Discovery 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

Ng, Maggie C. Y.; Graff, Mariaelisa; Lu, Yingchang; Justice, Anne E.; Mudgal, Poorva; Liu, Ching-Ti; Young, Kristin L.; Yanek, Lisa R.; Feitosa, Mary F.; Wojczynski, Mary K.; Rand, Kristin; Brody, Jennifer A.; Cade, Brian E.; Dimitrov, Latchezar; Duan, Qing; Guo, Xiuqing; Lange, Leslie A.; Nalls, Michael A.; Okut, Hayrettin; Tajuddin, Salman M.; Tayo, Bamidele O.; Vedantam, Sailaja; Bradfield, Jonathan P.; Chen, Guanjie; Chen, Wei-Min; Chesi, Alessandra; Irvin, Marguerite Ryan; Padhukasahasram, Badri; Smith, Jennifer A.; Zheng, Wei; Allison, Matthew A.; Ambrosone, Christine B.; Bandera, Elisa V.; Bartz, Traci M.; Berndt, Sonja I.; Bernstein, Leslie; Blot, William J.; Bottinger, Erwin P.; Carpten, John; Chanock, Stephen J.; Chen, Yii-Der Ida; Conti, David V.; Cooper, Richard S.; Fornage, Myriam; Freedman, Barry I.; Garcia, Melissa; Goodman, Phyllis J.; Hsu, Yu-Han H.; Hu, Jennifer; Huff, Chad D.; Ingles, Sue A.; John, Esther M.; Kittles, Rick; Klein, Eric; Li, Jin; McKnight, Barbara; Nayak, Uma; Nemesure, Barbara; Ogunniyi, Adesola; Olshan, Andrew F.; Press, Michael F.; Rohde, Rebecca; Rybicki, Benjamin A.; Salako, Babatunde; Sanderson, Maureen; Shao, Yaming; Siscovick, David S.; Stanford, Janet L.; Stevens, Victoria L.; Stram, Alex; Strom, Sara S.; Vaidya, Dhananjay; Witte, John S.; Yao, Jie; Zhu, Xiaofeng; Ziegler, Regina G.; Zonderman, Alan B.; Adeyemo, Adebowale; Ambs, Stefan; Cushman, Mary; Faul, Jessica D.; Hakonarson, Hakon; Levin, Albert M.; Nathanson, Katherine L.; Ware, Erin B.; Weir, David R.; Zhao, Wei; Zhi, Degui; the Bone Mineral Density in Childhood Study (BMDCS) Group; Arnett, Donna K.; Grant, Struan F. A.; Kardia, Sharon L. R.; Oloapde, Olufunmilayo I.; Rao, Dabeeru C.; Rotimi, Charles N.; Sale, Michele M.; Williams, L. Keoki; Zemel, Babette S.; Becker, Diane M.; Borecki, Ingrid B.; Evans, Michele K.; Harris, Tamara B.; Hirschhorn, Joel N.; Li, Yun; Patel, Sanjay R.; Psaty, Bruce M.; Rotter, Jerome I.; Wilson, James G.; Bowden, Donald W.; Cupples, L. Adrienne; Haiman, Christopher A.; Loos, Ruth J. F.; & North, Kari E. (2017). Discovery 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. PLOS Genetics, 13(4), e1006719. PMCID: PMC5419579

Ng, Maggie C. Y.; Graff, Mariaelisa; Lu, Yingchang; Justice, Anne E.; Mudgal, Poorva; Liu, Ching-Ti; Young, Kristin L.; Yanek, Lisa R.; Feitosa, Mary F.; Wojczynski, Mary K.; Rand, Kristin; Brody, Jennifer A.; Cade, Brian E.; Dimitrov, Latchezar; Duan, Qing; Guo, Xiuqing; Lange, Leslie A.; Nalls, Michael A.; Okut, Hayrettin; Tajuddin, Salman M.; Tayo, Bamidele O.; Vedantam, Sailaja; Bradfield, Jonathan P.; Chen, Guanjie; Chen, Wei-Min; Chesi, Alessandra; Irvin, Marguerite Ryan; Padhukasahasram, Badri; Smith, Jennifer A.; Zheng, Wei; Allison, Matthew A.; Ambrosone, Christine B.; Bandera, Elisa V.; Bartz, Traci M.; Berndt, Sonja I.; Bernstein, Leslie; Blot, William J.; Bottinger, Erwin P.; Carpten, John; Chanock, Stephen J.; Chen, Yii-Der Ida; Conti, David V.; Cooper, Richard S.; Fornage, Myriam; Freedman, Barry I.; Garcia, Melissa; Goodman, Phyllis J.; Hsu, Yu-Han H.; Hu, Jennifer; Huff, Chad D.; Ingles, Sue A.; John, Esther M.; Kittles, Rick; Klein, Eric; Li, Jin; McKnight, Barbara; Nayak, Uma; Nemesure, Barbara; Ogunniyi, Adesola; Olshan, Andrew F.; Press, Michael F.; Rohde, Rebecca; Rybicki, Benjamin A.; Salako, Babatunde; Sanderson, Maureen; Shao, Yaming; Siscovick, David S.; Stanford, Janet L.; Stevens, Victoria L.; Stram, Alex; Strom, Sara S.; Vaidya, Dhananjay; Witte, John S.; Yao, Jie; Zhu, Xiaofeng; Ziegler, Regina G.; Zonderman, Alan B.; Adeyemo, Adebowale; Ambs, Stefan; Cushman, Mary; Faul, Jessica D.; Hakonarson, Hakon; Levin, Albert M.; Nathanson, Katherine L.; Ware, Erin B.; Weir, David R.; Zhao, Wei; Zhi, Degui; the Bone Mineral Density in Childhood Study (BMDCS) Group; Arnett, Donna K.; Grant, Struan F. A.; Kardia, Sharon L. R.; Oloapde, Olufunmilayo I.; Rao, Dabeeru C.; Rotimi, Charles N.; Sale, Michele M.; Williams, L. Keoki; Zemel, Babette S.; Becker, Diane M.; Borecki, Ingrid B.; Evans, Michele K.; Harris, Tamara B.; Hirschhorn, Joel N.; Li, Yun; Patel, Sanjay R.; Psaty, Bruce M.; Rotter, Jerome I.; Wilson, James G.; Bowden, Donald W.; Cupples, L. Adrienne; Haiman, Christopher A.; Loos, Ruth J. F.; & North, Kari E. (2017). Discovery 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. PLOS Genetics, 13(4), e1006719. PMCID: PMC5419579

