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 language | English (US) |
|---|---|
| Pages (from-to) | 564-582 |
| Number of pages | 19 |
| Journal | American Journal of Human Genetics |
| Volume | 108 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2021 |
Keywords
- African ancestry
- fine-mapping
- genome-wide
- height
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
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Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. / Graff, Mariaelisa; Justice, Anne E.; Young, Kristin L.; Marouli, Eirini; Zhang, Xinruo; Fine, Rebecca S.; Lim, Elise; Buchanan, Victoria; Rand, Kristin; Feitosa, Mary F.; Wojczynski, Mary K.; Yanek, Lisa R.; Shao, Yaming; Rohde, Rebecca; Adeyemo, Adebowale A.; Aldrich, Melinda C.; Allison, Matthew A.; Ambrosone, Christine B.; Ambs, Stefan; Amos, Christopher; Arnett, Donna K.; Atwood, Larry; Bandera, Elisa V.; Bartz, Traci; Becker, Diane M.; Berndt, Sonja I.; Bernstein, Leslie; Bielak, Lawrence F.; Blot, William J.; Bottinger, Erwin P.; Bowden, Donald W.; Bradfield, Jonathan P.; Brody, Jennifer A.; Broeckel, Ulrich; Burke, Gregory; Cade, Brian E.; Cai, Qiuyin; Caporaso, Neil; Carlson, Chris; Carpten, John; Casey, Graham; Chanock, Stephen J.; Chen, Guanjie; Chen, Minhui; Chen, Yii Der I.; Chen, Wei Min; Chesi, Alessandra; Chiang, Charleston W.K.; Chu, Lisa; Coetzee, Gerry A.; Conti, David V.; Cooper, Richard S.; Cushman, Mary; Demerath, Ellen; Deming, Sandra L.; Dimitrov, Latchezar; Ding, Jingzhong; Diver, W. Ryan; Duan, Qing; Evans, Michele K.; Falusi, Adeyinka G.; Faul, Jessica D.; Fornage, Myriam; Fox, Caroline; Freedman, Barry I.; Garcia, Melissa; Gillanders, Elizabeth M.; Goodman, Phyllis; Gottesman, Omri; Grant, Struan F.A.; Guo, Xiuqing; Hakonarson, Hakon; Haritunians, Talin; Harris, Tamara B.; Harris, Curtis C.; Henderson, Brian E.; Hennis, Anselm; Hernandez, Dena G.; Hirschhorn, Joel N.; McNeill, Lorna Haughton; Howard, Timothy D.; Howard, Barbara; Hsing, Ann W.; Hsu, Yu Han H.; Hu, Jennifer J.; Huff, Chad D.; Huo, Dezheng; Ingles, Sue A.; Irvin, Marguerite R.; John, Esther M.; Johnson, Karen C.; Jordan, Joanne M.; Kabagambe, Edmond K.; Kang, Sun J.; Kardia, Sharon L.; Keating, Brendan J.; Kittles, Rick A.; Klein, Eric A.; Kolb, Suzanne; Kolonel, Laurence N.; Kooperberg, Charles; Kuller, Lewis; Kutlar, Abdullah; Lange, Leslie; Langefeld, Carl D.; Le Marchand, Loic; Leonard, Hampton; Lettre, Guillaume; Levin, Albert M.; Li, Yun; Li, Jin; Liu, Yongmei; Liu, Youfang; Liu, Simin; Lohman, Kurt; Lotay, Vaneet; Lu, Yingchang; Maixner, William; Manson, Jo Ann E.; McKnight, Barbara; Meng, Yan; Monda, Keri L.; Monroe, Kris; Moore, Jason H.; Mosley, Thomas H.; Mudgal, Poorva; Murphy, Adam B.; Nadukuru, Rajiv; Nalls, Mike A.; Nathanson, Katherine L.; Nayak, Uma; N'Diaye, Amidou; Nemesure, Barbara; Neslund-Dudas, Christine; Neuhouser, Marian L.; Nyante, Sarah; Ochs-Balcom, Heather; Ogundiran, Temidayo O.; Ogunniyi, Adesola; Ojengbede, Oladosu; Okut, Hayrettin; Olopade, Olufunmilayo I.; Olshan, Andrew; Padhukasahasram, Badri; Palmer, Julie; Palmer, Cameron D.; Palmer, Nicholette D.; Papanicolaou, George; Patel, Sanjay R.; Pettaway, Curtis A.; Peyser, Patricia A.; Press, Michael F.; Rao, D. C.; Rasmussen-Torvik, Laura J.; Redline, Susan; Reiner, Alex P.; Rhie, Suhn K.; Rodriguez-Gil, Jorge L.; Rotimi, Charles N.; Rotter, Jerome I.; Ruiz-Narvaez, Edward