Common nonsynonymous variants in PCSK1 confer risk of obesity

Nat Genet. 2008 Aug;40(8):943-5. doi: 10.1038/ng.177. Epub 2008 Jul 6.


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.

MeSH terms

  • Adult
  • Case-Control Studies
  • Child
  • European Continental Ancestry Group
  • Genetic Predisposition to Disease*
  • Humans
  • Obesity / genetics*
  • Obesity / metabolism
  • Polymorphism, Single Nucleotide*
  • Proprotein Convertase 1 / genetics*
  • Proprotein Convertase 1 / metabolism


  • Proprotein Convertase 1