Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci

Lindsay Fernández-Rhodes, Jian Gong, Jeffrey Haessler, Nora Franceschini, Mariaelisa Graff, Katherine K. Nishimura, Yujie Wang, Heather M. Highland, Sachiko Yoneyama, William S. Bush, Robert Goodloe, Marylyn D. Ritchie, Dana Crawford, Myron Gross, Myriam Fornage, Petra Buzkova, Ran Tao, Carmen Isasi, Larissa Avilés-Santa, Martha Daviglus & 46 others Rachel H. Mackey, Denise Houston, C. Charles Gu, Georg Ehret, Khanh Dung H. Nguyen, Cora E. Lewis, Mark Leppert, Marguerite R. Irvin, Unhee Lim, Christopher A. Haiman, Loic Le Marchand, Fredrick Schumacher, Lynne Wilkens, Yingchang Lu, Erwin P. Bottinger, Ruth J.L. Loos, Wayne H.H. Sheu, Xiuqing Guo, Wen Jane Lee, Yang Hai, Yi Jen Hung, Devin Absher, I. Chien Wu, Kent D. Taylor, I. Te Lee, Yeheng Liu, Tzung Dau Wang, Thomas Quertermous, Jyh Ming J. Juang, Jerome I. Rotter, Themistocles Assimes, Chao A. Hsiung, Yii Der Ida Chen, Ross Prentice, Lewis H. Kuller, Jo Ann E. Manson, Charles Kooperberg, Paul Smokowski, Whitney R. Robinson, Penny Gordon-Larsen, Rongling Li, Lucia Hindorff, Steven Buyske, Tara C. Matise, Ulrike Peters, Kari E. North

Research output: Contribution to journalArticle

Abstract

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5–70 kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

Original languageEnglish (US)
Pages (from-to)771-800
Number of pages30
JournalHuman Genetics
Volume136
Issue number6
DOIs
StatePublished - Jun 1 2017

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Genetic Loci
Genomics
Epidemiology
Body Mass Index
Population
Hispanic Americans
Single Nucleotide Polymorphism
Meta-Analysis
Asian Americans
Proxy
Ethnic Groups
Gene Frequency
Linear Models
Alleles

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. / Fernández-Rhodes, Lindsay; Gong, Jian; Haessler, Jeffrey; Franceschini, Nora; Graff, Mariaelisa; Nishimura, Katherine K.; Wang, Yujie; Highland, Heather M.; Yoneyama, Sachiko; Bush, William S.; Goodloe, Robert; Ritchie, Marylyn D.; Crawford, Dana; Gross, Myron; Fornage, Myriam; Buzkova, Petra; Tao, Ran; Isasi, Carmen; Avilés-Santa, Larissa; Daviglus, Martha; Mackey, Rachel H.; Houston, Denise; Gu, C. Charles; Ehret, Georg; Nguyen, Khanh Dung H.; Lewis, Cora E.; Leppert, Mark; Irvin, Marguerite R.; Lim, Unhee; Haiman, Christopher A.; Le Marchand, Loic; Schumacher, Fredrick; Wilkens, Lynne; Lu, Yingchang; Bottinger, Erwin P.; Loos, Ruth J.L.; Sheu, Wayne H.H.; Guo, Xiuqing; Lee, Wen Jane; Hai, Yang; Hung, Yi Jen; Absher, Devin; Wu, I. Chien; Taylor, Kent D.; Lee, I. Te; Liu, Yeheng; Wang, Tzung Dau; Quertermous, Thomas; Juang, Jyh Ming J.; Rotter, Jerome I.; Assimes, Themistocles; Hsiung, Chao A.; Chen, Yii Der Ida; Prentice, Ross; Kuller, Lewis H.; Manson, Jo Ann E.; Kooperberg, Charles; Smokowski, Paul; Robinson, Whitney R.; Gordon-Larsen, Penny; Li, Rongling; Hindorff, Lucia; Buyske, Steven; Matise, Tara C.; Peters, Ulrike; North, Kari E.

In: Human Genetics, Vol. 136, No. 6, 01.06.2017, p. 771-800.