A.; Rybicki, Benjamin A.; Salako, Babatunde; Sale, Michele M.; Sanderson, Maureen; Schadt, Eric; Schreiner, Pamela J.; Schurmann, Claudia; Schwartz, Ann G.; Shriner, Daniel A.; Signorello, Lisa B.; Singleton, Andrew B.; Siscovick, David S.; Smith, Jennifer A.; Smith, Shad; Speliotes, Elizabeth; Spitz, Margaret; Stanford, Janet L.; Stevens, Victoria L.; Stram, Alex; Strom, Sara S.; Sucheston, Lara; Sun, Yan V.; Tajuddin, Salman M.; Taylor, Herman; Taylor, Kira; Tayo, Bamidele O.; Thun, Michael J.; Tucker, Margaret A.; Vaidya, Dhananjay; Van Den Berg, David J.; Vedantam, Sailaja; Vitolins, Mara; Wang, Zhaoming; Ware, Erin B.; Wassertheil-Smoller, Sylvia; Weir, David R.; Wiencke, John K.; Williams, Scott M.; Williams, L. Keoki; Wilson, James G.; Witte, John S.; Wrensch, Margaret; Wu, Xifeng; Yao, Jie; Zakai, Neil; Zanetti, Krista; Zemel, Babette S.; Zhao, Wei; Zhao, Jing Hua; Zheng, Wei; Zhi, Degui; Zhou, Jie; Zhu, Xiaofeng; Ziegler, Regina G.; Zmuda, Joe; Zonderman, Alan B.; Psaty, Bruce M.; Borecki, Ingrid B.; Cupples, L. Adrienne; Liu, Ching Ti; Haiman, Christopher A.; Loos, Ruth; Ng, Maggie C.Y.; North, Kari E.
In: American Journal of Human Genetics, Vol. 108, No. 4, 01.04.2021, p. 564-582.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry
AU - Graff, Mariaelisa
AU - Justice, Anne E.
AU - Young, Kristin L.
AU - Marouli, Eirini
AU - Zhang, Xinruo
AU - Fine, Rebecca S.
AU - Lim, Elise
AU - Buchanan, Victoria
AU - Rand, Kristin
AU - Feitosa, Mary F.
AU - Wojczynski, Mary K.
AU - Yanek, Lisa R.
AU - Shao, Yaming
AU - Rohde, Rebecca
AU - Adeyemo, Adebowale A.
AU - Aldrich, Melinda C.
AU - Allison, Matthew A.
AU - Ambrosone, Christine B.
AU - Ambs, Stefan
AU - Amos, Christopher
AU - Arnett, Donna K.
AU - Atwood, Larry
AU - Bandera, Elisa V.
AU - Bartz, Traci
AU - Becker, Diane M.
AU - Berndt, Sonja I.
AU - Bernstein, Leslie
AU - Bielak, Lawrence F.
AU - Blot, William J.
AU - Bottinger, Erwin P.
AU - Bowden, Donald W.
AU - Bradfield, Jonathan P.
AU - Brody, Jennifer A.
AU - Broeckel, Ulrich
AU - Burke, Gregory
AU - Cade, Brian E.
AU - Cai, Qiuyin
AU - Caporaso, Neil
AU - Carlson, Chris
AU - Carpten, John
AU - Casey, Graham
AU - Chanock, Stephen J.
AU - Chen, Guanjie
AU - Chen, Minhui
AU - Chen, Yii Der I.
AU - Chen, Wei Min
AU - Chesi, Alessandra
AU - Chiang, Charleston W.K.
AU - Chu, Lisa
AU - Coetzee, Gerry A.
AU - Conti, David V.
AU - Cooper, Richard S.
AU - Cushman, Mary
AU - Demerath, Ellen
AU - Deming, Sandra L.
AU - Dimitrov, Latchezar
AU - Ding, Jingzhong
AU - Diver, W. Ryan
AU - Duan, Qing
AU - Evans, Michele K.
AU - Falusi, Adeyinka G.
AU - Faul, Jessica D.
AU - Fornage, Myriam
AU - Fox, Caroline
AU - Freedman, Barry I.
AU - Garcia, Melissa
AU - Gillanders, Elizabeth M.
AU - Goodman, Phyllis
AU - Gottesman, Omri
AU - Grant, Struan F.A.
AU - Guo, Xiuqing
AU - Hakonarson, Hakon
AU - Haritunians, Talin
AU - Harris, Tamara B.
AU - Harris, Curtis C.
AU - Henderson, Brian E.
AU - Hennis, Anselm
AU - Hernandez, Dena G.
AU - Hirschhorn, Joel N.
AU - McNeill, Lorna Haughton
AU - Howard, Timothy D.
AU - Howard, Barbara
AU - Hsing, Ann W.
AU - Hsu, Yu Han H.
AU - Hu, Jennifer J.
AU - Huff, Chad D.
AU - Huo, Dezheng
AU - Ingles, Sue A.
AU - Irvin, Marguerite R.
AU - John, Esther M.
AU - Johnson, Karen C.
AU - Jordan, Joanne M.
AU - Kabagambe, Edmond K.
AU - Kang, Sun J.
AU - Kardia, Sharon L.
AU - Keating, Brendan J.
AU - Kittles, Rick A.
