sotoodehnia1 aNorris, Jill, M1 aNwuba, Chiamaka, Vivian1 aO'Connell, Jeff1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPorteous, David, J1 aPoveda, Alaitz1 aRaitakari, Olli, T1 aRich, Stephen, S1 aRisch, Neil1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchreiner, Pamela, J1 aScott, Robert, A1 aSidney, Stephen, S1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aSofer, Tamar1 aStarr, John, M1 aSternfeld, Barbara1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTsai, Michael, Y1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 avan der Ende, Yldau1 avan Heemst, Diana1 aVoortman, Trudy1 aWaldenberger, Melanie1 aWennberg, Patrik1 aWilson, Gregory1 aXiang, Yong-Bing1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aKato, Norihiro1 aLaakso, Markku1 aLakka, Timo, A1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aSamani, Nilesh, J1 aShu, Xiao-Ou1 aHarst, Pim1 avan Vliet-Ostaptchouk, Jana, V1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWang, Ya, X1 aWareham, Nicholas, J1 aWeir, David, R1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aEvans, Michele, K1 aFranks, Paul, W1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKelly, Tanika, N1 aLiu, Yongmei1 aNorth, Kari, E1 aPereira, Alexandre, C1 aRidker, Paul, M1 aTai, Shyong, E1 avan Dam, Rob, M1 aFox, Ervin, R1 aKardia, Sharon, L R1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aProvince, Michael, A1 aRedline, Susan1 aDuijn, Cornelia, M1 aRotter, Jerome, I1 aKooperberg, Charles, B1 aGauderman, James1 aPsaty, Bruce, M1 aRice, Kenneth1 aMunroe, Patricia, B1 aFornage, Myriam1 aCupples, Adrienne, L1 aRotimi, Charles, N1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aLoos, Ruth, J F1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/797605314nas a2201501 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2020 eng d a1939-327X00aGenetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.0 aGenetic Studies of Leptin Concentrations Implicate Leptin in the c2020 Sep 113 aLeptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.
1 aYaghootkar, Hanieh1 aZhang, Yiying1 aSpracklen, Cassandra, N1 aKaraderi, Tugce1 aHuang, Lam, Opal1 aBradfield, Jonathan1 aSchurmann, Claudia1 aFine, Rebecca, S1 aPreuss, Michael, H1 aKutalik, Zoltán1 aWittemans, Laura, Bl1 aLu, Yingchang1 aMetz, Sophia1 aWillems, Sara, M1 aLi-Gao, Ruifang1 aGrarup, Niels1 aWang, Shuai1 aMolnos, Sophie1 aSandoval-Zárate, América, A1 aNalls, Mike, A1 aLange, Leslie, A1 aHaesser, Jeffrey1 aGuo, Xiuqing1 aLyytikäinen, Leo-Pekka1 aFeitosa, Mary, F1 aSitlani, Colleen, M1 aVenturini, Cristina1 aMahajan, Anubha1 aKacprowski, Tim1 aWang, Carol, A1 aChasman, Daniel, I1 aAmin, Najaf1 aBroer, Linda1 aRobertson, Neil1 aYoung, Kristin, L1 aAllison, Matthew1 aAuer, Paul, L1 aBlüher, Matthias1 aBorja, Judith, B1 aBork-Jensen, Jette1 aCarrasquilla, Germán, D1 aChristofidou, Paraskevi1 aDemirkan, Ayse1 aDoege, Claudia, A1 aGarcia, Melissa, E1 aGraff, Mariaelisa1 aGuo, Kaiying1 aHakonarson, Hakon1 aHong, Jaeyoung1 aChen, Yii-Der, Ida1 aJackson, Rebecca1 aJakupović, Hermina1 aJousilahti, Pekka1 aJustice, Anne, E1 aKähönen, Mika1 aKizer, Jorge, R1 aKriebel, Jennifer1 aLeDuc, Charles, A1 aLi, Jin1 aLind, Lars1 aLuan, Jian'an1 aMackey, David1 aMangino, Massimo1 aMännistö, Satu1 aCarli, Jayne, F Martin1 aMedina-Gómez, Carolina1 aMook-Kanamori, Dennis, O1 aMorris, Andrew, P1 ade Mutsert, Renée1 aNauck, Matthias1 aNedeljkovic, Ivana1 aPennell, Craig, E1 aPradhan, Arund, D1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aScott, Robert, A1 aSkaaby, Tea1 aStrauch, Konstantin1 aTaylor, Kent, D1 aTeumer, Alexander1 aUitterlinden, André, G1 aWu, Ying1 aYao, Jie1 aWalker, Mark1 aNorth, Kari, E1 aKovacs, Peter1 aIkram, Arfan, M1 aDuijn, Cornelia, M1 aRidker, Paul, M1 aLye, Stephen1 aHomuth, Georg1 aIngelsson, Erik1 aSpector, Tim, D1 aMcKnight, Barbara1 aProvince, Michael, A1 aLehtimäki, Terho1 aAdair, Linda, S1 aRotter, Jerome, I1 aReiner, Alexander, P1 aWilson, James, G1 aHarris, Tamara, B1 aRipatti, Samuli1 aGrallert, Harald1 aMeigs, James, B1 aSalomaa, Veikko1 aHansen, Torben1 avan Dijk, Ko, Willems1 aWareham, Nicholas, J1 aGrant, Struan, Fa1 aLangenberg, Claudia1 aFrayling, Timothy, M1 aLindgren, Cecilia, M1 aMohlke, Karen, L1 aLeibel, Rudolph, L1 aLoos, Ruth, Jf1 aKilpeläinen, Tuomas, O uhttps://chs-nhlbi.org/node/849106209nas a2201549 4500008004100000022001400041245014600055210006900201260001300270300001200283490000700295520185100302100001502153700001502168700001702183700001802200700001802218700001502236700002402251700001902275700001702294700002002311700001802331700001902349700002202368700001902390700002802409700002002437700001802457700001902475700002802494700002402522700001902546700002302565700001602588700002202604700002002626700002602646700001902672700002202691700002102713700002602734700002002760700002402780700001902804700002002823700002102843700002502864700003202889700002002921700002102941700001902962700002002981700001403001700002803015700001903043700002203062700002203084700001903106700002403125700002103149700002503170700001303195700002103208700002203229700001903251700002203270700002403292700002203316700001803338700002603356700002003382700001903402700001603421700001803437700002303455700002203478700001903500700001703519700001403536700001703550700002103567700002203588700002103610700002003631700002003651700002103671700002203692700002003714700002403734700002303758700001703781700002503798700002903823700002203852700001703874700001803891700002603909700002003935700002303955700002003978700001903998700002804017700002304045700002004068700002204088700001704110700002104127700001904148700002404167700002204191700002204213700002504235700001904260700002204279700002104301700002004322700002104342700002304363700002504386700002404411700001904435700002104454700002104475700002904496700002504525700002004550700001904570700002304589700001104612856003604623 2020 eng d a1573-728400aMendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.0 aMendelian randomization analysis does not support causal associa c2020 Jul a685-6970 v353 aEpidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.