Research output: Contribution to journalArticle

Fernández-Rhodes, L, Gong, J, Haessler, J, Franceschini, N, Graff, M, Nishimura, KK, Wang, Y, Highland, HM, Yoneyama, S, Bush, WS, Goodloe, R, Ritchie, MD, Crawford, D, Gross, M, Fornage, M, Buzkova, P, Tao, R, Isasi, C, Avilés-Santa, L, Daviglus, M, Mackey, RH, Houston, D, Gu, CC, Ehret, G, Nguyen, KDH, Lewis, CE, Leppert, M, Irvin, MR, Lim, U, Haiman, CA, Le Marchand, L, Schumacher, F, Wilkens, L, Lu, Y, Bottinger, EP, Loos, RJL, Sheu, WHH, Guo, X, Lee, WJ, Hai, Y, Hung, YJ, Absher, D, Wu, IC, Taylor, KD, Lee, IT, Liu, Y, Wang, TD, Quertermous, T, Juang, JMJ, Rotter, JI, Assimes, T, Hsiung, CA, Chen, YDI, Prentice, R, Kuller, LH, Manson, JAE, Kooperberg, C, Smokowski, P, Robinson, WR, Gordon-Larsen, P, Li, R, Hindorff, L, Buyske, S, Matise, TC, Peters, U & North, KE 2017, 'Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci', Human Genetics, vol. 136, no. 6, pp. 771-800. https://doi.org/10.1007/s00439-017-1787-6
Fernández-Rhodes, Lindsay ; Gong, Jian ; Haessler, Jeffrey ; Franceschini, Nora ; Graff, Mariaelisa ; Nishimura, Katherine K. ; Wang, Yujie ; Highland, Heather M. ; Yoneyama, Sachiko ; Bush, William S. ; Goodloe, Robert ; Ritchie, Marylyn D. ; Crawford, Dana ; Gross, Myron ; Fornage, Myriam ; Buzkova, Petra ; Tao, Ran ; Isasi, Carmen ; Avilés-Santa, Larissa ; Daviglus, Martha ; Mackey, Rachel H. ; Houston, Denise ; Gu, C. Charles ; Ehret, Georg ; Nguyen, Khanh Dung H. ; Lewis, Cora E. ; Leppert, Mark ; Irvin, Marguerite R. ; Lim, Unhee ; Haiman, Christopher A. ; Le Marchand, Loic ; Schumacher, Fredrick ; Wilkens, Lynne ; Lu, Yingchang ; Bottinger, Erwin P. ; Loos, Ruth J.L. ; Sheu, Wayne H.H. ; Guo, Xiuqing ; Lee, Wen Jane ; Hai, Yang ; Hung, Yi Jen ; Absher, Devin ; Wu, I. Chien ; Taylor, Kent D. ; Lee, I. Te ; Liu, Yeheng ; Wang, Tzung Dau ; Quertermous, Thomas ; Juang, Jyh Ming J. ; Rotter, Jerome I. ; Assimes, Themistocles ; Hsiung, Chao A. ; Chen, Yii Der Ida ; Prentice, Ross ; Kuller, Lewis H. ; Manson, Jo Ann E. ; Kooperberg, Charles ; Smokowski, Paul ; Robinson, Whitney R. ; Gordon-Larsen, Penny ; Li, Rongling ; Hindorff, Lucia ; Buyske, Steven ; Matise, Tara C. ; Peters, Ulrike ; North, Kari E. / Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. In: Human Genetics. 2017 ; Vol. 136, No. 6. pp. 771-800.
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abstract = "Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5–70 kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.",
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T1 - Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci

AU - Fernández-Rhodes, Lindsay

AU - Gong, Jian

AU - Haessler, Jeffrey

AU - Franceschini, Nora

AU - Graff, Mariaelisa

AU - Nishimura, Katherine K.

AU - Wang, Yujie

AU - Highland, Heather M.

AU - Yoneyama, Sachiko

AU - Bush, William S.

AU - Goodloe, Robert

AU - Ritchie, Marylyn D.

AU - Crawford, Dana

AU - Gross, Myron

AU - Fornage, Myriam

AU - Buzkova, Petra

AU - Tao, Ran

AU - Isasi, Carmen

AU - Avilés-Santa, Larissa

AU - Daviglus, Martha

AU - Mackey, Rachel H.

AU - Houston, Denise

AU - Gu, C. Charles

AU - Ehret, Georg

AU - Nguyen, Khanh Dung H.

AU - Lewis, Cora E.

AU - Leppert, Mark

AU - Irvin, Marguerite R.

AU - Lim, Unhee

AU - Haiman, Christopher A.

AU - Le Marchand, Loic

AU - Schumacher, Fredrick

AU - Wilkens, Lynne

AU - Lu, Yingchang

AU - Bottinger, Erwin P.

AU - Loos, Ruth J.L.

AU - Sheu, Wayne H.H.

AU - Guo, Xiuqing

AU - Lee, Wen Jane

AU - Hai, Yang

AU - Hung, Yi Jen

AU - Absher, Devin

AU - Wu, I. Chien

AU - Taylor, Kent D.

AU - Lee, I. Te

AU - Liu, Yeheng

AU - Wang, Tzung Dau

AU - Quertermous, Thomas

AU - Juang, Jyh Ming J.

AU - Rotter, Jerome I.

AU - Assimes, Themistocles

AU - Hsiung, Chao A.

AU - Chen, Yii Der Ida

AU - Prentice, Ross

AU - Kuller, Lewis H.

AU - Manson, Jo Ann E.

AU - Kooperberg, Charles

AU - Smokowski, Paul

AU - Robinson, Whitney R.

AU - Gordon-Larsen, Penny

AU - Li, Rongling

AU - Hindorff, Lucia

AU - Buyske, Steven

AU - Matise, Tara C.

AU - Peters, Ulrike

AU - North, Kari E.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5–70 kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

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