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Genome-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 < 5x10-8: 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.



JOUR



Ng, Maggie C. Y.
Graff, Mariaelisa
Lu, Yingchang
Justice, Anne E.
Mudgal, Poorva
Liu, Ching-Ti
Young, Kristin L.
Yanek, Lisa R.
Feitosa, Mary F.
Wojczynski, Mary K.
Rand, Kristin
Brody, Jennifer A.
Cade, Brian E.
Dimitrov, Latchezar
Duan, Qing
Guo, Xiuqing
Lange, Leslie A.
Nalls, Michael A.
Okut, Hayrettin
Tajuddin, Salman M.
Tayo, Bamidele O.
Vedantam, Sailaja
Bradfield, Jonathan P.
Chen, Guanjie
Chen, Wei-Min
Chesi, Alessandra
Irvin, Marguerite Ryan
Padhukasahasram, Badri
Smith, Jennifer A.
Zheng, Wei
Allison, Matthew A.
Ambrosone, Christine B.
Bandera, Elisa V.
Bartz, Traci M.
Berndt, Sonja I.
Bernstein, Leslie
Blot, William J.
Bottinger, Erwin P.
Carpten, John
Chanock, Stephen J.
Chen, Yii-Der Ida
Conti, David V.
Cooper, Richard S.
Fornage, Myriam
Freedman, Barry I.
Garcia, Melissa
Goodman, Phyllis J.
Hsu, Yu-Han H.
Hu, Jennifer
Huff, Chad D.
Ingles, Sue A.
John, Esther M.
Kittles, Rick
Klein, Eric
Li, Jin
McKnight, Barbara
Nayak, Uma
Nemesure, Barbara
Ogunniyi, Adesola
Olshan, Andrew F.
Press, Michael F.
Rohde, Rebecca
Rybicki, Benjamin A.
Salako, Babatunde
Sanderson, Maureen
Shao, Yaming
Siscovick, David S.
Stanford, Janet L.
Stevens, Victoria L.
Stram, Alex
Strom, Sara S.
Vaidya, Dhananjay
Witte, John S.
Yao, Jie
Zhu, Xiaofeng
Ziegler, Regina G.
Zonderman, Alan B.
Adeyemo, Adebowale
Ambs, Stefan
Cushman, Mary
Faul, Jessica D.
Hakonarson, Hakon
Levin, Albert M.
Nathanson, Katherine L.
Ware, Erin B.
Weir, David R.
Zhao, Wei
Zhi, Degui
the Bone Mineral Density in Childhood Study (BMDCS) Group
Arnett, Donna K.
Grant, Struan F. A.
Kardia, Sharon L. R.
Oloapde, Olufunmilayo I.
Rao, Dabeeru C.
Rotimi, Charles N.
Sale, Michele M.
Williams, L. Keoki
Zemel, Babette S.
Becker, Diane M.
Borecki, Ingrid B.
Evans, Michele K.
Harris, Tamara B.
Hirschhorn, Joel N.
Li, Yun
Patel, Sanjay R.
Psaty, Bruce M.
Rotter, Jerome I.
Wilson, James G.
Bowden, Donald W.
Cupples, L. Adrienne
Haiman, Christopher A.
Loos, Ruth J. F.
North, Kari E.



2017


PLOS Genetics

13

4

e1006719








PMC5419579


10083

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