1 aZheng, Yan1 aHuang, Tao1 aWang, Tiange1 aMei, Zhendong1 aSun, Zhonghan1 aZhang, Tao1 aEllervik, Christina1 aChai, Jin-Fang1 aSim, Xueling1 avan Dam, Rob, M1 aTai, E-Shyong1 aKoh, Woon-Puay1 aDorajoo, Rajkumar1 aSaw, Seang-Mei1 aSabanayagam, Charumathi1 aWong, Tien, Yin1 aGupta, Preeti1 aRossing, Peter1 aAhluwalia, Tarunveer, S1 aVinding, Rebecca, K1 aBisgaard, Hans1 aBønnelykke, Klaus1 aWang, Yujie1 aGraff, Mariaelisa1 aVoortman, Trudy1 avan Rooij, Frank, J A1 aHofman, Albert1 avan Heemst, Diana1 aNoordam, Raymond1 aEstampador, Angela, C1 aVarga, Tibor, V1 aEnzenbach, Cornelia1 aScholz, Markus1 aThiery, Joachim1 aBurkhardt, Ralph1 aOrho-Melander, Marju1 aSchulz, Christina-Alexandra1 aEricson, Ulrika1 aSonestedt, Emily1 aKubo, Michiaki1 aAkiyama, Masato1 aZhou, Ang1 aKilpeläinen, Tuomas, O1 aHansen, Torben1 aKleber, Marcus, E1 aDelgado, Graciela1 aMcCarthy, Mark1 aLemaitre, Rozenn, N1 aFelix, Janine, F1 aJaddoe, Vincent, W V1 aWu, Ying1 aMohlke, Karen, L1 aLehtimäki, Terho1 aWang, Carol, A1 aPennell, Craig, E1 aSchunkert, Heribert1 aKessler, Thorsten1 aZeng, Lingyao1 aWillenborg, Christina1 aPeters, Annette1 aLieb, Wolfgang1 aGrote, Veit1 aRzehak, Peter1 aKoletzko, Berthold1 aErdmann, Jeanette1 aMunz, Matthias1 aWu, Tangchun1 aHe, Meian1 aYu, Caizheng1 aLecoeur, Cécile1 aFroguel, Philippe1 aCorella, Dolores1 aMoreno, Luis, A1 aLai, Chao-Qiang1 aPitkänen, Niina1 aBoreham, Colin, A1 aRidker, Paul, M1 aRosendaal, Frits, R1 ade Mutsert, Renée1 aPower, Chris1 aPaternoster, Lavinia1 aSørensen, Thorkild, I A1 aTjønneland, Anne1 aOvervad, Kim1 aDjoussé, Luc1 aRivadeneira, Fernando1 aLee, Nanette, R1 aRaitakari, Olli, T1 aKähönen, Mika1 aViikari, Jorma1 aLanghendries, Jean-Paul1 aEscribano, Joaquin1 aVerduci, Elvira1 aDedoussis, George1 aKönig, Inke1 aBalkau, Beverley1 aColtell, Oscar1 aDallongeville, Jean1 aMeirhaeghe, Aline1 aAmouyel, Philippe1 aGottrand, Frédéric1 aPahkala, Katja1 aNiinikoski, Harri1 aHyppönen, Elina1 aMärz, Winfried1 aMackey, David, A1 aGruszfeld, Dariusz1 aTucker, Katherine, L1 aFumeron, Frédéric1 aEstruch, Ramon1 aOrdovas, Jose, M1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aMozaffarian, Dariush1 aPsaty, Bruce, M1 aNorth, Kari, E1 aChasman, Daniel, I1 aQi, Lu uhttps://chs-nhlbi.org/node/841009591nas a2202833 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2021 eng d a1537-660500aDiscovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.0 aDiscovery and finemapping of height loci via highdensity imputat c2021 Apr 01 a564-5820 v1083 aAlthough many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
1 aGraff, Mariaelisa1 aJustice, Anne, E1 aYoung, Kristin, L1 aMarouli, Eirini1 aZhang, Xinruo1 aFine, Rebecca, S1 aLim, Elise1 aBuchanan, Victoria1 aRand, Kristin1 aFeitosa, Mary, F1 aWojczynski, Mary, K1 aYanek, Lisa, R1 aShao, Yaming1 aRohde, Rebecca1 aAdeyemo, Adebowale, A1 aAldrich, Melinda, C1 aAllison, Matthew, A1 aAmbrosone, Christine, B1 aAmbs, Stefan1 aAmos, Christopher1 aArnett, Donna, K1 aAtwood, Larry1 aBandera, Elisa, V1 aBartz, Traci1 aBecker, Diane, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBielak, Lawrence, F1 aBlot, William, J1 aBottinger, Erwin, P1 aBowden, Donald, W1 aBradfield, Jonathan, P1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aBurke, Gregory1 aCade, Brian, E1 aCai, Qiuyin1 aCaporaso, Neil1 aCarlson, Chris1 aCarpten, John1 aCasey, Graham1 aChanock, Stephen, J1 aChen, Guanjie1 aChen, Minhui1 aChen, Yii-der, I1 aChen, Wei-Min1 aChesi, Alessandra1 aChiang, Charleston, W K1 aChu, Lisa1 aCoetzee, Gerry, A1 aConti, David, V1 aCooper, Richard, S1 aCushman, Mary1 aDemerath, Ellen1 aDeming, Sandra, L1 aDimitrov, Latchezar1 aDing, Jingzhong1 aDiver, Ryan1 aDuan, Qing1 aEvans, Michele, K1 aFalusi, Adeyinka, G1 aFaul, Jessica, D1 aFornage, Myriam1 aFox, Caroline1 aFreedman, Barry, I1 aGarcia, Melissa1 aGillanders, Elizabeth, M1 aGoodman, Phyllis1 aGottesman, Omri1 aGrant, Struan, F A1 aGuo, Xiuqing1 aHakonarson, Hakon1 