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Although 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/870505493nas 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/9484