Abstract

Samoans are a unique founder population with a high prevalence of obesity1,2,3, making them well suited for identifying new genetic contributors to obesity4. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10−14), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10−9). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10−20). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36–1.45 kg/m2 per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a 'thrifty' variant hypothesis as a factor in human obesity.

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Acknowledgements

The authors would like to thank the Samoan participants of the study, and local village authorities and the many Samoan and other field workers over the years. We acknowledge the Samoan Ministry of Health and the Samoan Bureau of Statistics, and the American Samoan Department of Health for their support of this research. We also acknowledge S.S. Shiva and C.G. Corey at the University of Pittsburgh Center for Metabolism and Mitochondrial Biology for assistance with cellular bioenergetic profiling. This work was funded by NIH grants R01-HL093093 (S.T.M.), R01-AG09375 (S.T.M.), R01-HL52611 (I. Kamboh), R01-DK59642 (S.T.M.), P30 ES006096 (S.M. Ho), R01-DK55406. (R.D.), R01-HL090648 (Z.U.), and R01-DK090166 (E.E.K.) and by Brown University student research funds. Genotyping was performed in the Core Genotyping Laboratory at the University of Cincinnati, funded by NIH grant P30 ES006096 (S.M. Ho). Illumina sequencing was conducted at the Genetic Resources Core Facility, Johns Hopkins Institute of Genetic Medicine (Baltimore).

Author information

Author notes

    • Chi-Ting Su
    •  & Olive D Buhule

    Present addresses: Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan (C.-T.S.) and Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Institutes of Health, Bethesda, Maryland, USA (O.D.B.).

    • Ryan L Minster
    • , Nicola L Hawley
    • , Chi-Ting Su
    •  & Guangyun Sun

    These authors contributed equally to this work.

    • Zsolt Urban
    • , Ranjan Deka
    • , Daniel E Weeks
    •  & Stephen T McGarvey

    These authors jointly supervised this work.

Affiliations

  1. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Ryan L Minster
    • , Chi-Ting Su
    • , Jerome Lin
    • , Zsolt Urban
    •  & Daniel E Weeks
  2. Department of Epidemiology (Chronic Disease), Yale University School of Public Health, New Haven, Connecticut, USA.

    • Nicola L Hawley
  3. Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

    • Guangyun Sun
    • , Hong Cheng
    •  & Ranjan Deka
  4. Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Erin E Kershaw
  5. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Olive D Buhule
    •  & Daniel E Weeks
  6. Bureau of Statistics, Government of Samoa, Apia, Samoa.

    • Muagututi'a Sefuiva Reupena
  7. Samoa National Health Service, Apia, Samoa.

    • Satupa'itea Viali
  8. Department of Health, American Samoa Government, Pago Pago, American Samoa, USA.

    • John Tuitele
  9. Ministry of Health, Government of Samoa, Apia, Samoa.

    • Take Naseri
  10. International Health Institute, Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, USA.

    • Stephen T McGarvey
  11. Department of Anthropology, Brown University, Providence, Rhode Island, USA.

    • Stephen T McGarvey

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Contributions

R.L.M. performed the genotype quality control and association analyses, with guidance from D.E.W. and assistance from O.D.B. and J.L.; D.E.W. and R.L.M. wrote the relevant sections of the manuscript. N.L.H. led the field work data collection and phenotype analyses with guidance from S.T.M. G.S. led and directed genotyping experiments (using the Affymetrix 6.0 chip) and assay development for validation and replication (using the TaqMan platform) with guidance from R.D. H.C. participated extensively in DNA extraction, genotyping, and quality control of the data under the supervision of G.S. and R.D. Z.U. and C.-T.S. designed and performed the CREBRF overexpression, lipid accumulation, and adipocyte differentiation and starvation experiments, analyzed the data, and wrote the relevant sections of the manuscript. E.E.K. contributed mouse and human gene expression profiling data as well as contributed to the design and analysis of the functional studies. M.S.R., S.V., and J.T. facilitated fieldwork in Samoa and American Samoa. T.N. contributed to the discussion of the public health implications of the findings. All authors contributed to this work, discussed the results, and critically reviewed and revised the manuscript.

Competing interests

Some authors are listed as inventors on a provisional patent application covering aspects of this work that has been filed with the US Patent and Trademark Office (S.T.M., N.L.H., R.D., D.E.W., R.L.M., Z.U., C.-T.S., and E.E.K.).

Corresponding author

Correspondence to Stephen T McGarvey.

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    Supplementary Text and Figures

    Supplementary Figures 1–8, Supplementary Tables 1–3 and Supplementary Note.

Videos

  1. 1.

    Principal-components analyses.

    A rotating animation of a scatterplot of the first three principal components from the principal-components analysis of the Samoan and HapMap phase 3 populations. Continental population abbreviations: SAM, Samoans (n = 250); EUR, Europeans (n = 253); AFR, Africans (n = 511); EAS, East Asians (n = 255); SAS, South Asians (n = 88); AMR, admixed Americans (n = 77).

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https://doi.org/10.1038/ng.3620

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