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Common nonsynonymous variants in PCSK1 confer risk of obesity

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

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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.

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Correspondence to Philippe Froguel.

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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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