aHaritunians, Talin1 aHarris, Tamara, B1 aHarris, Curtis, C1 aHenderson, Brian, E1 aHennis, Anselm1 aHernandez, Dena, G1 aHirschhorn, Joel, N1 aMcNeill, Lorna, Haughton1 aHoward, Timothy, D1 aHoward, Barbara1 aHsing, Ann, W1 aHsu, Yu-Han, H1 aHu, Jennifer, J1 aHuff, Chad, D1 aHuo, Dezheng1 aIngles, Sue, A1 aIrvin, Marguerite, R1 aJohn, Esther, M1 aJohnson, Karen, C1 aJordan, Joanne, M1 aKabagambe, Edmond, K1 aKang, Sun, J1 aKardia, Sharon, L1 aKeating, Brendan, J1 aKittles, Rick, A1 aKlein, Eric, A1 aKolb, Suzanne1 aKolonel, Laurence, N1 aKooperberg, Charles1 aKuller, Lewis1 aKutlar, Abdullah1 aLange, Leslie1 aLangefeld, Carl, D1 aLe Marchand, Loïc1 aLeonard, Hampton1 aLettre, Guillaume1 aLevin, Albert, M1 aLi, Yun1 aLi, Jin1 aLiu, Yongmei1 aLiu, Youfang1 aLiu, Simin1 aLohman, Kurt1 aLotay, Vaneet1 aLu, Yingchang1 aMaixner, William1 aManson, JoAnn, E1 aMcKnight, Barbara1 aMeng, Yan1 aMonda, Keri, L1 aMonroe, Kris1 aMoore, Jason, H1 aMosley, Thomas, H1 aMudgal, Poorva1 aMurphy, Adam, B1 aNadukuru, Raj1 aNalls, Mike, A1 aNathanson, Katherine, L1 aNayak, Uma1 aN'diaye, Amidou1 aNemesure, Barbara1 aNeslund-Dudas, Christine1 aNeuhouser, Marian, L1 aNyante, Sarah1 aOchs-Balcom, Heather1 aOgundiran, Temidayo, O1 aOgunniyi, Adesola1 aOjengbede, Oladosu1 aOkut, Hayrettin1 aOlopade, Olufunmilayo, I1 aOlshan, Andrew1 aPadhukasahasram, Badri1 aPalmer, Julie1 aPalmer, Cameron, D1 aPalmer, Nicholette, D1 aPapanicolaou, George1 aPatel, Sanjay, R1 aPettaway, Curtis, A1 aPeyser, Patricia, A1 aPress, Michael, F1 aRao, D, C1 aRasmussen-Torvik, Laura, J1 aRedline, Susan1 aReiner, Alex, P1 aRhie, Suhn, K1 aRodriguez-Gil, Jorge, L1 aRotimi, Charles, N1 aRotter, Jerome, I1 aRuiz-Narvaez, Edward, A1 aRybicki, Benjamin, A1 aSalako, Babatunde1 aSale, Michèle, M1 aSanderson, Maureen1 aSchadt, Eric1 aSchreiner, Pamela, J1 aSchurmann, Claudia1 aSchwartz, Ann, G1 aShriner, Daniel, A1 aSignorello, Lisa, B1 aSingleton, Andrew, B1 aSiscovick, David, S1 aSmith, Jennifer, A1 aSmith, Shad1 aSpeliotes, Elizabeth1 aSpitz, Margaret1 aStanford, Janet, L1 aStevens, Victoria, L1 aStram, Alex1 aStrom, Sara, S1 aSucheston, Lara1 aSun, Yan, V1 aTajuddin, Salman, M1 aTaylor, Herman1 aTaylor, Kira1 aTayo, Bamidele, O1 aThun, Michael, J1 aTucker, Margaret, A1 aVaidya, Dhananjay1 aVan Den Berg, David, J1 aVedantam, Sailaja1 aVitolins, Mara1 aWang, Zhaoming1 aWare, Erin, B1 aWassertheil-Smoller, Sylvia1 aWeir, David, R1 aWiencke, John, K1 aWilliams, Scott, M1 aWilliams, Keoki1 aWilson, James, G1 aWitte, John, S1 aWrensch, Margaret1 aWu, Xifeng1 aYao, Jie1 aZakai, Neil1 aZanetti, Krista1 aZemel, Babette, S1 aZhao, Wei1 aZhao, Jing Hua1 aZheng, Wei1 aZhi, Degui1 aZhou, Jie1 aZhu, Xiaofeng1 aZiegler, Regina, G1 aZmuda, Joe1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aLiu, Ching-Ti1 aHaiman, Christopher, A1 aLoos, Ruth1 aC Y Ng, Maggie1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/870504415nas a2200805 4500008004100000022001400041245024200055210006900297260001300366300001200379490000700391520195900398100002402357700002002381700002202401700002102423700002002444700003002464700001902494700002002513700002102533700002102554700002202575700002202597700002002619700002002639700001802659700002002677700003202697700002102729700001902750700002402769700002902793700001602822700001902838700002902857700002202886700002002908700002202928700001902950700002202969700002402991700002003015700002803035700002003063700002503083700002203108700002003130700002203150700002303172700002403195700002003219700002103239700002103260700002303281700002003304700002103324700001603345700002003361700001803381700002003399700002203419700002303441700002703464700002003491700001903511700002003530700002303550856003603573 2021 eng d a2574-830000aSugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations.0 aSugarSweetened Beverage Consumption May Modify Associations Betw c2021 Aug ae0032880 v143 aBACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the locus and dyslipidemia.
METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.
RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95% CI, 0.02-0.09] ln-mg/dL per allele, =0.001) but not the lowest SSB consumers (=0.84; =0.0005).
CONCLUSIONS: Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.
1 aHaslam, Danielle, E1 aPeloso, Gina, M1 aGuirette, Melanie1 aImamura, Fumiaki1 aBartz, Traci, M1 aPitsillides, Achilleas, N1 aWang, Carol, A1 aLi-Gao, Ruifang1 aWestra, Jason, M1 aPitkänen, Niina1 aYoung, Kristin, L1 aGraff, Mariaelisa1 aWood, Alexis, C1 aBraun, Kim, V E1 aLuan, Jian'an1 aKähönen, Mika1 ade Jong, Jessica, C Kiefte-1 aGhanbari, Mohsen1 aTintle, Nathan1 aLemaitre, Rozenn, N1 aMook-Kanamori, Dennis, O1 aNorth, Kari1 aHelminen, Mika1 aMossavar-Rahmani, Yasmin1 aSnetselaar, Linda1 aMartin, Lisa, W1 aViikari, Jorma, S1 aOddy, Wendy, H1 aPennell, Craig, E1 aRosendall, Frits, R1 aIkram, Arfan, M1 aUitterlinden, André, G1 aPsaty, Bruce, M1 aMozaffarian, Dariush1 aRotter, Jerome, I1 aTaylor, Kent, D1 aLehtimäki, Terho1 aRaitakari, Olli, T1 aLivingston, Kara, A1 aVoortman, Trudy1 aForouhi, Nita, G1 aWareham, Nick, J1 ade Mutsert, Renée1 aRich, Steven, S1 aManson, JoAnn, E1 aMora, Samia1 aRidker, Paul, M1 aMerino, Jordi1 aMeigs, James, B1 aDashti, Hassan, S1 aChasman, Daniel, I1 aLichtenstein, Alice, H1 aSmith, Caren, E1 aDupuis, Josée1 aHerman, Mark, A1 aMcKeown, Nicola, M uhttps://chs-nhlbi.org/node/883001045nas a2200325 4500008004100000022001400041245014300055210006900198260001600267300001200283490000800295653002100303653002100324653001400345653003400359653004100393653001400434653001800448100002400466700002500490700001600515700002300531700002000554700002100574700002000595700002400615700002200639700002200661856003600683 2022 eng d a1524-457100aGenome Wide Association Studies of Variant-by-Thiazide Interaction on Lipids Identifies a Novel Low-Density Lipoprotein Cholesterol Locus.0 aGenome Wide Association Studies of VariantbyThiazide Interaction c2022 Jul 22 a277-2790 v13110aCholesterol, HDL10aCholesterol, LDL10aDiuretics10aGenome-Wide Association Study10aSodium Chloride Symporter Inhibitors10aThiazides10aTriglycerides1 aDownie, Carolina, G1 aHighland, Heather, M1 aLee, Moa, P1 aRaffield, Laura, M1 aPreuss, Michael1 aWhitsel, Eric, A1 aPsaty, Bruce, M1 aSitlani, Colleen, M1 aGraff, Mariaelisa1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/945205087nas a2201237 4500008004100000022001400041245010900055210006900164260001200233300001400245490000700259520156200266653002801828653003801856653003401894653001101928653003601939653001701975100002701992700001502019700002402034700002002058700002302078700001602101700002002117700001802137700001402155700001802169700001802187700002402205700002002229700002102249700002302270700001802293700002202311700002802333700002502361700002302386700002202409700002202431700002302453700002002476700001502496700001802511700001602529700001902545700002402564700002202588700002002610700001202630700002002642700002502662700001902687700002202706700002202728700002702750700002302777700002202800700001902822700002102841700001702862700002102879700001602900700002002916700002302936700002102959700002002980700002003000700002003020700001903040700002403059700001503083700002403098700002303122700002203145700002403167700002203191700001603213700001903229700002203248700002503270700002203295700002103317700002103338700002103359700001503380700002103395700002303416700002503439700002403464700002103488700002003509700002003529700002303549700002303572700001403595700001603609700002003625700003003645700002903675710003003704710003303734710001803767710002803785856003603813 2022 eng d a1546-170X00aLarge-scale genome-wide association study of coronary artery disease in genetically diverse populations.0 aLargescale genomewide association study of coronary artery disea c2022 08 a1679-16920 v283 aWe report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
10aCoronary Artery Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors1 aTcheandjieu, Catherine1 aZhu, Xiang1 aHilliard, Austin, T1 aClarke, Shoa, L1 aNapolioni, Valerio1 aMa, Shining1 aLee, Kyung, Min1 aFang, Huaying1 aChen, Fei1 aLu, Yingchang1 aTsao, Noah, L1 aRaghavan, Sridharan1 aKoyama, Satoshi1 aGorman, Bryan, R1 aVujkovic, Marijana1 aKlarin, Derek1 aLevin, Michael, G1 aSinnott-Armstrong, Nasa1 aWojcik, Genevieve, L1 aPlomondon, Mary, E1 aMaddox, Thomas, M1 aWaldo, Stephen, W1 aBick, Alexander, G1 aPyarajan, Saiju1 aHuang, Jie1 aSong, Rebecca1 aHo, Yuk-Lam1 aBuyske, Steven1 aKooperberg, Charles1 aHaessler, Jeffrey1 aLoos, Ruth, J F1 aDo, Ron1 aVerbanck, Marie1 aChaudhary, Kumardeep1 aNorth, Kari, E1 aAvery, Christy, L1 aGraff, Mariaelisa1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aWilkens, Lynne, R1 aBis, Joshua, C1 aLeonard, Hampton1 aShen, Botong1 aLange, Leslie, A1 aGiri, Ayush1 aDikilitas, Ozan1 aKullo, Iftikhar, J1 aStanaway, Ian, B1 aJarvik, Gail, P1 aGordon, Adam, S1 aHebbring, Scott1 aNamjou, Bahram1 aKaufman, Kenneth, M1 aIto, Kaoru1 aIshigaki, Kazuyoshi1 aKamatani, Yoichiro1 aVerma, Shefali, S1 aRitchie, Marylyn, D1 aKember, Rachel, L1 aBaras, Aris1 aLotta, Luca, A1 aKathiresan, Sekar1 aHauser, Elizabeth, R1 aMiller, Donald, R1 aLee, Jennifer, S1 aSaleheen, Danish1 aReaven, Peter, D1 aCho, Kelly1 aGaziano, Michael1 aNatarajan, Pradeep1 aHuffman, Jennifer, E1 aVoight, Benjamin, F1 aRader, Daniel, J1 aChang, Kyong-Mi1 aLynch, Julie, A1 aDamrauer, Scott, M1 aWilson, Peter, W F1 aTang, Hua1 aSun, Yan, V1 aTsao, Philip, S1 aO'Donnell, Christopher, J1 aAssimes, Themistocles, L1 aRegeneron Genetics Center1 aCARDIoGRAMplusC4D Consortium1 aBiobank Japan1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/917613363nas a2204429 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2022 eng d a1546-171800aMulti-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.0 aMultiancestry genetic study of type 2 diabetes highlights the po c2022 May a560-5720 v543 aWe assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
10aDiabetes Mellitus, Type 210aEthnicity10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aZhang, Weihua1 aC Y Ng, Maggie1 aPetty, Lauren, E1 aKitajima, Hidetoshi1 aYu, Grace, Z1 aRüeger, Sina1 aSpeidel, Leo1 aKim, Young, Jin1 aHorikoshi, Momoko1 aMercader, Josep, M1 aTaliun, Daniel1 aMoon, Sanghoon1 aKwak, Soo-Heon1 aRobertson, Neil, R1 aRayner, Nigel, W1 aLoh, Marie1 aKim, Bong-Jo1 aChiou, Joshua1 aMiguel-Escalada, Irene1 aParolo, Pietro, Della Brio1 aLin, Kuang1 aBragg, Fiona1 aPreuss, Michael, H1 aTakeuchi, Fumihiko1 aNano, Jana1 aGuo, Xiuqing1 aLamri, Amel1 aNakatochi, Masahiro1 aScott, Robert, A1 aLee, Jung-Jin1 aHuerta-Chagoya, Alicia1 aGraff, Mariaelisa1 aChai, Jin-Fang1 aParra, Esteban, J1 aYao, Jie1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aSteinthorsdottir, Valgerdur1 aCook, James, P1 aKals, Mart1 aGrarup, Niels1 aSchmidt, Ellen, M1 aPan, Ian1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aAhmad, Meraj1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aLecoeur, Cécile1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aJensen, Richard, A1 aTajuddin, Salman1 aKabagambe, Edmond, K1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aFlanagan, Jack1 aAbaitua, Fernando1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAkiyama, Masato1 aAnand, Sonia, S1 aBertoni, Alain1 aBian, Zheng1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aBrummett, Chad, M1 aBuchanan, Thomas, A1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFornage, Myriam1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aFuchsberger, Christian1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGoodarzi, Mark, O1 aGordon-Larsen, Penny1 aGorkin, David1 aGross, Myron1 aGuo, Yu1 aHackinger, Sophie1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKamatani, Yoichiro1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKohara, Katsuhiko1 aKriebel, Jennifer1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLigthart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLyssenko, Valeriya1 aMamakou, Vasiliki1 aMani, Radha, K1 aMeitinger, Thomas1 aMetspalu, Andres1 aMorris, Andrew, D1 aNadkarni, Girish, N1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNongmaithem, Suraj, S1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPorneala, Bianca1 aPrasad, Gauri1 aPreissl, Sebastian1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Kathryn1 aSabanayagam, Charumathi1 aSander, Maike1 aSandow, Kevin1 aSattar, Naveed1 aSchönherr, Sebastian1 aSchurmann, Claudia1 aShahriar, Mohammad1 aShi, Jinxiu1 aShin, Dong, Mun1 aShriner, Daniel1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aSuzuki, Ken1 aTakahashi, Atsushi1 aTaylor, Kent, D1 aThorand, Barbara1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTorres, Jason, M1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aVujkovic, Marijana1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWhitsel, Eric, A1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamauchi, Toshimasa1 aYengo, Loic1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZhang, Liang1 aZheng, Wei1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aHanis, Craig, L1 aPeyser, Patricia, A1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aZeggini, Eleftheria1 aYokota, Mitsuhiro1 aRich, Stephen, S1 aKooperberg, Charles1 aPankow, James, S1 aEngert, James, C1 aChen, Yii-Der Ida1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aKardia, Sharon, L R1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aGroop, Leif1 aMook-Kanamori, Dennis, O1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aBottinger, Erwin, P1 aDehghan, Abbas1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aPalmer, Colin, N A1 aLiu, Simin1 aAbecasis, Goncalo1 aKooner, Jaspal, S1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aFlorez, Jose, C1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aMägi, Reedik1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aMaeda, Shiro1 aKadowaki, Takashi1 aLee, Juyoung1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aMyers, Simon, R1 aFerrer, Jorge1 aGaulton, Kyle, J1 aMeigs, James, B1 aMohlke, Karen, L1 aGloyn, Anna, L1 aBowden, Donald, W1 aBelow, Jennifer, E1 aChambers, John, C1 aSim, Xueling1 aBoehnke, Michael1 aRotter, Jerome, I1 aMcCarthy, Mark, I1 aMorris, Andrew, P1 aFinnGen1 aeMERGE Consortium uhttps://chs-nhlbi.org/node/910408881nas a2202605 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2022 eng d a1537-660500aRare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.0 aRare coding variants in 35 genes associate with circulating lipi c2022 01 06 a81-960 v1093 aLarge-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
