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Genetics and Epigenetics

Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations

International Journal of Obesity volume 41, pages 324–331 (2017)Cite this article

Subjects

Abstract

Background/Objectives:

Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition.

Subjects/Methods:

To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants.

Results:

Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses.

Conclusions:

Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

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Acknowledgements

The PAGE consortium thanks the staff and participants of PAGE studies for their important contributions. The PAGE program is funded by the NHGRI, supported by U01HG004803 (CALiCo), U01HG004802 (MEC), U01HG004790 (WHI) and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The National Institutes of Mental Health also contributes to the support for the Coordinating Center. The contents of this paper are solely the responsibility of the authors and do not necessarily represent NIH official views. See detailed acknowledgment for full PAGE and collaborating study acknowledgements (Supplementary Information).

Author information

Author notes

  1. B Henderson: Deceased 20 June 2015.

Authors and Affiliations

  1. Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA

    S Yoneyama, L Fernandez-Rhodes, M Graff & K E North

  2. Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA

    J Yao, X Guo, Y-DI Chen, K D Taylor & J I Rotter

  3. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

    U Lim, L Le Marchand & L Wilkens

  4. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA

    J Boston

  5. Department of Biostatistics, University of Washington, Seattle, WA, USA

    P Buzková

  6. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    C S Carlson, J Gong, J Haessler, S A Bien, C Kooperberg & U Peters

  7. Cancer Prevention Institute of California, Fremont, CA, USA

    I Cheng

  8. Baylor College of Medicine, Houston, TX, USA

    B Cochran

  9. Division of Cardiology, Geneva University Hospital, Genève, Switzerland

    B Cochran

  10. Department of Public Health Sciences, Loyola University, Chicago, IL, USA

    R Cooper

  11. Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    G Ehret, K-DH Nguyen & A Chakravarti

  12. The Human Genetics Center and Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA

    M Fornage

  13. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    M Gross & N Pankratz

  14. Department of Biostatistics, Washington University, St Louis, MO, USA

    C C Gu

  15. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    C A Haiman, B Henderson, L Pooler & F Schumacher

  16. Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    L A Hindorff & R Li

  17. Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

    D Houston

  18. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA

    M R Irvin

  19. Department of Internal Medicine, Ohio State Medical Center, Columbus, OH, USA

    R Jackson

  20. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    L Kuller

  21. Department of Human Genetics, University of Utah, Salt Lake City, UT, USA

    M Leppert

  22. Department of Medicine, University of Alabama, Birmingham, AL, USA

    C E Lewis

  23. Department of Genetics, Rutgers University, Piscataway, NJ, USA

    T C Matise & S Buyske

  24. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA

    J S Pankow & P J Schreiner

  25. Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, PA, USA

    M D Ritchie

  26. Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Colchester, VT, USA

    C L Wassel

  27. Department of Preventive Medicine, School of Medicine, University of California San Diego, San Diego, CA, USA

    M Allison

  28. The Human Genetics Center and Institute of Molecular Medicine, Houston, TX, USA

    E Boerwinkle

  29. Department of Statistics and Biostatistics, Rutgers University, Piscataway, NJ, USA

    E Boerwinkle

  30. Carolina Center for Genome Sciences, Chapel Hill, NC, USA

    K E North

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  1. S Yoneyama
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PAGE Consortium

Corresponding author

Correspondence to M Graff.

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Supplementary Information accompanies this paper on International Journal of Obesity website

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Yoneyama, S., Yao, J., Guo, X. et al. Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations. Int J Obes 41, 324–331 (2017). https://doi.org/10.1038/ijo.2016.207

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