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

Mariaelisa Graff, Anne E. Justice, Kristin L. Young, Eirini Marouli, Xinruo Zhang, Rebecca S. Fine, Elise Lim, Victoria Buchanan, Kristin Rand, Mary F. Feitosa, Mary K. Wojczynski, Lisa R. Yanek, Yaming Shao, Rebecca Rohde, Adebowale A. Adeyemo, Melinda C. Aldrich, Matthew A. Allison, Christine B. Ambrosone, Stefan Ambs, Christopher AmosDonna K. Arnett, Larry Atwood, Elisa V. Bandera, Traci Bartz, Diane M. Becker, Sonja I. Berndt, Leslie Bernstein, Lawrence F. Bielak, William J. Blot, Erwin P. Bottinger, Donald W. Bowden, Jonathan P. Bradfield, Jennifer A. Brody, Ulrich Broeckel, Gregory Burke, Brian E. Cade, Qiuyin Cai, Neil Caporaso, Chris Carlson, John Carpten, Graham Casey, Stephen J. Chanock, Guanjie Chen, Minhui Chen, Yii Der I. Chen, Wei Min Chen, Alessandra Chesi, Charleston W.K. Chiang, Lisa Chu, Gerry A. Coetzee, David V. Conti, Richard S. Cooper, Mary Cushman, Ellen Demerath, Sandra L. Deming, Latchezar Dimitrov, Jingzhong Ding, W. Ryan Diver, Qing Duan, Michele K. Evans, Adeyinka G. Falusi, Jessica D. Faul, Myriam Fornage, Caroline Fox, Barry I. Freedman, Melissa Garcia, Elizabeth M. Gillanders, Phyllis Goodman, Omri Gottesman, Struan F.A. Grant, Xiuqing Guo, Hakon Hakonarson, Talin Haritunians, Tamara B. Harris, Curtis C. Harris, Brian E. Henderson, Anselm Hennis, Dena G. Hernandez, Joel N. Hirschhorn, Lorna Haughton McNeill, Timothy D. Howard, Barbara Howard, Ann W. Hsing, Yu Han H. Hsu, Jennifer J. Hu, Chad D. Huff, Dezheng Huo, Sue A. Ingles, Marguerite R. Irvin, Esther M. John, Karen C. Johnson, Joanne M. Jordan, Edmond K. Kabagambe, Sun J. Kang, Sharon L. Kardia, Brendan J. Keating, Rick A. Kittles, Eric A. Klein, Suzanne Kolb, Laurence N. Kolonel, Charles Kooperberg, Lewis Kuller, Abdullah Kutlar, Leslie Lange, Carl D. Langefeld, Loic Le Marchand, Hampton Leonard, Guillaume Lettre, Albert M. Levin, Yun Li, Jin Li, Yongmei Liu, Youfang Liu, Simin Liu, Kurt Lohman, Vaneet Lotay, Yingchang Lu, William Maixner, Jo Ann E. Manson, Barbara McKnight, Yan Meng, Keri L. Monda, Kris Monroe, Jason H. Moore, Thomas H. Mosley, Poorva Mudgal, Adam B. Murphy, Rajiv Nadukuru, Mike A. Nalls, Katherine L. Nathanson, Uma Nayak, Amidou N'Diaye, Barbara Nemesure, Christine Neslund-Dudas, Marian L. Neuhouser, Sarah Nyante, Heather Ochs-Balcom, Temidayo O. Ogundiran, Adesola Ogunniyi, Oladosu Ojengbede, Hayrettin Okut, Olufunmilayo I. Olopade, Andrew Olshan, Badri Padhukasahasram, Julie Palmer, Cameron D. Palmer, Nicholette D. Palmer, George Papanicolaou, Sanjay R. Patel, Curtis A. Pettaway, Patricia A. Peyser, Michael F. Press, D. C. Rao, Laura J. Rasmussen-Torvik, Susan Redline, Alex P. Reiner, Suhn K. Rhie, Jorge L. Rodriguez-Gil, Charles N. Rotimi, Jerome I. Rotter, Edward A. Ruiz-Narvaez, Benjamin A. Rybicki, Babatunde Salako, Michele M. Sale, Maureen Sanderson, Eric Schadt, Pamela J. Schreiner, Claudia Schurmann, Ann G. Schwartz, Daniel A. Shriner, Lisa B. Signorello, Andrew B. Singleton, David S. Siscovick, Jennifer A. Smith, Shad Smith, Elizabeth Speliotes, Margaret Spitz, Janet L. Stanford, Victoria L. Stevens, Alex Stram, Sara S. Strom, Lara Sucheston, Yan V. Sun, Salman M. Tajuddin, Herman Taylor, Kira Taylor, Bamidele O. Tayo, Michael J. Thun, Margaret A. Tucker, Dhananjay Vaidya, David J. Van Den Berg, Sailaja Vedantam, Mara Vitolins, Zhaoming Wang, Erin B. Ware, Sylvia Wassertheil-Smoller, David R. Weir, John K. Wiencke, Scott M. Williams, L. Keoki Williams, James G. Wilson, John S. Witte, Margaret Wrensch, Xifeng Wu, Jie Yao, Neil Zakai, Krista Zanetti, Babette S. Zemel, Wei Zhao, Jing Hua Zhao, Wei Zheng, Degui Zhi, Jie Zhou, Xiaofeng Zhu, Regina G. Ziegler, Joe Zmuda, Alan B. Zonderman, Bruce M. Psaty, Ingrid B. Borecki, L. Adrienne Cupples, Ching Ti Liu, Christopher A. Haiman, Ruth Loos, Maggie C.Y. Ng, Kari E. North

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)564-582
Number of pages19
JournalAmerican journal of human genetics
Volume108
Issue number4
DOIs
StatePublished - Apr 1 2021

Keywords

  • African ancestry
  • fine-mapping
  • genome-wide
  • height

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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