Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

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Citation: American Journal of Human Genetics. 108(4):564-582, 2021 04 01.PMID: 33713608Institution: MedStar Health Research InstituteForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *African Continental Ancestry Group/ge [Genetics] | *Body Height/ge [Genetics] | *Genome-Wide Association Study | Africa/eh [Ethnology] | African Americans/ge [Genetics] | Europe/eh [Ethnology] | Female | Humans | Male | Polymorphism, Single Nucleotide/ge [Genetics]Year: 2021ISSN:
  • 0002-9297
Name of journal: American journal of human geneticsAbstract: 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. Copyright (c) 2021 American Society of Human Genetics. All rights reserved.All authors: Adeyemo AA, Aldrich MC, Allison MA, Ambrosone CB, Ambs S, Amos C, Arnett DK, Atwood L, Bandera EV, Bartz T, Becker DM, Berndt SI, Bernstein L, Bielak LF, Blot WJ, Borecki IB, Bottinger EP, Bowden DW, Bradfield JP, Brody JA, Broeckel U, Buchanan V, Burke G, Cade BE, Cai Q, Caporaso N, Carlson C, Carpten J, Casey G, Chanock SJ, Chen G, Chen M, Chen WM, Chen YI, Chesi A, Chiang CWK, Chu L, Coetzee GA, Conti DV, Cooper RS, Cupples LA, Cushman M, Demerath E, Deming SL, Dimitrov L, Ding J, Diver WR, Duan Q, Evans MK, Falusi AG, Faul JD, Feitosa MF, Fine RS, Fornage M, Fox C, Freedman BI, Garcia M, Gillanders EM, Goodman P, Gottesman O, Graff M, Grant SFA, Guo X, Haiman CA, Hakonarson H, Haritunians T, Harris CC, Harris TB, Henderson BE, Hennis A, Hernandez DG, Hirschhorn JN, Howard B, Howard TD, Hsing AW, Hsu YH, Hu JJ, Huff CD, Huo D, Ingles SA, Irvin MR, John EM, Johnson KC, Jordan JM, Justice AE, Kabagambe EK, Kang SJ, Kardia SL, Keating BJ, Kittles RA, Klein EA, Kolb S, Kolonel LN, Kooperberg C, Kuller L, Kutlar A, Lange L, Langefeld CD, Le Marchand L, Leonard H, Lettre G, Levin AM, Li J, Li Y, Lim E, Liu CT, Liu S, Liu Y, Lohman K, Loos R, Lotay V, Lu Y, Maixner W, Manson JE, Marouli E, McKnight B, McNeill LH, Meng Y, Monda KL, Monroe K, Moore JH, Mosley TH, Mudgal P, Murphy AB, N'Diaye A, Nadukuru R, Nalls MA, Nathanson KL, Nayak U, Nemesure B, Neslund-Dudas C, Neuhouser ML, Ng MCY, North KE, Nyante S, Ochs-Balcom H, Ogundiran TO, Ogunniyi A, Ojengbede O, Okut H, Olopade OI, Olshan A, Padhukasahasram B, Palmer CD, Palmer J, Palmer ND, Papanicolaou G, Patel SR, Pettaway CA, Peyser PA, Press MF, Psaty BM, Rand K, Rao DC, Rasmussen-Torvik LJ, Redline S, Reiner AP, Rhie SK, Rodriguez-Gil JL, Rohde R, Rotimi CN, Rotter JI, Ruiz-Narvaez EA, Rybicki BA, Salako B, Sale MM, Sanderson M, Schadt E, Schreiner PJ, Schurmann C, Schwartz AG, Shao Y, Shriner DA, Signorello LB, Singleton AB, Siscovick DS, Smith JA, Smith S, Speliotes E, Spitz M, Stanford JL, Stevens VL, Stram A, Strom SS, Sucheston L, Sun YV, Tajuddin SM, Taylor H, Taylor K, Tayo BO, Thun MJ, Tucker MA, Vaidya D, Van Den Berg DJ, Vedantam S, Vitolins M, Wang Z, Ware EB, Wassertheil-Smoller S, Weir DR, Wiencke JK, Williams LK, Williams SM, Wilson JG, Witte JS, Wojczynski MK, Wrensch M, Wu X, Yanek LR, Yao J, Young KL, Zakai N, Zanetti K, Zemel BS, Zhang X, Zhao JH, Zhao W, Zheng W, Zhi D, Zhou J, Zhu X, Ziegler RG, Zmuda J, Zonderman ABOriginally published: American Journal of Human Genetics. 108(4):564-582, 2021 04 01.American Journal of Human Genetics. 108(4):564-582, 2021 Apr 01.Fiscal year: FY2021Fiscal year of original publication: FY2021Digital Object Identifier: Date added to catalog: 2021-06-07
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Journal Article MedStar Authors Catalog Article 33713608 Available 33713608

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. Copyright (c) 2021 American Society of Human Genetics. All rights reserved.

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