Common nonsynonymous variants in PCSK1 confer risk of obesity

• DOI: 10.1038/ng.177
• Publication Date: 2008-07-06T18:55:56Z
• Authors: Michael Benzinou; John W M Creemers; Helene Choquet; Stephane Lobbens; Christian Dina; Emmanuelle Durand; Audrey Guerardel; Philippe Boutin; Beatrice Jouret; Barbara Heude; Beverley Balkau; Jean Tichet; Michel Marre; Natascha Potoczna; Fritz Horber; Catherine Le Stunff; Sebastien Czernichow; Annelli Sandbaek; Torsten Lauritzen; Knut Borch-Johnsen; Gitte Andersen; Wieland Kiess; Antje Körner; Peter Kovacs; Peter Jacobson; Lena M S Carlsson; Andrew J Walley; Torben Jørgensen; Torben Hansen; Oluf Pedersen; David Meyre; Philippe Froguel
• Keywords: Adult; 2. Zero hunger; 0303 health sciences; European Continental Ancestry Group; Polymorphism, Single Nucleotide; White People; 03 medical and health sciences; Proprotein Convertase 1; Case-Control Studies; Humans; Genetic Predisposition to Disease; Obesity; Child

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 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.