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Common nonsynonymous variants in PCSK1 confer risk of obesity

Nature Genetics volume 40, pages 943–945 (2008)Cite this article

Abstract

Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 × 10−8 and P = 2.31 × 10−12, respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.

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Figure 1: Linkage disequilibrium map of the PCSK1 genomic region and functional characterization of the N221D and Q665E–S690T substitutions.

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Authors and Affiliations

  1. Genomic Medicine, Imperial College London, Hammersmith Hospital, London, W120NN, UK

    Michael Benzinou, Andrew J Walley & Philippe Froguel

  2. Centre National de la Recherche Scientifique (CNRS) 8090-Institute of Biology, Pasteur Institute, Lille, 59000, France

    Michael Benzinou, Helene Choquet, Stephane Lobbens, Christian Dina, Emmanuelle Durand, Audrey Guerardel, Philippe Boutin, David Meyre & Philippe Froguel

  3. Department of Human Genetics, University of Leuven, Leuven, B-3000, Belgium

    John W M Creemers

  4. Institut National de la Santé et de la Recherche Médicale (INSERM) U563, Children's Hospital, Toulouse, 31000, France

    Beatrice Jouret

  5. INSERM, U780-IFR69, Villejuif, France and Université Paris Sud, Faculty of Medicine, Le Kremlin-Bicêtre, 94270, France

    Barbara Heude & Beverley Balkau

  6. The Regional Institut for Health, Tours, 37000, France

    Jean Tichet & Natascha Potoczna

  7. INSERM U695, Paris, 75018, France

    Michel Marre

  8. Université Paris Diderot - Paris 7, Paris, 75018, France

    Michel Marre

  9. Department of Endocrinology-Diabetology and Nutrition, Bichat Claude Bernard Hospital, Paris, 75870, France

    Michel Marre

  10. Klinik Lindberg, Winterthur, 8400, Switzerland

    Fritz Horber

  11. Department of Pediatric Endocrinology and INSERM U561, Saint Vincent de Paul Hospital, René Descartes University, Paris, 75014, France

    Catherine Le Stunff

  12. INSERM U557, Institut Scientifique de Recherche Agronomique (INRA) U1125, CNAM EA3200, Université Paris 13, CRNH IdF and Hôpital Avicenne (AP-HP), Bobigny, F-93017, France

    Sebastien Czernichow

  13. Department of General Practice, University of Aarhus, Aarhus, DK-8000, Denmark

    Annelli Sandbaek & Torsten Lauritzen

  14. Steno Diabetes Center, DK-2820 Gentofte, Copenhagen, Denmark

    Knut Borch-Johnsen, Gitte Andersen, Torben Hansen & Oluf Pedersen

  15. Faculty of Health Science, University of Aarhus, Aarhus, DK-8000, Denmark

    Knut Borch-Johnsen & Oluf Pedersen

  16. University Hospital for Children and Adolescents, University of Leipzig, Leipzig, D-04109, Germany

    Wieland Kiess & Antje Körner

  17. Department of Internal Medicine III, Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, D-04109, Germany

    Peter Kovacs

  18. Department of Molecular and Clinical Medicine Institute of Medicine, The Sahlgrenska Academy, Göteborg University, Göteborg, SE-431, Sweden

    Peter Jacobson & Lena M S Carlsson

  19. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, DK-2600, Denmark

    Torben Jørgensen

Authors
  1. Michael Benzinou
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  5. Christian Dina
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  6. Emmanuelle Durand
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  7. Audrey Guerardel
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  8. Philippe Boutin
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  15. Fritz Horber
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  16. Catherine Le Stunff
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  18. Annelli Sandbaek
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  31. David Meyre
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  32. Philippe Froguel
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Contributions

M.B. was responsible for the study design, project follow-up and statistical analysis, was involved in the in vitro study and wrote the manuscript. J.W.M.C. was responsible for the in vitro study. H.C. was involved in the in vitro study. S.L., E.D. were involved in the genotyping. C.D. was involved in the statistical analysis. A.G. was involved in the sequencing. P.B. was involved in the study design. B.J., B.H., B.B., J.T., M.M., N.P. provided the DNA and quantitative data for the D.E.S.I.R. study. F.H. provided the DNA and quantitative data for the Swiss study. C.L.S. and S.C. provided the DNA and quantitative data for the second French children obesity study. W.K., A.K. and P.K. provided the DNA and quantitative data for the German study. P.J. and L.M.S.C. provided the DNA and quantitative data for the Swedish study. A.J.W. helped draft the manuscript. A.S., T.L., K.B.-J., G.A., T.J., T.H. and O.P. provided the DNA and quantitative data for the Danish case-control study. D.M. was involved in the study design and helped draft the manuscript. P.F. was the principal investigator on the project was involved in the study design, data analyses and in the manuscript writing.

Corresponding author

Correspondence to Philippe Froguel.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Figure 1, Supplementary Tables 1–6 (PDF 923 kb)

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Benzinou, M., Creemers, J., Choquet, H. et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet 40, 943–945 (2008). https://doi.org/10.1038/ng.177

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