10aAlleles10aBlood Glucose10aCase-Control Studies10aComputational Biology10aDatabases, Genetic10aDiabetes Mellitus, Type 210aExome10aGenetic Predisposition to Disease10aGenetic Variation10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLipid Metabolism10aLipids10aLiver10aMolecular Sequence Annotation10aMultifactorial Inheritance10aOpen Reading Frames10aPhenotype10aPolymorphism, Single Nucleotide1 aHindy, George1 aDornbos, Peter1 aChaffin, Mark, D1 aLiu, Dajiang, J1 aWang, Minxian1 aSelvaraj, Margaret, Sunitha1 aZhang, David1 aPark, Joseph1 aAguilar-Salinas, Carlos, A1 aAntonacci-Fulton, Lucinda1 aArdissino, Diego1 aArnett, Donna, K1 aAslibekyan, Stella1 aAtzmon, Gil1 aBallantyne, Christie, M1 aBarajas-Olmos, Francisco1 aBarzilai, Nir1 aBecker, Lewis, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBottinger, Erwin1 aBowden, Donald, W1 aBown, Matthew, J1 aBrody, Jennifer, A1 aBroome, Jai, G1 aBurtt, Noel, P1 aCade, Brian, E1 aCenteno-Cruz, Federico1 aChan, Edmund1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aCheng, Ching-Yu1 aChoi, Won, Jung1 aChowdhury, Raj1 aContreras-Cubas, Cecilia1 aCórdova, Emilio, J1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDanesh, John1 ade Vries, Paul, S1 aDeFronzo, Ralph, A1 aDoddapaneni, Harsha1 aDuggirala, Ravindranath1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aEmery, Leslie, S1 aFlorez, Jose, C1 aFornage, Myriam1 aFreedman, Barry, I1 aFuster, Valentin1 aGaray-Sevilla, Ma, Eugenia1 aGarcía-Ortiz, Humberto1 aGermer, Soren1 aGibbs, Richard, A1 aGieger, Christian1 aGlaser, Benjamin1 aGonzalez, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGraff, Mariaelisa1 aGraham, Sarah, E1 aGrarup, Niels1 aGroop, Leif, C1 aGuo, Xiuqing1 aGupta, Namrata1 aHan, Sohee1 aHanis, Craig, L1 aHansen, Torben1 aHe, Jiang1 aHeard-Costa, Nancy, L1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aIrvin, Marguerite, R1 aIslas-Andrade, Sergio1 aJarvik, Gail, P1 aKang, Hyun, Min1 aKardia, Sharon, L R1 aKelly, Tanika1 aKenny, Eimear, E1 aKhan, Alyna, T1 aKim, Bong-Jo1 aKim, Ryan, W1 aKim, Young, Jin1 aKoistinen, Heikki, A1 aKooperberg, Charles1 aKuusisto, Johanna1 aKwak, Soo, Heon1 aLaakso, Markku1 aLange, Leslie, A1 aLee, Jiwon1 aLee, Juyoung1 aLee, Seonwook1 aLehman, Donna, M1 aLemaitre, Rozenn, N1 aLinneberg, Allan1 aLiu, Jianjun1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aLyssenko, Valeriya1 aMa, Ronald, C W1 aMartin, Lisa, Warsinger1 aMartínez-Hernández, Angélica1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMcPherson, Ruth1 aMeigs, James, B1 aMeitinger, Thomas1 aMelander, Olle1 aMendoza-Caamal, Elvia1 aMetcalf, Ginger, A1 aMi, Xuenan1 aMohlke, Karen, L1 aMontasser, May, E1 aMoon, Jee-Young1 aMoreno-Macias, Hortensia1 aMorrison, Alanna, C1 aMuzny, Donna, M1 aNelson, Sarah, C1 aNilsson, Peter, M1 aO'Connell, Jeffrey, R1 aOrho-Melander, Marju1 aOrozco, Lorena1 aPalmer, Colin, N A1 aPalmer, Nicholette, D1 aPark, Cheol, Joo1 aPark, Kyong, Soo1 aPedersen, Oluf1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aPost, Wendy, S1 aPreuss, Michael1 aPsaty, Bruce, M1 aQi, Qibin1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aRevilla-Monsalve, Cristina1 aRich, Stephen, S1 aSamani, Nilesh1 aSchunkert, Heribert1 aSchurmann, Claudia1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSim, Xueling1 aSladek, Rob1 aSmall, Kerrin, S1 aSo, Wing, Yee1 aStilp, Adrienne, M1 aTai, Shyong, E1 aTam, Claudia, H T1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aThameem, Farook1 aTomlinson, Brian1 aTsai, Michael, Y1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 avan Dam, Rob, M1 aVasan, Ramachandran, S1 aMartinez, Karine, A Viaud1 aWang, Fei, Fei1 aWang, Xuzhi1 aWatkins, Hugh1 aWeeks, Daniel, E1 aWilson, James, G1 aWitte, Daniel, R1 aWong, Tien-Yin1 aYanek, Lisa, R1 aKathiresan, Sekar1 aRader, Daniel, J1 aRotter, Jerome, I1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aFlannick, Jason, A1 aKhera, Amit, V1 aPeloso, Gina, M1 aAMP-T2D-GENES, Myocardial Infarction Genetics Consortium1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aNHLBI TOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/897513865nas a2204393 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2023 eng d00aMulti-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.0 aMultiancestry genomewide study in 25 million individuals reveals c2023 Mar 313 aType 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.