AU - Klein, Eric A.
AU - Kolb, Suzanne
AU - Kolonel, Laurence N.
AU - Kooperberg, Charles
AU - Kuller, Lewis
AU - Kutlar, Abdullah
AU - Lange, Leslie
AU - Langefeld, Carl D.
AU - Le Marchand, Loic
AU - Leonard, Hampton
AU - Lettre, Guillaume
AU - Levin, Albert M.
AU - Li, Yun
AU - Li, Jin
AU - Liu, Yongmei
AU - Liu, Youfang
AU - Liu, Simin
AU - Lohman, Kurt
AU - Lotay, Vaneet
AU - Lu, Yingchang
AU - Maixner, William
AU - Manson, Jo Ann E.
AU - McKnight, Barbara
AU - Meng, Yan
AU - Monda, Keri L.
AU - Monroe, Kris
AU - Moore, Jason H.
AU - Mosley, Thomas H.
AU - Mudgal, Poorva
AU - Murphy, Adam B.
AU - Nadukuru, Rajiv
AU - Nalls, Mike A.
AU - Nathanson, Katherine L.
AU - Nayak, Uma
AU - N'Diaye, Amidou
AU - Nemesure, Barbara
AU - Neslund-Dudas, Christine
AU - Neuhouser, Marian L.
AU - Nyante, Sarah
AU - Ochs-Balcom, Heather
AU - Ogundiran, Temidayo O.
AU - Ogunniyi, Adesola
AU - Ojengbede, Oladosu
AU - Okut, Hayrettin
AU - Olopade, Olufunmilayo I.
AU - Olshan, Andrew
AU - Padhukasahasram, Badri
AU - Palmer, Julie
AU - Palmer, Cameron D.
AU - Palmer, Nicholette D.
AU - Papanicolaou, George
AU - Patel, Sanjay R.
AU - Pettaway, Curtis A.
AU - Peyser, Patricia A.
AU - Press, Michael F.
AU - Rao, D. C.
AU - Rasmussen-Torvik, Laura J.
AU - Redline, Susan
AU - Reiner, Alex P.
AU - Rhie, Suhn K.
AU - Rodriguez-Gil, Jorge L.
AU - Rotimi, Charles N.
AU - Rotter, Jerome I.
AU - Ruiz-Narvaez, Edward A.
AU - Rybicki, Benjamin A.
AU - Salako, Babatunde
AU - Sale, Michele M.
AU - Sanderson, Maureen
AU - Schadt, Eric
AU - Schreiner, Pamela J.
AU - Schurmann, Claudia
AU - Schwartz, Ann G.
AU - Shriner, Daniel A.
AU - Signorello, Lisa B.
AU - Singleton, Andrew B.
AU - Siscovick, David S.
AU - Smith, Jennifer A.
AU - Smith, Shad
AU - Speliotes, Elizabeth
AU - Spitz, Margaret
AU - Stanford, Janet L.
AU - Stevens, Victoria L.
AU - Stram, Alex
AU - Strom, Sara S.
AU - Sucheston, Lara
AU - Sun, Yan V.
AU - Tajuddin, Salman M.
AU - Taylor, Herman
AU - Taylor, Kira
AU - Tayo, Bamidele O.
AU - Thun, Michael J.
AU - Tucker, Margaret A.
AU - Vaidya, Dhananjay
AU - Van Den Berg, David J.
AU - Vedantam, Sailaja
AU - Vitolins, Mara
AU - Wang, Zhaoming
AU - Ware, Erin B.
AU - Wassertheil-Smoller, Sylvia
AU - Weir, David R.
AU - Wiencke, John K.
AU - Williams, Scott M.
AU - Williams, L. Keoki
AU - Wilson, James G.
AU - Witte, John S.
AU - Wrensch, Margaret
AU - Wu, Xifeng
AU - Yao, Jie
AU - Zakai, Neil
AU - Zanetti, Krista
AU - Zemel, Babette S.
AU - Zhao, Wei
AU - Zhao, Jing Hua
AU - Zheng, Wei
AU - Zhi, Degui
AU - Zhou, Jie
AU - Zhu, Xiaofeng
AU - Ziegler, Regina G.
AU - Zmuda, Joe
AU - Zonderman, Alan B.
AU - Psaty, Bruce M.
AU - Borecki, Ingrid B.
AU - Cupples, L. Adrienne
AU - Liu, Ching Ti
AU - Haiman, Christopher A.
AU - Loos, Ruth
AU - Ng, Maggie C.Y.
AU - North, Kari E.
N1 - Publisher Copyright: © 2021 American Society of Human Genetics
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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.
AB - 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.
KW - African ancestry
KW - fine-mapping
KW - genome-wide
KW - height
UR - http://www.scopus.com/inward/record.url?scp=85103409847&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103409847&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2021.02.011
DO - 10.1016/j.ajhg.2021.02.011
M3 - Article
C2 - 33713608
AN - SCOPUS:85103409847
VL - 108
SP - 564
EP - 582
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -