Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals

Kevin T Nead, Aihua Li, Mackenzie R Wehner, Binod Neupane, Stefan Gustafsson, Adam Butterworth, James C Engert, A Darlene Davis, Robert A Hegele, Ruby Miller, Marcel den Hoed, Kay-Tee Khaw, Tuomas O Kilpeläinen, Nick Wareham, Todd L Edwards, Göran Hallmans, Tibor V Varga, Sharon L R Kardia, Jennifer A Smith, Wei ZhaoJessica D Faul, David Weir, Jie Mi, Bo Xi, Samuel Canizales Quinteros, Cyrus Cooper, Avan Aihie Sayer, Karen Jameson, Anders Grøntved, Myriam Fornage, Stephen Sidney, Craig L Hanis, Heather M Highland, Hans-Ulrich Häring, Martin Heni, Jessica Lasky-Su, Scott T Weiss, Glenn S Gerhard, Christopher Still, Melkaey M Melka, Zdenka Pausova, Tomáš Paus, Struan F A Grant, Hakon Hakonarson, R Arlen Price, Kai Wang, Andre Scherag, Johannes Hebebrand, Anke Hinney, Paul W Franks, BioBank Japan, AGEN-BMI, GIANT Consortium

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

Original languageEnglish
JournalHuman Molecular Genetics
Volume24
Issue number12
Pages (from-to)3582-3594
Number of pages13
ISSN0964-6906
DOIs
Publication statusPublished - 15. Jun 2015

Keywords

  • Alleles
  • Body Mass Index
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Obesity/diagnosis
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Proprotein Convertase 1/genetics

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