1 aSuzuki, Ken1 aHatzikotoulas, Konstantinos1 aSoutham, Lorraine1 aTaylor, Henry, J1 aYin, Xianyong1 aLorenz, Kim, M1 aMandla, Ravi1 aHuerta-Chagoya, Alicia1 aRayner, Nigel, W1 aBocher, Ozvan1 ade, S, V Arruda A1 aSonehara, Kyuto1 aNamba, Shinichi1 aLee, Simon, S K1 aPreuss, Michael, H1 aPetty, Lauren, E1 aSchroeder, Philip1 aVanderwerff, Brett1 aKals, Mart1 aBragg, Fiona1 aLin, Kuang1 aGuo, Xiuqing1 aZhang, Weihua1 aYao, Jie1 aKim, Young, Jin1 aGraff, Mariaelisa1 aTakeuchi, Fumihiko1 aNano, Jana1 aLamri, Amel1 aNakatochi, Masahiro1 aMoon, Sanghoon1 aScott, Robert, A1 aCook, James, P1 aLee, Jung-Jin1 aPan, Ian1 aTaliun, Daniel1 aParra, Esteban, J1 aChai, Jin-Fang1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aThorleifsson, Gudmar1 aGrarup, Niels1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aKwak, Soo-Heon1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aNongmaithem, Suraj, S1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aBrody, Jennifer, A1 aKabagambe, Edmond1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aBroadaway, Alaine1 aWilliamson, Alice1 aKamali, Zoha1 aCui, Jinrui1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAhluwalia, Tarunveer, S1 aAnand, Sonia, S1 aBertoni, Alain1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBuchanan, Thomas, A1 aBurant, Charles, F1 aButterworth, Adam, S1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDanesh, John1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGordon-Larsen, Penny1 aGross, Myron1 aGuare, Lindsay, A1 aHackinger, Sophie1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHorikoshi, Momoko1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Torben1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Kyung, Min1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLithgart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLynch, Julie, A1 aLyssenko, Valeriya1 aMaeda, Shiro1 aMamakou, Vasiliki1 aMansuri, Sohail, Rafik1 aMatsuda, Koichi1 aMeitinger, Thomas1 aMetspalu, Andres1 aMo, Huan1 aMorris, Andrew, D1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPatil, Snehal1 aPei, Pei1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPolikowsky, Hannah, G1 aPorneala, Bianca1 aPrasad, Gauri1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Katheryn1 aSabanayagam, Charumathi1 aSandow, Kevin1 aSankareswaran, Alagu1 aSattar, Naveed1 aSchönherr, Sebastian1 aShahriar, Mohammad1 aShen, Botong1 aShi, Jinxiu1 aShin, Dong, Mun1 aShojima, Nobuhiro1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aSteinthorsdottir, Valgerdur1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aTaylor, Kent, D1 aThorand, Barbara1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTran, Tam, C1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamamoto, Kenichi1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZawistowski, Matthew1 aZhang, Liang1 aZheng, Wei1 aProject, Biobank, Japan1 aBioBank, Penn, Medicine1 aCenter, Regeneron, Genetics1 aConsortium, eMERGE1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aFornage, Myriam1 aHanis, Craig, L1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aYokota, Mitsuhiro1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aPankow, James, S1 aEngert, James, C1 aBonnefond, Amélie1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aMook-Kanamori, Dennis, O1 aTuomi, Tiinamaija1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aChen, Yii-Der Ida1 aRich, Stephen, S1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aGhanbari, Mohsen1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aBowden, Donald, W1 aPalmer, Colin, N A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aLiu, Simin1 aNorth, Kari, E1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aWareham, Nicholas, J1 aLee, Juyoung1 aKim, Bong-Jo1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aGoodarzi, Mark, O1 aMohlke, Karen, L1 aLangenberg, Claudia1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aFlorez, Jose, C1 aRader, Daniel, J1 aRitchie, Marylyn, D1 aZöllner, Sebastian1 aMägi, Reedik1 aDenny, Joshua, C1 aYamauchi, Toshimasa1 aKadowaki, Takashi1 aChambers, John, C1 aC Y Ng, Maggie1 aSim, Xueling1 aBelow, Jennifer, E1 aTsao, Philip, S1 aChang, Kyong-Mi1 aMcCarthy, Mark, I1 aMeigs, James, B1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aMercader, Josep, M1 aBoehnke, Michael1 aRotter, Jerome, I1 aVujkovic, Marijana1 aVoight, Benjamin, F1 aMorris, Andrew, P1 aZeggini, Eleftheria1 aVA Million Veteran Program, AMED GRIFIN Diabetes Initiative Japan1 aInternational Consortium for Blood Pressure (ICBP)1 aMeta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) uhttps://chs-nhlbi.org/node/938505493nas a2201573 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2023 eng d00aWHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.0 aWHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES N c2023 Aug 223 aObesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.
1 aZhang, Xinruo1 aBrody, Jennifer, A1 aGraff, Mariaelisa1 aHighland, Heather, M1 aChami, Nathalie1 aXu, Hanfei1 aWang, Zhe1 aFerrier, Kendra1 aChittoor, Geetha1 aJosyula, Navya, S1 aLi, Xihao1 aLi, Zilin1 aAllison, Matthew, A1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBoorgula, Meher, Preethi1 aBowden, Donald, W1 aBroome, Jai, G1 aButh, Erin, J1 aCarlson, Christopher, S1 aChang, Kyong-Mi1 aChavan, Sameer1 aChiu, Yen-Feng1 aChuang, Lee-Ming1 aConomos, Matthew, P1 aDeMeo, Dawn, L1 aDu, Margaret1 aDuggirala, Ravindranath1 aEng, Celeste1 aFohner, Alison, E1 aFreedman, Barry, I1 aGarrett, Melanie, E1 aGuo, Xiuqing1 aHaiman, Chris1 aHeavner, Benjamin, D1 aHidalgo, Bertha1 aHixson, James, E1 aHo, Yuk-Lam1 aHobbs, Brian, D1 aHu, Donglei1 aHui, Qin1 aHwu, Chii-Min1 aJackson, Rebecca, D1 aJain, Deepti1 aKalyani, Rita, R1 aKardia, Sharon, L R1 aKelly, Tanika, N1 aLange, Ethan, M1 aLeNoir, Michael1 aLi, Changwei1 aLe Marchand, Loic1 aMcDonald, Merry-Lynn, N1 aMcHugh, Caitlin, P1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey1 aO'Donnell, Christopher, J1 aPalmer, Nicholette, D1 aPankow, James, S1 aPerry, James, A1 aPeters, Ulrike1 aPreuss, Michael, H1 aRao, D, C1 aRegan, Elizabeth, A1 aReupena, Sefuiva, M1 aRoden, Dan, M1 aRodriguez-Santana, Jose1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aTiwari, Hemant, K1 aVasan, Ramachandran, S1 aWang, Zeyuan1 aWeeks, Daniel, E1 aWessel, Jennifer1 aWiggins, Kerri, L1 aWilkens, Lynne, R1 aWilson, Peter, W F1 aYanek, Lisa, R1 aYoneda, Zachary, T1 aZhao, Wei1 aZöllner, Sebastian1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBlangero, John1 aBoerwinkle, Eric1 aBurchard, Esteban, G1 aCarson, April, P1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aCurran, Joanne, E1 aFornage, Myriam1 aGordeuk, Victor, R1 aHe, Jiang1 aHeckbert, Susan, R1 aHou, Lifang1 aIrvin, Marguerite, R1 aKooperberg, Charles1 aMinster, Ryan, L1 aMitchell, Braxton, D1 aNouraie, Mehdi1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aReiner, Alexander, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aShoemaker, Benjamin1 aSmith, Nicholas, L1 aTaylor, Kent, D1 aTelen, Marilyn, J1 aWeiss, Scott, T1 aZhang, Yingze1 aCosta, Nancy, Heard-1 aSun, Yan, V1 aLin, Xihong1 aCupples, Adrienne, L1 aLange, Leslie, A1 aLiu, Ching-Ti1 aLoos, Ruth, J F1 aNorth, Kari, E1 aJustice, Anne, E1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/948414002nas a2204477 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2024 eng d a1476-468700aGenetic drivers of heterogeneity in type 2 diabetes pathophysiology.0 aGenetic drivers of heterogeneity in type 2 diabetes pathophysiol c2024 Feb 193 aType 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
1 aSuzuki, Ken1 aHatzikotoulas, Konstantinos1 aSoutham, Lorraine1 aTaylor, Henry, J1 aYin, Xianyong1 aLorenz, Kim, M1 aMandla, Ravi1 aHuerta-Chagoya, Alicia1 aMelloni, Giorgio, E M1 aKanoni, Stavroula1 aRayner, Nigel, W1 aBocher, Ozvan1 aArruda, Ana, Luiza1 aSonehara, Kyuto1 aNamba, Shinichi1 aLee, Simon, S K1 aPreuss, Michael, H1 aPetty, Lauren, E1 aSchroeder, Philip1 aVanderwerff, Brett1 aKals, Mart1 aBragg, Fiona1 aLin, Kuang1 aGuo, Xiuqing1 aZhang, Weihua1 aYao, Jie1 aKim, Young, Jin1 aGraff, Mariaelisa1 aTakeuchi, Fumihiko1 aNano, Jana1 aLamri, Amel1 aNakatochi, Masahiro1 aMoon, Sanghoon1 aScott, Robert, A1 aCook, James, P1 aLee, Jung-Jin1 aPan, Ian1 aTaliun, Daniel1 aParra, Esteban, J1 aChai, Jin-Fang1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aThorleifsson, Gudmar1 aGrarup, Niels1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aKwak, Soo-Heon1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aNongmaithem, Suraj, S1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aBrody, Jennifer, A1 aKabagambe, Edmond1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aBroadaway, Alaine1 aWilliamson, Alice1 aKamali, Zoha1 aCui, Jinrui1 aThangam, Manonanthini1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAhluwalia, Tarunveer, S1 aAnand, Sonia, S1 aBertoni, Alain1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBuchanan, Thomas, A1 aBurant, Charles, F1 aButterworth, Adam, S1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDanesh, John1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 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Torben1 aPedersen, Oluf1 aWareham, Nicholas, J1 aLee, Juyoung1 aKim, Bong-Jo1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aAhlqvist, Emma1 aGoodarzi, Mark, O1 aMohlke, Karen, L1 aLangenberg, Claudia1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aFlorez, Jose, C1 aRader, Daniel, J1 aRitchie, Marylyn, D1 aZöllner, Sebastian1 aMägi, Reedik1 aMarston, Nicholas, A1 aRuff, Christian, T1 avan Heel, David, A1 aFiner, Sarah1 aDenny, Joshua, C1 aYamauchi, Toshimasa1 aKadowaki, Takashi1 aChambers, John, C1 aC Y Ng, Maggie1 aSim, Xueling1 aBelow, Jennifer, E1 aTsao, Philip, S1 aChang, Kyong-Mi1 aMcCarthy, Mark, I1 aMeigs, James, B1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aMercader, Josep, M1 aBoehnke, Michael1 aRotter, Jerome, I1 aVujkovic, Marijana1 aVoight, Benjamin, F1 aMorris, Andrew, P1 aZeggini, Eleftheria1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/9619