Brief Communication abstract
Nature Genetics 40, 943 - 945 (2008)
Published online: 6 July 2008 | doi:10.1038/ng.177
Common nonsynonymous variants in PCSK1 confer risk of obesity
Michael Benzinou1,2, John W M Creemers3, Helene Choquet2, Stephane Lobbens2, Christian Dina2, Emmanuelle Durand2, Audrey Guerardel2, Philippe Boutin2, Beatrice Jouret4, Barbara Heude5, Beverley Balkau5, Jean Tichet6, Michel Marre7,8,9, Natascha Potoczna6, Fritz Horber10, Catherine Le Stunff11, Sebastien Czernichow12, Annelli Sandbaek13, Torsten Lauritzen13, Knut Borch-Johnsen14,15, Gitte Andersen14, Wieland Kiess16, Antje Körner16, Peter Kovacs17, Peter Jacobson18, Lena M S Carlsson18, Andrew J Walley1, Torben Jørgensen19, Torben Hansen14, Oluf Pedersen14,15, David Meyre2 & Philippe Froguel1,2
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.
- Genomic Medicine, Imperial College London, Hammersmith Hospital, London W120NN, UK.
- Centre National de la Recherche Scientifique (CNRS) 8090-Institute of Biology, Pasteur Institute, Lille 59000, France.
- Department of Human Genetics, University of Leuven, Leuven B-3000, Belgium.
- Institut National de la Santé et de la Recherche Médicale (INSERM) U563, Children's Hospital, Toulouse 31000, France.
- INSERM, U780-IFR69, Villejuif, France and Université Paris Sud, Faculty of Medicine, Le Kremlin-Bicêtre 94270, France.
- The Regional Institut for Health, Tours 37000, France.
- INSERM U695, Paris 75018, France.
- Université Paris Diderot - Paris 7, Paris 75018, France.
- Department of Endocrinology-Diabetology and Nutrition, Bichat Claude Bernard Hospital, Paris 75870, France.
- Klinik Lindberg, Winterthur 8400, Switzerland.
- Department of Pediatric Endocrinology and INSERM U561, Saint Vincent de Paul Hospital, René Descartes University, Paris 75014, France.
- 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.
- Department of General Practice, University of Aarhus, Aarhus DK-8000, Denmark.
- Steno Diabetes Center, DK-2820 Gentofte, Copenhagen, Denmark.
- Faculty of Health Science, University of Aarhus, Aarhus DK-8000, Denmark.
- University Hospital for Children and Adolescents, University of Leipzig, Leipzig D-04109, Germany.
- Department of Internal Medicine III, Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig D-04109, Germany.
- Department of Molecular and Clinical Medicine Institute of Medicine, The Sahlgrenska Academy, Göteborg University, Göteborg SE-431, Sweden.
- Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup DK-2600, Denmark.
Correspondence to: Philippe Froguel1,2 e-mail: p.froguel@imperial.ac.uk
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