Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

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  • Y. Li
  • Thomas Hempel Sparsø
  • G. Tian
  • H. Cao
  • T. Jiang
  • S.Y. Kim
  • Q. Li
  • C. Nie
  • R. Wu
  • Line Skotte
  • A.P. Morris
  • C. Ladenvall
  • S. Cauchi
  • A. Stancáková
  • G. Andersen
  • A.J. Bennett
  • Lars Bolund
  • G. Charpentier
  • Y. Chen
  • J.M. Dekker
  • A.S.F. Doney
  • M. Dorkhan
  • T. Forsen
  • T.M. Frayling
  • C.J. Groves
  • Y. Gui
  • G. Hallmans
  • A.T. Hattersley
  • K. He
  • G.A. Hitman
  • J. Holmkvist
  • S. Huang
  • H. Jiang
  • X. Jin
  • J. Kuusisto
  • M. Lajer
  • O. Lantieri
  • W. Li
  • H. Liang
  • Q. Liao
  • X. Liu
  • T. Ma
  • X. Ma
  • M.P. Manijak
  • M. Marre
  • Jacek Mokrosinski
  • A.D. Morris
  • B. Mu
  • A.A. Nielsen
  • G. Nijpels
  • P. Nilsson
  • C.N.A. Palmer
  • N.W. Rayner
  • F. Renström
  • Rasmus Ribel-Madsen
  • N. Robertson
  • O. Rolandsson
  • P. Rossing
  • P.E. Slagboom
  • M. Sterner
  • M. Tang
  • L. Tarnow
  • T. Tuomi
  • E. Van't Riet
  • N. van Leeuwen
  • M. Walker
  • B. Wang
  • Y. Wang
  • H. Wu
  • F. Xi
  • L. Yengo
  • C. Yu
  • X. Zhang
  • J. Zhang
  • Q. Zhang
  • W. Zhang
  • H. Zheng
  • Y. Zhou
  • D. Altshuler
  • L.M. 't Hart
  • P.W. Franks
  • B. Balkau
  • P. Froguel
  • M.I. McCarthy
  • M. Laakso
  • L. Groop
  • C. Christensen
  • I. Brandslund
  • T. Lauritzen
  • D.R. Witte
  • A. Linneberg
  • Torben Jørgensen
  • Jun Wang
AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p¿1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p¿=¿8.5¿×¿10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p¿=¿1.2¿×¿10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p¿=¿8.2¿×¿10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Original languageEnglish
JournalDiabetologia
Volume56
Issue number2
Pages (from-to)298-310
Number of pages13
ISSN0012-186X
DOIs
Publication statusPublished - 2013

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